Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Hypoxic Pulmonary Hypertension of the Newborn

Yuansheng Gao, J Usha Raj

10.1002/cphy.c090015

Source: Volume 1, Issue 1, January 2011

Published online: November 2010

Full Article on Wiley Online Library



Abstract

Hypoxic pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance and pressure due to vascular remodeling and increased vessel tension secondary to chronic hypoxia during the fetal and newborn period. In comparison to the adult, the pulmonary vasculature of the fetus and the newborn undergoes tremendous developmental changes that increase susceptibility to a hypoxic insult. Substantial evidence indicates that chronic hypoxia alters the production and responsiveness of various vasoactive agents such as endothelium‐derived nitric oxide, endothelin‐1, prostanoids, platelet‐activating factor, and reactive oxygen species, resulting in sustained vasoconstriction and vascular remodeling. These changes occur in most cell types within the vascular wall, particularly endothelial and smooth muscle cells. At the cellular level, suppressed nitric oxide‐cGMP signaling and augmented RhoA‐Rho kinase signaling appear to be critical to the development of hypoxic pulmonary hypertension of the newborn. © 2011 American Physiological Society. Compr Physiol 1:61‐79, 2011.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Diagram showing postnatal structural changes and the effect of chronic hypoxia in pulmonary arteries based on studies with fetal and newborn piglets 114,115,120,122,126,161. Fetal pulmonary arteries have thick walls and narrow lumen. Smooth muscle cells (SMCs) are rounded, densely packed, and appear immature and synthetic in type and contractile organelles do not predominate. After birth, the overlap of adjacent SMCs rapidly decreases and a reorganization of the cytoskeleton occurs within 1 week of life so that the SMCs become thinner and spread around a larger lumen. Later, the medial thickness of the vessel wall decreases further to mature levels at about 6‐month old with reduced cell packing density and increased myofilament density. The shape of SMCs is elongated with stable cytoskeleton. Postnatal exposure to chronic hypoxia prevents these postnatal adaptive changes and promotes SMC proliferation and/or hypertrophy, leading to thickened vessel wall and narrowed vessel lumen. The shape of SMCs is more rounded because of abnormal cytoskeletal composition and organization.
Figure 2. Figure 2.

Possible mechanisms for vascular remodeling caused by ET‐1 in perinatal lungs. ET‐1 may promote smooth muscle cell (SMC) proliferation by activating transforming growth factor β (TGF‐β)‐Smad signaling 8,118,143 and by inhibiting apoptosis through phosphoinositide 3‐kinase (PI3K)/AKT and p38 mitogen‐activated protein kinase pathway 145,164,243,295. ET‐1 may also increase the extracellular matrix deposition through increasing the release of TGF‐β 8 and by inhibiting the activity of metalloproteinases (MMPs) and stimulating the activity of the tissue inhibitors of metalloproteinases (TIMPs) 9,94,232. The dashed line indicates inhibitory action.
Figure 3. Figure 3.

A possible mechanism for perinatal pulmonary vascular smooth muscle cells (SMCs) to switch from contractile to proliferation phenotype induced by hypoxia‐induced downregulation of PKG. Myocardin, a transcriptional coactivator of serum response factor (SRF), is upregulated by PKG under normoxia. Consequently, more myocardin is associated with SRF, which leads to SMC marker gene expression and the cells at contractile phenotype. Under hypoxia, the depressed PKG level results in decreased myocardin expression and consequently increased binding of E‐26‐like protein 1(Elk‐1) to SRF. The binding of phosphorylated Elk‐1 to SRF leads to suppression of SMC marker genes and activation of expression of genes involved in cell proliferation (modified from reference 309, with permission).
Figure 4. Figure 4.

Effects of hypoxia on perinatal pulmonary vasodilatation caused by endothelial nitric oxide (NO). Hypoxia reduces the release of endothelial NO by directly inhibiting eNOS activity, as oxygen is necessary for the conversion of l‐arginine to NO and l‐citrulline and by downregulating eNOS mRNA and protein expression. Hypoxia may impair the l‐arginine uptake 78,81 and inhibit eNOS through the downregulation of dimethyl‐arginine dimethylaminohydrolase (DDAH), an enzyme that degrades asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS 16. NO causes vasodilatation primarily via elevating cGMP level through soluble guanylyl cyclase (sGC) followed by stimulating cGMP‐dependent protein kinase (PKG). Hypoxia may downregulate the expressions and activities of sGC 28,297 and PKG 99,100,193. Hypoxia may also augment the degradation of cGMP by increasing the activity of phosphodiesterase type 5 (PDE5) 116,117,121,292. The dashed line indicates inhibitory action.
Figure 5. Figure 5.

Possible signal transduction pathways in pulmonary arteries for the opposing actions of PKG and RhoA‐ROCK and the effects of chronic hypoxia. Chronic hypoxia may increase the Ca2+ sensitivity of the contractile filaments of smooth muscle through the inhibition of myosin light‐chain phosphatase (MLCP) via RhoA‐ROCK pathway. ROCKs inhibit MLCP by phosphorylating the regulatory subunit of MLCP (MYPT1) at Thr696 and Thr853 (human sequence). ROCK may also inhibit the activity of MLCP through phosphorylation of PKC‐potentiated inhibitor protein of 17 kDa (CPI‐17). Activation of PKG by nitric oxide (NO) and cGMP may interfere with the activation of RhoA. PKG may phosphorylate MYPT1 at Ser695 and Ser852, which results in a decreased ROCK‐mediated phosphorylation of MYPT1 at Thr696 and Thr853. This antagonizing effect of PKG may be impaired by chronic hypoxia. PKG can also directly stimulate MLCP activity through interaction between the leucine zipper (LZ) motives of PKG and MYPT1. GPCR, G‐protein‐coupled receptors; G, G protein; DAG, diacylglycerol; RhoA, a small monomeric GTPase; M20, a 20‐kDa subunit of MLCP with unknown function. The dashed line indicates inhibitory action (modified from reference 100, with permission).


Figure 1.

Diagram showing postnatal structural changes and the effect of chronic hypoxia in pulmonary arteries based on studies with fetal and newborn piglets 114,115,120,122,126,161. Fetal pulmonary arteries have thick walls and narrow lumen. Smooth muscle cells (SMCs) are rounded, densely packed, and appear immature and synthetic in type and contractile organelles do not predominate. After birth, the overlap of adjacent SMCs rapidly decreases and a reorganization of the cytoskeleton occurs within 1 week of life so that the SMCs become thinner and spread around a larger lumen. Later, the medial thickness of the vessel wall decreases further to mature levels at about 6‐month old with reduced cell packing density and increased myofilament density. The shape of SMCs is elongated with stable cytoskeleton. Postnatal exposure to chronic hypoxia prevents these postnatal adaptive changes and promotes SMC proliferation and/or hypertrophy, leading to thickened vessel wall and narrowed vessel lumen. The shape of SMCs is more rounded because of abnormal cytoskeletal composition and organization.



Figure 2.

Possible mechanisms for vascular remodeling caused by ET‐1 in perinatal lungs. ET‐1 may promote smooth muscle cell (SMC) proliferation by activating transforming growth factor β (TGF‐β)‐Smad signaling 8,118,143 and by inhibiting apoptosis through phosphoinositide 3‐kinase (PI3K)/AKT and p38 mitogen‐activated protein kinase pathway 145,164,243,295. ET‐1 may also increase the extracellular matrix deposition through increasing the release of TGF‐β 8 and by inhibiting the activity of metalloproteinases (MMPs) and stimulating the activity of the tissue inhibitors of metalloproteinases (TIMPs) 9,94,232. The dashed line indicates inhibitory action.



Figure 3.

A possible mechanism for perinatal pulmonary vascular smooth muscle cells (SMCs) to switch from contractile to proliferation phenotype induced by hypoxia‐induced downregulation of PKG. Myocardin, a transcriptional coactivator of serum response factor (SRF), is upregulated by PKG under normoxia. Consequently, more myocardin is associated with SRF, which leads to SMC marker gene expression and the cells at contractile phenotype. Under hypoxia, the depressed PKG level results in decreased myocardin expression and consequently increased binding of E‐26‐like protein 1(Elk‐1) to SRF. The binding of phosphorylated Elk‐1 to SRF leads to suppression of SMC marker genes and activation of expression of genes involved in cell proliferation (modified from reference 309, with permission).



Figure 4.

Effects of hypoxia on perinatal pulmonary vasodilatation caused by endothelial nitric oxide (NO). Hypoxia reduces the release of endothelial NO by directly inhibiting eNOS activity, as oxygen is necessary for the conversion of l‐arginine to NO and l‐citrulline and by downregulating eNOS mRNA and protein expression. Hypoxia may impair the l‐arginine uptake 78,81 and inhibit eNOS through the downregulation of dimethyl‐arginine dimethylaminohydrolase (DDAH), an enzyme that degrades asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS 16. NO causes vasodilatation primarily via elevating cGMP level through soluble guanylyl cyclase (sGC) followed by stimulating cGMP‐dependent protein kinase (PKG). Hypoxia may downregulate the expressions and activities of sGC 28,297 and PKG 99,100,193. Hypoxia may also augment the degradation of cGMP by increasing the activity of phosphodiesterase type 5 (PDE5) 116,117,121,292. The dashed line indicates inhibitory action.



Figure 5.

Possible signal transduction pathways in pulmonary arteries for the opposing actions of PKG and RhoA‐ROCK and the effects of chronic hypoxia. Chronic hypoxia may increase the Ca2+ sensitivity of the contractile filaments of smooth muscle through the inhibition of myosin light‐chain phosphatase (MLCP) via RhoA‐ROCK pathway. ROCKs inhibit MLCP by phosphorylating the regulatory subunit of MLCP (MYPT1) at Thr696 and Thr853 (human sequence). ROCK may also inhibit the activity of MLCP through phosphorylation of PKC‐potentiated inhibitor protein of 17 kDa (CPI‐17). Activation of PKG by nitric oxide (NO) and cGMP may interfere with the activation of RhoA. PKG may phosphorylate MYPT1 at Ser695 and Ser852, which results in a decreased ROCK‐mediated phosphorylation of MYPT1 at Thr696 and Thr853. This antagonizing effect of PKG may be impaired by chronic hypoxia. PKG can also directly stimulate MLCP activity through interaction between the leucine zipper (LZ) motives of PKG and MYPT1. GPCR, G‐protein‐coupled receptors; G, G protein; DAG, diacylglycerol; RhoA, a small monomeric GTPase; M20, a 20‐kDa subunit of MLCP with unknown function. The dashed line indicates inhibitory action (modified from reference 100, with permission).

References
 1. Abman SH. Recent advances in the pathogenesis and treatment of persistent pulmonary hypertension of the newborn. Neonatology 91: 283‐290, 2007.
 2. Abman SH, Chatfield BA, Hall SL, McMurtry IF. Role of endothelium‐derived relaxing factor during transition of pulmonary circulation at birth. Am J Physiol Heart Circ Physiol 259: H1921‐H1927, 1990.
 3. Acarregui MJ, Brown JJ, Penisten ST. Cyclic AMP‐dependent protein kinase (PKA) gene expression is developmentally regulated in fetal lung. Biochim Biophys Acta 1402: 303‐312, 1998.
 4. Acharya G, Sitras V. Oxygen uptake of the human fetus at term. Acta Obstet Gynecol Scand 88: 104‐109, 2009.
 5. Alexander SPH, Mathie A, Peters JA. Guide to receptors and channels (GRAC), 4th ed. Br J Pharmacol 158 (Suppl 2): S1‐S254, 2009.
 6. Ambalavanan N, Bulger A, Murphy‐Ullrich J, Oparil S, Chen YF. Endothelin‐A receptor blockade prevents and partially reverses neonatal hypoxic pulmonary vascular remodeling. Pediatr Res 57: 631‐636, 2005.
 7. Ambalavanan N, Li P, Bulger A, Murphy‐Ullrich J, Oparil S, Chen YF. Endothelin‐1 mediates hypoxia‐induced increases in vascular collagen in the newborn mouse lung. Pediatr Res 61: 559‐564, 2007.
 8. Ambalavanan N, Nicola T, Hagood J, Bulger A, Serra R, Murphy‐Ullrich J, Oparil S, Chen YF. Transforming growth factor‐beta signaling mediates hypoxia‐induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 295: L86‐L95, 2008.
 9. Ambalavanan N, Nicola T, Li P, Bulger A, Murphy‐Ullrich J, Oparil S, Chen YF. Role of matrix metalloproteinase‐2 in newborn mouse lungs under hypoxic conditions. Pediatr Res 63: 26‐32, 2008.
 10. Archer SL, Gomberg‐Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: A mitochondria‐ ROS‐HIF‐1alpha‐KV1.5 O2‐sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 294: H570‐H578, 2008.
 11. Archer SL, London B, Hampl V, Wu X, Nsair A, Puttagunta L, Hashimoto K, Waite RE, Michelakis ED. Impairment of hypoxic pulmonary vasoconstriction in mice lacking the voltage‐gated potassium channel KV1.5. FASEB J 15: 1801‐1803, 2001.
 12. Archer SL, Nelson DP, Weir EK. Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung. J Appl Physiol 67: 1903‐1911, 1989.
 13. Archer SL, Souil E, Dinh‐Xuan AT, Schremmer B, Mercier JC, El Yaagoubi A, Nguyen‐Huu L, Reeve HL, Hampl V. Molecular identification of the role of voltage‐gated K+ channels, KV1.5 and KV2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest 101: 2319‐2330, 1998.
 14. Archer SL, Wu XC, Thébaud B, Nsair A, Bonnet S, Tyrrell B, McMurtry MS, Hashimoto K, Harry G, Michelakis ED. Preferential expression and function of voltage‐gated, O2‐sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: Ionic diversity in smooth muscle cells. Circ Res 95: 308‐318, 2004.
 15. Arrigoni FI, Hislop AA, Haworth SG, Mitchell JA. Newborn intrapulmonary veins are more reactive than arteries in normal and hypertensive piglets. Am J Physiol Lung Cell Mol Physiol 277: L887‐L892, 1999.
 16. Arrigoni FI, Vallance P, Haworth SG, Leiper JM. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation 107: 1195‐1201, 2003.
 17. Aschner JL, Foster SL, Kaplowitz M, Zhang Y, Zeng H, Fike CD. Heat shock protein 90 modulates endothelial nitric oxide synthase activity and vascular reactivity in the newborn piglet pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 292: L1515‐L1525, 2007.
 18. Aschner JL, Zeng H, Kaplowitz MR, Zhang Y, Slaughter JC, Fike CD. Heat shock protein 90‐eNOS interactions mature with postnatal age in the pulmonary circulation of the piglet. Am J Physiol Lung Cell Mol Physiol 296: L555‐L564, 2009.
 19. Asikainen TM, Raivio KO, Saksela M, Kinnula VL. Expression and developmental profile of antioxidant enzymes in human lung and liver. Am J Respir Cell Mol Biol 19: 942‐949, 1998.
 20. Badesch DB, Orton EC, Zapp LM, Westcott JY, Hester J, Voelkel NF, Stenmark KR. Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. Am J Respir Cell Mol Biol 1: 489‐498, 1989.
 21. Bailly K, Ridley AJ, Hall SM, Haworth SG. RhoA activation by hypoxia in pulmonary arterial smooth muscle cells is age and site specific. Circ Res 94: 1383‐1391, 2004.
 22. Bedard K, Krause K‐H. The NOX family of ROS‐generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 87: 245‐313, 2007.
 23. Belik J, González‐Luis GE, Perez‐Vizcaino F, Villamor E. Isoprostanes in fetal and neonatal health and disease. Free Radic Biol Med 48: 177‐188, 2010.
 24. Belknap JK, Orton EC, Ensley B, Tucker A, Stenmark KR. Hypoxia increases bromodeoxyuridine labeling indices in bovine neonatal pulmonary arteries. Am J Respir Cell Mol Biol 16: 366‐371, 1997.
 25. Benveniste J. Platelet‐activating factor, a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophils. Nature 249: 581‐582, 1974.
 26. Benveniste J, Henson PM, Cochrane CG. Leukocyte‐dependent histamine release from rabbit platelets. The role of IgE, basophils, and a platelet‐activating factor. J Exp Med 136: 1356‐1377, 1972.
 27. Berkenbosch JW, Baribeau J, Ferretti E, Perreault T. Role of protein kinase C and phosphatases in the pulmonary vasculature of neonatal piglets. Crit Care Med 29: 1229‐1233, 2001.
 28. Berkenbosch JW, Baribeau J, Perreault T. Decreased synthesis and vasodilation to nitric oxide in piglets with hypoxia‐induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 278: L276‐L283, 2000.
 29. Bixby CE, Ibe BO, Abdallah MF, Zhou W, Hislop AA, Longo LD, Raj JU. Role of platelet‐activating factor in pulmonary vascular remodeling associated with chronic high altitude hypoxia in ovine fetal lambs. Am J Physiol Lung Cell Mol Physiol 293: L1475‐L1482, 2007.
 30. Black SM, Johengen MJ, Ma ZD, Bristow J, Soifer SJ. Ventilation and oxygenation induce endothelial nitric oxide synthase gene expression in the lungs of fetal lambs. J Clin Invest 100: 1448‐1458, 1997.
 31. Bobik A. Transforming growth factor‐βs and vascular disorders. Arterioscler Thromb Vasc Biol 26: 1712‐1720, 2006.
 32. Bochnowicz S, Osborn RR, Luttmann MA, Louden C, Hart T, Hay DW, Underwood DC. Differences in time‐related cardiopulmonary responses to hypoxia in three rat strains. Clin Exp Hypertens 22: 471‐492, 2000.
 33. Boels PJ, Deutsch J, Gao B, Haworth SG. Perinatal development influences mechanisms of bradykinin‐induced relaxations in pulmonary resistance and conduit arteries differently. Cardiovasc Res 51: 140‐150, 2001.
 34. Bonds DR, Crosby LO, Cheek TG, Hagerdal M, Gutsche BB, Gabbe SG. Estimation of human fetal‐placental unit metabolic rate by application of the Bohr principle. J Dev Physiol 8: 49‐54, 1986.
 35. Bonnet S, Archer SL. Potassium channel diversity in the pulmonary arteries and pulmonary veins: Implications for regulation of the pulmonary vasculature in health and during pulmonary hypertension. Pharmacol Ther 115: 56‐69, 2007.
 36. Born GV, Dawes GS, Mott JC, Rennick BR. The constriction of the ductus arteriosus caused by oxygen and by asphyxia in newborn lambs. J Physiol 132, 304‐342, 1956
 37. Botney MD, Bahadori L, Gold LI. Vascular remodeling in primary pulmonary hypertension: Potential role for transforming growth factor‐beta. Am J Pathol 144: 286‐295, 1994.
 38. Boutet K, Montani D, Jaïs X, Yaïci A, Sitbon O, Simonneau G, Humbert M. Therapeutic advances in pulmonary arterial hypertension. Ther Adv Respir Dis 2: 249‐265, 2008.
 39. Brannon TS, North AJ, Wells LB, Shaul PW. Prostacyclin synthesis in ovine pulmonary artery is developmentally regulated by changes in cyclooxygenase‐1 gene expression. J Clin Invest 93: 2230‐2235, 1994.
 40. Brash AR. Arachidonic acid as a bioactive molecule. J Clin Invest 107: 1339‐1345, 2001.
 41. Brittain T. Molecular aspects of embryonic hemoglobin function. Mol Aspects Med 23: 293‐342, 2002.
 42. Carter AM. Placental oxygen transfer and the oxygen supply to the fetus. Fetal Matern Med Rev 11: 151‐161, 1999.
 43. Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 43: 62S‐67S, 2004.
 44. Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 146: 389‐397, 1995.
 45. Chen S, Crawford M, Day RM, Briones VR, Leader JE, Jose PA, Lechleider RJ. RhoA modulates Smad signaling during transforming growth factor‐beta‐induced smooth muscle differentiation. J Biol Chem 281: 1765‐1770, 2006.
 46. Chen XY, Dun JN, Miao QF, Zhang YJ. Fasudil hydrochloride hydrate, a Rho‐kinase inhibitor, suppresses 5‐hydroxytryptamine‐induced pulmonary artery smooth muscle cell proliferation via JNK and ERK1/2 pathway. Pharmacology 83: 67‐79, 2009.
 47. Chen YF, Feng JA, Li P, Xing D, Zhang Y, Serra R, Ambalavanan N, Majid‐Hassan E, Oparil S. Dominant negative mutation of the TGF‐beta receptor blocks hypoxia‐induced pulmonary vascular remodeling. J Appl Physiol 100: 564‐571, 2006.
 48. Chicoine LG, Avitia JW, Deen C, Nelin LD, Early S, Walker BR. Developmental differences in pulmonary eNOS expression in response to chronic hypoxia in rats. J Appl Physiol 93: 311‐318, 2002.
 49. Chicoine LG, Paffett ML, Girton MR, Metropoulus MJ, Joshi MS, Bauer JA, Nelin LD, Resta TC, Walker BR. Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats. Am J Physiol Lung Cell Mol Physiol 293: L1261‐L1270, 2007
 50. Christou H, Adatia I, Van Marter LJ, Kane JW, Thompson JE, Stark AR, Wessel DL, Kourembanas S. Effect of inhaled nitric oxide on endothelin‐1 and cyclic guanosine 5′‐monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension. J Pediatr 130: 603‐611, 1997.
 51. Clerch LB, Massaro D. Rat lung antioxidant enzymes: Differences in perinatal gene expression and regulation. Am J Physiol Lung Cell Mol Physiol 263: L466‐L470, 1992.
 52. Coe Y, Haleen SJ, Welch KM, Liu YA, Coceani F. The endothelin A receptor antagonists PD 156707 (CI‐1020) and PD 180988 (CI‐1034) reverse the hypoxic pulmonary vasoconstriction in the perinatal lamb. J Pharmacol Exp Ther 302: 672‐680, 2002.
 53. Cogolludo A, Moreno L, Lodi F, Tamargo J, Perez‐Vizcaino F. Postnatal maturational shift from PKCzeta and voltage‐gated K+ channels to RhoA/Rho kinase in pulmonary vasoconstriction. Cardiovasc Res 66: 84‐93, 2005.
 54. Cornfield DN, Chatfield BA, McQueston JA, McMurtry IF, Abman SH. Effects of birth‐related stimuli on l‐arginine‐dependent pulmonary vasodilation in ovine fetus. Am J Physiol Heart Circ Physiol 262: H1474‐H1481, 1992.
 55. Cornfield DN, Reeve HL, Tolarova S, Weir EK, Archer S. Oxygen causes fetal pulmonary vasodilation through activation of a calcium‐dependent potassium channel. Proc Natl Acad Sci U S A 93: 8089‐8094, 1996.
 56. Cornfield DN, Saqueton CB, Porter VA, Herron J, Resnik E, Haddad IY, Reeve HL. Voltage‐gated K (+)‐channel activity in ovine pulmonary vasculature is developmentally regulated. Am J Physiol Lung Cell Mol Physiol 278: L1297‐L1304, 2000.
 57. Cornfield DN, Stevens T, McMurtry IF, Abman SH, Rodman DM. Acute hypoxia increases cytosolic calcium in fetal pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 265: L53‐L56, 1993.
 58. Cornfield DN, Stevens T, McMurtry IF, Abman SH, Rodman DM. Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 266: L469‐L475, 1994.
 59. Custer JR, Hales CA. Influence of alveolar oxygen on pulmonary vasoconstriction in newborn lambs versus sheep. Am Rev Respir Dis 132: 326‐331, 1985.
 60. Dakshinamurti S. Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 39: 492‐503, 2005.
 61. Das M, Burns N, Wilson SJ, Zawada WM, Stenmark KR. Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKCzeta in the pulmonary artery adventitia. Cardiovasc Res 78: 440‐448, 2008.
 62. Das M, Stenmark KR, Dempsey EC. Enhanced growth of fetal and neonatal pulmonary artery adventitial fibroblasts is dependent on protein kinase C. Am J Physiol Lung Cell Mol Physiol 269: L660‐L667, 1995.
 63. Das M, Stenmark KR, Ruff LJ, Dempsey EC. Selected isozymes of PKC contribute to augmented growth of fetal and neonatal bovine PA adventitial fibroblasts. Am J Physiol Lung Cell Mol Physiol 273: L1276‐L1284, 1997.
 64. Davie NJ, Crossno JT Jr, Frid MG, Hofmeister SE, Reeves JT, Hyde DM, Carpenter TC, Brunetti JA, McNiece IK, Stenmark KR. Hypoxia‐induced pulmonary artery adventitial remodeling and neovascularization: Contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 286: L668‐L678, 2004.
 65. Dawes GS, Mott JC, Widdicombe JG. The foetal circulation in the lamb. J Physiol 126, 563‐587, 1954.
 66. Delannoy E, Courtois A, Freund‐Michel V, Leblais V, Marthan R, Muller B. Hypoxia‐induced hyperreactivity of pulmonary arteries: Role of cyclooxygenase‐2, isoprostanes, and thromboxane receptors. Cardiovasc Res 85: 582‐592, 2010.
 67. Dempsey EC, Das M, Frid MG, Stenmark KR. Unique growth properties of neonatal pulmonary vascular cells: Importance of time‐ and site‐specific responses, cell‐cell interaction, and synergy. J Perinatol 16: S2‐S11, 1996.
 68. Dennis KE, Aschner JL, Milatovic D, Schmidt JW, Aschner M, Kaplowitz MR, Zhang Y, Fike CD. NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia‐induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 297: L596‐L607, 2009.
 69. Dhanakoti S, Gao Y, Nguyen MQ, Raj JU. Involvement of cGMP‐dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP. J Appl Physiol 88: 1637‐1642, 2000.
 70. Dingemans KP, Wagenvoort CA. Pulmonary arteries and veins in experimental hypoxia. An ultrastructural study. Am J Pathol 93: 353‐368, 1978.
 71. Dupuis J, Jasmin JF, Prie S, Cernacek P. Importance of local production of endothelin‐1 and of the ETB receptor in the regulation of pulmonary vascular tone. Pulm Pharmacol Ther 13: 135‐40, 2000.
 72. Durmowicz AG, Orton EC, Stenmark KR. Progressive loss of vasodilator responsive component of pulmonary hypertension in neonatal calves exposed to 4,570 m. Am J Physiol Heart Circ Physiol 265: H2175‐H2183, 1993.
 73. Durmowicz AG, Parks WC, Hyde DM, Mecham RP, Stenmark KR. Persistence, re‐expression, and induction of pulmonary arterial fibronectin, tropoelastin, and type I procollagen mRNA expression in neonatal hypoxic pulmonary hypertension. Am J Pathol 145: 1411‐1420, 1994.
 74. Edelstone DI, Caine ME, Fumia FD. Relationship of fetal oxygen consumption and acid‐base balance to fetal hematocrit. Am J Obstet Gynecol 151: 844‐851, 1985.
 75. Endo A, Ayusawa M, Minato M, Takada M, Takahashi S, Harada K. Endogenous nitric oxide and endothelin‐1 in persistent pulmonary hypertension of the newborn. Eur J Pediatr 160: 217‐222, 2001.
 76. Evans AM, Osipenko ON, Haworth SG, Gurney AM. Resting potentials and potassium currents during development of pulmonary artery smooth muscle cells. Am J Physiol Heart Circ Physiol 275: H887‐H899, 1998.
 77. Evans NJ, Archer LN. Doppler assessment of pulmonary artery pressure and extrapulmonary shunting in the acute phase of hyaline membrane disease. Arch Dis Child 66: 6‐11, 1991.
 78. Fike CD, Aschner JL, Zhang Y, Kaplowitz MR. Impaired NO signaling in small pulmonary arteries of chronically hypoxic newborn piglets. Am J Physiol Lung Cell Mol Physiol 286: L1244‐L1254, 2004.
 79. Fike CD, Kaplowitz MR. Chronic hypoxia alters nitric oxide‐dependent pulmonary vascular responses in lungs of newborn pigs. J Appl Physiol 81: 2078‐2087, 1996.
 80. Fike CD, Kaplowitz MR. Nifedipine inhibits pulmonary hypertension but does not prevent decreased lung eNOS in hypoxic newborn pigs. Am J Physiol Lung Cell Mol Physiol 277: L449‐L456, 1999.
 81. Fike, CD, Kaplowitz MR, Rehorst‐Paea LA, Nelin LD. l‐Arginine increases nitric oxide production in isolated lungs of chronically hypoxic newborn pigs. J Appl Physiol 88: 1797‐1803, 2000.
 82. Fike CD, Kaplowitz MR, Thomas CJ, Nelin LD. Chronic hypoxia decreases nitric oxide production and endothelial nitric oxide synthase in newborn pig lungs. Am J Physiol Lung Cell Mol Physiol 274: L517‐L526, 1998.
 83. Fike CD, Kaplowitz MR, Zhang Y, Madden JA. Voltage‐gated K+ channels at an early stage of chronic hypoxia‐induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 291: L1169‐L1176, 2006.
 84. Fike CD, Kaplowitz MR, Zhang Y, Pfister SL. Cyclooxygenase‐2 and an early stage of chronic hypoxia‐induced pulmonary hypertension in newborn pigs. J Appl Physiol 98: 1111‐1118, 2005.
 85. Fike CD, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL. Reactive oxygen species from NADPH oxidase contribute to altered pulmonary vascular responses in piglets with chronic hypoxia‐induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 295: L881‐L888, 2008.
 86. Fike CD, Zhang Y, Kaplowitz MR. Thromboxane inhibition reduces an early stage of chronic hypoxia‐induced pulmonary hypertension in piglets. J Appl Physiol 99: 670‐676, 2005.
 87. Franco‐Obregón A, López‐Barneo J. Differential oxygen sensitivity of calcium channels in rabbit smooth muscle cells of conduit and resistance pulmonary arteries. J Physiol 491: 511‐518, 1996.
 88. Frank L, Sosenko IR. Prenatal development of lung antioxidant enzymes in four species. J Pediatr 110: 106‐110, 1987.
 89. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR. Hypoxia‐induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168: 659‐669, 2006.
 90. Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial‐mesenchymal transdifferentiation: In vitro analysis. Circ Res 90: 1189‐1196, 2002.
 91. Frid MG, Li M, Gnanasekharan M, Burke DL, Fragoso M, Strassheim D, Sylman JL, Stenmark KR. Sustained hypoxia leads to the emergence of cells with enhanced growth, migratory, and promitogenic potentials within the distal pulmonary artery wall. Am J Physiol Lung Cell Mol Physiol 297: L1059‐L1072, 2009.
 92. Frid MG, Moiseeva EP, Stenmark KR. Multiple phenotypically distinct smooth muscle cell populations exist in the adult and developing bovine pulmonary arterial media in vivo. Circ Res 75: 669‐681, 1994.
 93. Fujikura T, Yoshida J. Blood gas analysis of placental and uterine blood during cesarean delivery. Obstet Gynecol 87: 133‐136, 1996.
 94. Fukuda Y, Ishizaki M, Okada Y, Seiki M, Yamanaka N. Matrix metalloproteinases and tissue inhibitor of metalloproteinase‐2 in fetal rabbit lung. Am J Physiol Lung Cell Mol Physiol 279: L555‐L561, 2000.
 95. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H. Acute vasodilator effects of a Rho‐kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 91: 391‐392, 2005.
 96. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JWR, Boonstra A, Postmus PE, Vonk‐Noordegraaf A. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest 132: 1906‐1912, 2007.
 97. Gao Y, Dhanakoti S, Tolsa J‐F, Raj JU. Role of protein kinase G in nitric oxide and cGMP‐induced relaxation of newborn ovine pulmonary veins. J Appl Physiol 87: 993‐998, 1999.
 98. Gao Y, Dhanakoti S, Trevino EM, Sander FC, Portugal AM, Raj JU. Effect of oxygen on cyclic GMP‐dependent protein kinase‐mediated relaxation in ovine fetal pulmonary arteries and veins. Am J Physiol Lung Cell Mol Physiol 285: L611‐L618, 2003.
 99. Gao Y, Portugal AD, Liu J, Negash S, Zhou W, Tian J, Xiang R, Longo LD, Raj JU. Preservation of cGMP‐induced relaxation of pulmonary veins of fetal lambs exposed to chronic high altitude hypoxia: Role of PKG and Rho kinase. Am J Physiol Lung Cell Mol Physiol 295: L889‐L896, 2008.
 100. Gao Y, Portugal AD, Negash S, Zhou W, Longo LD, Raj JU. Role of Rho kinases in PKG‐mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia. Am J Physiol Lung Cell Mol Physiol 292: L678‐L684, 2007.
 101. Gao Y, Raj JU. Role of veins in regulation of the pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 288: L213‐L226, 2005.
 102. Gao Y, Raj JU. cGMP‐dependent protein kinase in regulation of the pulmonary circulation. Curr Respir Med Rev 2: 373‐381, 2006.
 103. Gao Y, Tolsa J‐F, Botello M, Raj JU. Developmental change in isoproterenol‐mediated relaxation of pulmonary veins of fetal and newborn lambs. J Appl Physiol 84: 1535‐1539, 1998.
 104. Gao Y, Tolsa J‐F, Shen H, Raj JU. Effect of selective phosphodiesterase inhibitors on the responses of ovine pulmonary veins to prostaglandin E2. J Appl Physiol 84: 13‐18, 1998.
 105. Gao Y, Zhou H, Ibe BO, Raj JU. Prostaglandins E2 and I2 cause greater relaxations in pulmonary veins than in arteries of newborn lambs. J Appl Physiol 81: 2534‐2539, 1996.
 106. Gao Y, Zhou H, Raj JU. Endothelium‐derived nitric oxide plays a larger role in pulmonary veins than in arteries in newborn lambs. Circ Res 76: 559‐565, 1995.
 107. Gao Y, Zhou H, Raj JU. Heterogeneity in the role of endothelium‐derived nitric oxide in pulmonary arteries and veins of term fetal lambs. Am J Physiol Heart Circ Physiol 268: H1586‐H1592, 1995.
 108. Gerasimovskaya EV, Tucker DA, Stenmark KR. Activation of phosphatidylinositol 3‐kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia‐induced pulmonary artery adventitial fibroblast proliferation. J Appl Physiol 98: 722‐731, 2005.
 109. Giussani DA, Phillips PS, Anstee S, Barker DJ. Effects of altitude versus economic status on birth weight and body shape at birth. Pediatr Res 49: 490‐494, 2001.
 110. González‐Luis G, Pérez‐Vizcaíno F, García‐Muñoz F, de Mey JG, Blanco CE, Villamor E. Age‐related differences in vasoconstrictor responses to isoprostanes in piglet pulmonary and mesenteric vascular smooth muscle. Pediatr Res 57: 845‐852, 2005.
 111. Goyal R, Creel KD, Chavis EJ, Smith GD, Longo LD, Wilson SM. Maturation of intracellular calcium homeostasis in sheep pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 295: L905‐L914, 2008.
 112. Groenman F, Unger S, Post M. The molecular basis for abnormal human lung development. Biol Neonate 87: 164‐177, 2005
 113. Gu W, Jones CT, Parer JT. Metabolic and cardiovascular effects on fetal sheep of sustained reduction of uterine blood flow. J Physiol 368: 109‐129, 1985.
 114. Hall SM, Gorenflo M, Reader J, Lawson D, Haworth SG. Neonatal pulmonary hypertension prevents reorganization of the pulmonary arterial smooth muscle cytoskeleton after birth. J Anat 196: 391‐403, 2000.
 115. Hall SM, Hislop AA, Wu Z, Haworth SG. Remodeling of the pulmonary arteries during recovery from pulmonary hypertension induced by neonatal hypoxia. J Pathol 203: 575‐583, 2004.
 116. Hanson KA, Burns F, Rybalkin SD, Miller JW, Beavo J, Clarke WR. Developmental changes in lung cGMP phosphodiesterase‐5 activity, protein, and message. Am J Respir Crit Care Med 158: 279‐288, 1998.
 117. Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke WR. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am J Physiol Lung Cell Mol Physiol 275: L931‐L941, 1998.
 118. Harrison RE, Berger R, Haworth SG, Tulloh R, Mache CJ, Morrell NW, Aldred MA, Trembath RC. Transforming growth factor‐β receptor mutations and pulmonary arterial hypertension in childhood. Circulation 111: 435‐441, 2005.
 119. Haworth SG. The management of pulmonary hypertension in children. Arch Dis Child 93: 620‐625, 2008.
 120. Haworth SG, Hall SM, Chew M, Allen K. Thinning of fetal pulmonary arterial wall and postnatal remodeling: Ultrastructural studies on the respiratory unit arteries of the pig. Virchows Arch A Pathol Anat Histopathol 411: 161‐171, 1987.
 121. Herrera EA, Ebensperger G, Krause BJ, Riquelme RA, Reyes RV, Capetillo M, González S, Parer JT, Llanos AJ. Sildenafil reverses hypoxic pulmonary hypertension in highland and lowland newborn sheep. Pediatr Res 63: 169‐175, 2008.
 122. Herrera EA, Pulgar VM, Riquelme RA, Sanhueza EM, Reyes RV, Ebensperger G, Parer JT, Valdez EA, Giussani DA, Blanco CE, Hanson MA, Llanos AJ. High‐altitude chronic hypoxia during gestation and after birth modifies cardiovascular responses in newborn sheep. Am J Physiol Regul Integr Comp Physiol 292: R2234‐R2240, 2007.
 123. Hinton M, Gutsol A, Dakshinamurti S. Thromboxane hypersensitivity in hypoxic pulmonary artery myocytes: Altered TP receptor localization and kinetics. Am J Physiol Lung Cell Mol Physiol 292: L654‐L663, 2007.
 124. Hinton M, Mellow L, Halayko AJ, Gutsol A, Dakshinamurti S. Hypoxia induces hypersensitivity and hyperreactivity to thromboxane receptor agonist in neonatal pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 290: L375‐L384, 2006.
 125. Hirenallur‐S DK, Haworth ST, Leming JT, Chang J, Hernandez G, Gordon JB, Rusch NJ. Upregulation of vascular calcium channels in neonatal piglets with hypoxia‐induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 295: L915‐L924, 2008.
 126. Hislop A. Developmental biology of the pulmonary circulation. Paediatr Respir Rev 6: 35‐43, 2005.
 127. Hoshikawa Y, Nana‐Sinkam P, Moore MD, Sotto‐Santiago S, Phang T, Keith RL, Morris KG, Kondo T, Tuder RM, Voelkel NF, Geraci MW. Hypoxia induces different genes in the lungs of rats compared with mice. Physiol Genomics 12: 209‐219, 2003.
 128. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 351: 1425‐1436, 2004.
 129. Ibe BO, Abdallah MF, Portugal AM, Raj JU. Platelet‐activating factor stimulates ovine foetal pulmonary vascular smooth muscle cell proliferation: Role of nuclear factor‐kappa B and cyclin‐dependent kinases. Cell Prolif 41: 208‐229, 2008.
 130. Ibe BO, Hillyard RM, Raj JU. Heterogeneity in prostacyclin and thromboxane synthesis in ovine pulmonary vascular tree: Effect of age and oxygen tension. Exp Lung Res 22: 351‐374, 1996.
 131. Ibe BO, Pham HH, Kaapa P, Raj JU. Maturational changes in ovine pulmonary metabolism of platelet‐activating factor: Implications for postnatal adaptation. Mol Genet Metab 74: 385‐395, 2001.
 132. Ibe BO, Portugal AM, Chaturvedi S, Raj JU. Oxygen‐dependent PAF receptor binding and intracellular signaling in ovine fetal pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol 288: L879‐L886, 2005.
 133. Ibe BO, Raj JU. Endogenous arachidonic acid metabolism by calcium ionophore stimulated ferret lungs. Effect of age, hypoxia. Lab Invest 66: 370‐377, 1992.
 134. Inoue A, Yanagisawa M, Takuwa Y, Mitsui Y, Kobayashi M, Masaki T. The human preproendothelin‐1 gene. J Biol Chem 264: 14954‐14959, 1989.
 135. Ishii S, Nagase T, Shimizu T. Platelet‐activating factor receptor. Prostaglandins Other Lipid Mediat 68‐69: 599‐609, 2002.
 136. Ismail S, Sturrock A, Wu P, Cahill B, Norman K, Huecksteadt T, Sanders K, Kennedy T, Hoidal J. NOX4 mediates hypoxia‐induced proliferation of human pulmonary artery smooth muscle cells: The role of autocrine production of transforming growth factor‐β1 and insulin‐like growth factor binding protein‐3. Am J Physiol Lung Cell Mol Physiol 296: L489‐L499, 2009.
 137. Itskovitz J, LaGamma EF, Rudolph AM. Effects of cord compression on fetal blood flow distribution and O2 delivery. Am J Physiol Heart Circ Physiol 252: H100‐H109, 1987.
 138. Ivy DD, Le Cras TD, Horan MP, Abman SH. Increased lung preproET‐1 and decreased ETB‐receptor gene expression in fetal pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 274: L535‐L541, 1998.
 139. Ivy DD, McMurtry IF, Yanagisawa M, Gariepy CE, Le Cras TD, Gebb SA, Morris KG, Wiseman RC, Abman SH. Endothelin B receptor deficiency potentiates ET‐1 and hypoxic pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol 280: L1040‐L1048, 2001.
 140. Ivy DD, Parker TA, Abman SH. Prolonged endothelin B receptor blockade causes pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 279: L758‐L765, 2000.
 141. Ivy DD, Yanagisawa M, Gariepy CE, Gebb SA, Colvin KL, McMurtry IF. Exaggerated hypoxic pulmonary hypertension in endothelin B receptor‐deficient rats. Am J Physiol Lung Cell Mol Physiol 282: L703‐L712, 2002.
 142. Jaffe AB, Hall A. Rho GTPases: Biochemistry and biology. Annu Rev Cell Dev Biol 21: 247‐269, 2005.
 143. Jain R, Shaul PW, Borok Z, Willis BC. Endothelin‐1 induces alveolar epithelial‐mesenchymal transition through endothelin type A receptor‐mediated production of TGF‐beta1. Am J Respir Cell Mol Biol 37: 38‐47, 2007.
 144. Janakidevi K, Fisher MA, Del Vecchio PJ, Tiruppathi C, Figge J, Malik AB. Endothelin‐1 stimulates DNA synthesis and proliferation of pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 263: C1295‐C1301, 1992.
 145. Jankov RP, Kantores C, Belcastro R, Yi M, Tanswell AK. Endothelin‐1 inhibits apoptosis of pulmonary arterial smooth muscle in the neonatal rat. Pediatr Res 60: 245‐251, 2006.
 146. Jankov RP, Kantores C, Belcastro R, Yi S, Ridsdale RA, Post M, Tanswell AK. A role for platelet‐derived growth factor beta‐receptor in a newborn rat model of endothelin‐mediated pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 288: L1162‐L170, 2005.
 147. Jankov RP, Kantores C, Pan J, Belik J. Contribution of xanthine oxidase‐derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol 294: L233‐L245, 2008.
 148. Jankov RP, Luo X, Belcastro R, Copland I, Frndova H, Lye SJ, Hoidal JR, Post M, Tanswell AK. Gadolinium chloride inhibits pulmonary macrophage influx and prevents O2‐induced pulmonary hypertension in the neonatal rat. Pediatr Res 50: 172‐183, 2001.
 149. Jankov RP, Luo X, Cabacungan J, Belcastro R, Frndova H, Lye SJ, Tanswell AK. Endothelin‐1 and O2‐mediated pulmonary hypertension in neonatal rats: A role for products of lipid peroxidation. Pediatr Res 48: 289‐298, 2000.
 150. Janssen LJ. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol 39: 383‐389, 2008.
 151. Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: A target for therapeutic intervention in pulmonary hypertension. Pharmacol Ther 92: 1‐20, 2001.
 152. Jensen A, Garnier Y, Berger R. Dynamics of fetal circulatory responses to hypoxia and asphyxia. Eur J Obstet Gynecol Reprod Biol 84: 155‐172, 1999.
 153. Jensen A, Roman C, Rudolph AM. Effect of reduced uterine flow on fetal blood flow distribution and oxygen delivery. J Dev Physiol 15: 309‐323, 1991.
 154. Jeon ES, Park WS, Lee MJ, Kim YM, Han J, Kim JH. A Rho kinase/myocardin‐related transcription factor‐A‐dependent mechanism underlies the sphingosylphosphorylcholine‐induced differentiation of mesenchymal stem cells into contractile smooth muscle cells. Circ Res 103: 635‐642, 2008.
 155. Jernigan NL, Walker BR, Resta TC. Chronic hypoxia augments protein kinase G‐mediated Ca2+ desensitization in pulmonary vascular smooth muscle through inhibition of RhoA/Rho kinase signaling. Am J Physiol Lung Cell Mol Physiol 287: L1220‐L1229, 2004.
 156. Jernigan NL, Walker BR, Resta TC. Reactive oxygen species mediate RhoA/Rho kinase‐induced Ca2+ sensitization in pulmonary vascular smooth muscle following chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 295: L515‐L529, 2008.
 157. Johns RA, Yamaji‐Kegan K. Unveiling cell phenotypes in lung vascular remodeling. Am J Physiol Lung Cell Mol Physiol 297: L1056‐L1058, 2009.
 158. Johnson JE, Perkett EA, Meyrick B. Pulmonary veins and bronchial vessels undergo remodeling in sustained pulmonary hypertension induced by continuous air embolization into sheep. Exp Lung Res 23: 459‐473, 1997.
 159. Jones R, Jacobson M, Steudel W. alpha‐Smooth‐muscle actin and microvascular precursor smooth‐muscle cells in pulmonary hypertension. Am J Respir Cell Mol Biol 20: 582‐594, 1999.
 160. Kelly DA, Hislop AA, Hall SM, Haworth SG. Correlation of pulmonary arterial smooth muscle structure and reactivity during adaptation to extrauterine life. J Vasc Res 39: 30‐40, 2002.
 161. Kelly DA, Hislop AA, Hall SM, Haworth SG. Relationship between structural remodeling and reactivity in pulmonary resistance arteries from hypertensive piglets. Pediatr Res 58: 525‐530, 2005.
 162. Kiserud T, Acharya G. The fetal circulation. Prenat Diagn 24: 1049‐1059, 2004.
 163. Kolber KA, Gao Y, Raj JU. Maturational changes in endothelium‐derived nitric oxide‐mediated relaxation of ovine pulmonary arteries. Biol Neonate 77: 123‐130, 2000.
 164. Kulasekaran P, Scavone CA, Rogers DS, Arenberg DA, Thannickal VJ, Horowitz JC. Endothelin‐1 and transforming growth factor‐β1 independently induce fibroblast resistance to apoptosis via AKT activation. Am J Respir Cell Mol Biol 41: 484‐493, 2009.
 165. Lackman F, Capewell V, Gagnon R, Richardson B. Fetal umbilical cord oxygen values and birth to placental weight ratio in relation to size at birth. Am J Obstet Gynecol 185: 674‐682, 2001.
 166. Lafeber HN, Rolph TP, Jones CT. Studies on the growth of the fetal guinea pig. The effects of ligation of the uterine artery on organ growth and development. J Dev Physiol 6: 441‐59, 1984
 167. Lammers SR, Kao PH, Qi HJ, Hunter K, Lanning C, Albietz J, Hofmeister S, Mecham R, Stenmark KR, Shandas R. Changes in the structure‐function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves. Am J Physiol Heart Circ Physiol 295: H1451‐H1459, 2008.
 168. Lang F, Ritter M, Gamper N, Huber S, Fillon S, Tanneur V, Lepple‐Wienhues A, Szabo I, Gulbins E. Cell volume in the regulation of cell proliferation and apoptotic cell death. Cell Physiol Biochem 10: 417‐428, 2000.
 169. Lankhaar JW, Westerhof N, Faes TJ, Gan CT, Marques KM, Boonstra A, Van Den Berg FG, Postmus PE, Vonk‐Noordegraaf A. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur Heart J 29: 1688‐1695, 2008.
 170. Lankhaar JW, Westerhof N, Faes TJ, Marques KM, Marcus JT, Postmus PE, Vonk‐Noordegraaf A. Quantification of right ventricular afterload in patients with and without pulmonary hypertension. Am J Physiol Heart Circ Physiol 291: H1731‐H1737, 2006.
 171. Leung FP, Yung LM, Yao X, Laher I, Huang Y. Store‐operated calcium entry in vascular smooth muscle. Br J Pharmacol 153: 846‐857, 2008.
 172. Levy M, Maurey C, Chailley‐Heu B, Martinovic J, Jaubert F, Israël‐Biet D. Developmental changes in endothelial vasoactive and angiogenic growth factors in the human perinatal lung. Pediatr Res 57: 248‐253, 2005.
 173. Lin MJ, Leung GP, Zhang WM, Yang XR, Yip KP, Tse CM, Sham JS. Chronic hypoxia‐induced upregulation of store‐operated and receptor‐operated Ca2+ channels in pulmonary arterial smooth muscle cells: A novel mechanism of hypoxic pulmonary hypertension. Circ Res 95: 496‐505, 2004.
 174. Liu J, Gao Y, Negash S, Longo LD, Raj JU. Long‐term effects of prenatal hypoxia on endothelium‐dependent relaxation responses in pulmonary arteries of adult sheep. Am J Physiol Lung Cell Mol Physiol 296: L547‐L554, 2009.
 175. Liu JQ, Zelko IN, Erbynn EM, Sham JSK, Folz RJ. Hypoxic pulmonary hypertension: Role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 290: L2‐L10, 2006.
 176. Liu SF, Hislop AA, Haworth SG, Barnes PJ. Developmental changes in endothelium‐dependent pulmonary vasodilatation in pigs. Br J Pharmacol 106: 324‐330, 1992.
 177. Liu Y, Suzuki YJ, Day RM, Fanburg BL. Rho kinase‐induced nuclear translocation of ERK1/ERK2 in smooth muscle cell mitogenesis caused by serotonin. Circ Res 95: 579‐586, 2004.
 178. Longo LD, Pearce WJ. Fetal cerebrovascular acclimatization responses to high‐altitude, long‐term hypoxia: A model for prenatal programming of adult disease? Am J Physiol Regul Integr Comp Physiol 288: R16‐R24, 2005.
 179. MacLean MR, McCulloch KM, Baird M. Endothelin ETA‐ and ETB‐receptor‐mediated vasoconstriction in rat pulmonary arteries and arterioles. J Cardiovasc Pharmacol 23: 838‐845, 1994.
 180. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol 47: 799‐803, 2006.
 181. Marino M, Bény JL, Peyter AC, Bychkov R, Diaceri G, Tolsa JF. Perinatal hypoxia triggers alterations in K+ channels of adult pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 293: L1171‐L1182, 2007.
 182. McCulloch KM, Docherty CC, Morecroft I, MacLean MR. Endothelin B receptor‐mediated contraction in human pulmonary resistance arteries. Br J Pharmacol 119: 1125‐1130, 1996.
 183. McElroy MC, Postle AD, Kelly FJ. Catalase, superoxide dismutase and glutathione peroxidase activities of lung and liver during human development. Biochim Biophys Acta. 1117: 153‐158, 1992.
 184. McMurtry IF, Bauer NR, Fagan KA, Nagaoka T, Gebb SA, Oka M. Hypoxia and Rho/Rho‐kinase signaling. Lung development versus hypoxic pulmonary hypertension. Adv Exp Med Biol 543: 127‐137, 2003.
 185. McNamara PJ, Murthy P, Kantores C, Teixeira L, Engelberts D, van Vliet T, Kavanagh BP, Jankov RP. Acute vasodilator effects of Rho‐kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide. Am J Physiol Lung Cell Mol Physiol 294: L205‐L213, 2008.
 186. McQueston JA, Cornfield DN, McMurtry IF, Abman SH. Effects of oxygen and exogenous l‐arginine on EDRF activity in fetal pulmonary circulation. Am J Physiol Heart Circ Physiol 264: H865‐H871, 1993.
 187. Mehta JP, Campian JL, Guardiola J, Cabrera JA, Weir EK, Eaton JW. Generation of oxidants by hypoxic human pulmonary and coronary smooth‐muscle cells. Chest 133: 1410‐1414, 2008.
 188. Metcalfe J, Bartels H, Moll W. Gas exchange in the pregnant uterus. Physiol Rev 47: 782‐838, 1967.
 189. Michelakis ED, Hampl V, Nsair A, Wu X, Harry G, Haromy A, Gurtu R, Archer SL. Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ Res 90: 1307‐1315, 2002.
 190. Michelakis ED, Weir EK, Wu X, Nsair A, Waite R, Hashimoto K, Puttagunta L, Knaus HG, Archer SL. Potassium channels regulate tone in rat pulmonary veins. Am J Physiol Lung Cell Mol Physiol 280: L1138‐L1147, 2001.
 191. Milnor WR, Conti CR, Lewis KB, O'Rourke MF. Pulmonary arterial pulse wave velocity and impedance in man. Circ Res 25: 637‐649, 1969.
 192. Montrucchio G, Alloatti G, Camussi G. Role of platelet‐activating factor in cardiovascular pathophysiology. Physiol Rev 80: 1669‐1699, 2000.
 193. Negash S, Gao Y, Zhou W, Liu J, Chinta S, Raj JU. Regulation of cGMP‐dependent protein kinase (PKG1) mediated vasodilation by hypoxia‐induced reactive species in ovine fetal pulmonary veins. Am J Physiol Lung Cell Mol Physiol 293: L1012‐L1020, 2007.
 194. Nelin LD, Thomas CJ, Dawson CA. Effect of hypoxia on nitric oxide production in neonatal pig lung. Am J Physiol Heart Circ Physiol 271: H8‐H14, 1996.
 195. Nelson MT, Patlak JB, Worley JF, Standen NB. Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol Cell Physiol 259: 3‐18, 1990.
 196. Noguchi Y, Hislop AA, Haworth SG. Influence of hypoxia on endothelin‐1 binding sites in neonatal porcine pulmonary vasculature. Am J Physiol Heart Circ Physiol 272: H669‐H678, 1997.
 197. North AJ, Brannon TS, Wells LB, Campbell WB, Shaul PW. Hypoxia stimulates prostacyclin synthesis in newborn pulmonary artery endothelium by increasing cyclooxygenase‐1 protein. Circ Res 75: 33‐40, 1994.
 198. North AJ, Star RA, Brannon TS, Ujiie K, Wells LB, Lowenstein CJ, Snyder SH, Shaul PW. Nitric oxide synthase type I and type III gene expression are developmentally regulated in rat lung. Am J Physiol Lung Cell Mol Physiol 266: L635‐L641, 1994.
 199. Oka M, Fagan KA, Jones PL, McMurtry IF. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Pharmacol 155: 444‐454, 2008.
 200. Orton EC, LaRue SM, Ensley B, Stenmark K. Bromodeoxyuridine labeling and DNA content of pulmonary arterial medial cells from hypoxia‐exposed and nonexposed healthy calves. Am J Vet Res 53: 1925‐1930, 1992.
 201. Ostlund E, Lindholm H, Hemsen A, Fried G. Fetal erythropoietin and endothelin‐1: Relation to hypoxia and intrauterine growth retardation. Acta Obstet Gynecol Scand 79: 276‐282, 2000.
 202. Pak O, Aldashev A, Welsh D, Peacock A. The effects of hypoxia on the cells of the pulmonary vasculature. Eur Respir J 30: 364‐372, 2007.
 203. Parker TA, le Cras TD, Kinsella JP, Abman SH. Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung. Am J Physiol Lung Cell Mol Physiol 278: L202‐L208, 2000.
 204. Patil S, Bunderson M, Wilham J, Black SM. Important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol 287: L1314‐L1322, 2004.
 205. Paulone ME, Edelstone DI, Shedd A. Effects of maternal anemia on uteroplacental and fetal oxidative metabolism in sheep. Am J Obstet Gynecol 156: 230‐236, 1987.
 206. Pearl JM, Wellmann SA, McNamara JL, Lombardi JP, Wagner CJ, Raake JL, Nelson DP. Bosentan prevents hypoxia‐reoxygenation‐induced pulmonary hypertension and improves pulmonary function. Ann Thorac Surg 68: 1714‐1721, 1999.
 207. Peirson RE, Jensen R. Brisket disease. In: Fincher MG, Gibbons WJ, Mayer K, Park SE, editors. Diseases of Cattle. Evanston, IL: American Veterinary Publications, 1956, p. 717‐723.
 208. Perkett EA, Pelton RW, Meyrick B, Gold LI, Miller DA. Expression of transforming growth factor‐beta mRNAs and proteins in pulmonary vascular remodeling in the sheep air embolization model of pulmonary hypertension. Am J Respir Cell Mol Biol 11: 16‐24, 1994.
 209. Perreault T, Berkenbosch JW, Barrington KJ, Decker ER, Wu C, Brock TA, Baribeau J. TBC3711, an ET(A) receptor antagonist, reduces neonatal hypoxia‐induced pulmonary hypertension in piglets. Pediatr Res 50: 374‐383, 2001.
 210. Peyter AC, Muehlethaler V, Liaudet L, Marino M, Di Bernardo S, Diaceri G, Tolsa JF. Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice. Am J Physiol Lung Cell Mol Physiol 295: L201‐L213, 2008.
 211. Pierce CM, Krywawych S, Petros AJ. Asymmetric dimethyl arginine and symmetric dimethyl arginine levels in infants with persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 5: 517‐520, 2004.
 212. Pierce CM, Krywawych S, Petros AJ. Elevated levels of asymmetric di‐methylarginine in neonates with congenital diaphragmatic hernia. Eur J Pediatr 164: 248‐249, 2005.
 213. Porter VA, Reeve HL, Cornfield DN. Fetal rabbit pulmonary artery smooth muscle cell response to ryanodine is developmentally regulated. Am J Physiol Lung Cell Mol Physiol 279: L751‐L757, 2000.
 214. Porter VA, Rhodes MT, Reeve HL, Cornfield DN. Oxygen‐induced fetal pulmonary vasodilation is mediated by intracellular calcium activation of KCa channels. Am J Physiol Lung Cell Mol Physiol 281: L1379‐L1385, 2001.
 215. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 118: 2372‐2379, 2008.
 216. Rabinovitch M, Gamble WJ, Miettinen OS, Reid L. Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery. Am J Physiol Heart Circ Physiol 240: H62‐H72, 1981.
 217. Raj JU, Chen P. Micropuncture measurement of microvascular pressure in isolated lamb lungs during hypoxia. Circ Res 59: 398‐404, 1986.
 218. Raj JU, Chen P. Microvascular pressures measured by micropuncture in isolated lamb lungs. J Appl Physiol 61: 2194‐2201, 1986.
 219. Raj JU, Gao Y, Dhanakoti S, Sander F. cGMP‐dependent protein kinase in regulation of the perinatal pulmonary circulation. Chapter 23, in: Bhattacharya J, editor. Cell Signaling in Vascular Inflammation. New York: Futura Publishing Company, 2005, p. 381‐397.
 220. Raj JU, Hillyard R, Kaapa P, Gropper M, Anderson J. Pulmonary arterial and venous constriction during hypoxia in 3‐ to 5‐wk‐old and adult ferrets. J Appl Physiol 69: 2183‐2189, 1990.
 221. Raj JU, Shimoda L. Oxygen‐dependent signaling in pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol 283: L671‐L677, 2002.
 222. Rao GN, Berk BC. Active oxygen species stimulate vascular smooth muscle cell growth and proto‐oncogene expression. Circ Res 18: 775‐794, 1992.
 223. Reeve HL, Weir EK, Archer SL, Cornfield DN. A maturational shift in pulmonary K+ channels, from Ca2+ sensitive to voltage dependent. Am J Physiol Lung Cell Mol Physiol 275: L1019‐L1025, 1998.
 224. Reeves JT. High adventure in pulmonary hypertension: Acute and chronic hypoxia are not the same. Am J Respir Crit Care Med 166: 1537‐1538, 2002.
 225. Resnik E, Herron J, Fu R, Ivy DD, Cornfield DN. Oxygen tension modulates the expression of pulmonary vascular BKCa channel alpha‐ and beta‐subunits. Am J Physiol Lung Cell Mol Physiol 290: L761‐L768, 2006.
 226. Rhodes J. Comparative physiology of hypoxic pulmonary hypertension: Historical clues from brisket disease. J Appl Physiol 98: 1092‐1100, 2005.
 227. Rhodes MT, Porter VA, Saqueton CB, Herron JM, Resnik ER, Cornfield DN. Pulmonary vascular response to normoxia and KCa channel activity is developmentally regulated. Am J Physiol Lung Cell Mol Physiol 280: L1250‐L1257, 2001.
 228. Rickett GM, Kelly FJ. Developmental expression of antioxidant enzymes in guinea pig lung and liver. Development 108: 331‐336, 1990.
 229. Rosenberg AA, Kennaugh J, Koppenhafer SL, Loomis M, Chatfield BA, Abman SH. Elevated immunoreactive endothelin‐1 levels in newborn infants with persistent pulmonary hypertension. J Pediatr 123: 109‐114, 1993.
 230. Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ. Effects of long‐term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 46: 697‐704, 2005.
 231. Rurak DW, Richardson BS, Patrick JE, Carmichael L, Homan J. Blood flow and oxygen delivery to fetal organs and tissues during sustained hypoxemia. Am J Physiol Regul Integr Comp Physiol 258: R1116‐R1122, 1990.
 232. Ryu J, Vicencio AG, Yeager ME, Kashgarian M, Haddad GG, Eickelberg O. Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development. Thromb Haemost 94: 175‐183, 2005.
 233. Saqueton CB, Miller RB, Porter VA, Milla CE, Cornfield DN. NO causes perinatal pulmonary vasodilation through K+‐channel activation and intracellular Ca2+ release. Am J Physiol Lung Cell Mol Physiol 276: L925‐L932, 1999.
 234. Sartori C, Allemann Y, Trueb L, Delabays A, Nicod P, Scherrer U. Augmented vasoreactivity in adult life associated with perinatal vascular insult. Lancet 353: 2205‐2207, 1999.
 235. Schneider MP, Boesen EI, Pollock DM. Contrasting actions of endothelin ETA and ETB receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol 47: 731‐759, 2007.
 236. Schindler MB, Hislop AA, Haworth SG. Porcine pulmonary artery and bronchial responses to endothelin‐1 and norepinephrine on recovery from hypoxic pulmonary hypertension. Pediatr Res 60: 1‐6, 2006.
 237. Schindler MB, Hislop AA, Haworth SG. Postnatal changes in pulmonary vein responses to endothelin‐1 in the normal and chronically hypoxic lung. Am J Physiol Lung Cell Mol Physiol 292: L1273‐L1279, 2007.
 238. Sethy‐Coraci I, Crock LW, Silverstein SC. PAF‐receptor antagonists, lovastatin, and the PTK inhibitor genistein inhibit H2O2 secretion by macrophages cultured on oxidized‐LDL matrices. J Leukoc Biol 78: 1166‐1174, 2005.
 239. Shaul PW, Afshar S, Gibson LL, Sherman TS, Kerecman JD, Grubb PH, Yoder BA, McCurnin DC. Developmental changes in nitric oxide synthase isoform expression and nitric oxide production in fetal baboon lung. Am J Physiol Lung Cell Mol Physiol 283: L1192‐L1199, 2002.
 240. Shaul PW, Campbell WB, Farrar MA, Magness RR. Oxygen modulates prostacyclin synthesis in ovine fetal pulmonary arteries by an effect on cyclooxygenase. J Clin Invest 90: 2147‐2155, 1992.
 241. Shaul PW, Farrar MA, Magness RR. Oxygen modulation of pulmonary arterial prostacyclin synthesis is developmentally regulated. Am J Physiol Heart Circ Physiol 265: H621‐H628, H1056‐H1063, 1993.
 242. Shaul PW, Farrar MA, Magness RR. Pulmonary endothelial nitric oxide production is developmentally regulated in the fetus and newborn. Am J Physiol Heart Circ Physiol 265: H1056‐H1063, 1993.
 243. Shichiri M, Yokokura M, Marumo F, Hirata Y. Endothelin‐1 inhibits apoptosis of vascular smooth muscle cells induced by nitric oxide and serum deprivation via MAP kinase pathway. Arterioscler Thromb Vasc Biol 20: 989‐997, 2000.
 244. Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL. HIF‐1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 291: L941‐L949, 2006.
 245. Shimokawa H, Takeshita A. Rho‐kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 25: 1767‐1775, 2005.
 246. Short M, Nemenoff RA, Zawada WM, Stenmark KR, Das M. Hypoxia induces differentiation of pulmonary artery adventitial fibroblasts into myofibroblasts. Am J Physiol Cell Physiol 286: C416–C425, 2004.
 247. Sobin SS, Tremer HM, Hardy JD, Chiodi HP. Changes in arteriole in acute and chronic hypoxic pulmonary hypertension and recovery in rat. J Appl Physiol 55: 1445‐1455, 1983.
 248. Spitzer AR, Davis J, Clarke WT, Bernbaum J, Fox WW. Pulmonary hypertension and persistent fetal circulation in the newborn. Clin Perinatol 15: 389‐413, 1988.
 249. Steinhorn RH, Farrow KN. Pulmonary hypertension in the neonate. NeoReviews 8: e14‐e21, 2007.
 250. Steinhorn RH, Morin FC III, Gugino SF, Giese EC, Russell JA. Developmental differences in endothelium‐dependent responses in isolated ovine pulmonary arteries and veins. Am J Physiol Heart Circ Physiol 264: H2162‐H2167, 1993.
 251. Stenmark KR, Abman SH. Lung vascular development: Implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol 67: 623‐661, 2005.
 252. Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda) 21: 134‐145, 2006.
 253. Stenmark KR, Fagan KA, Frid MG. Hypoxia‐induced pulmonary vascular remodeling: Cellular and molecular mechanisms. Circ Res 99: 675‐691, 2006.
 254. Stenmark KR, Fasules J, Hyde DM, Voelkel NF, Henson J, Tucker A, Wilson H, Reeves JT. Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m. J Appl Physiol 62: 821‐830, 1987.
 255. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: The hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 297: L1013‐L1032, 2009.
 256. Stiebellehner L, Belknap JK, Ensley B, Tucker A, Orton EC, Reeves JT, Stenmark KR. Lung endothelial cell proliferation in normal and pulmonary hypertensive neonatal calves. Am J Physiol Lung Cell Mol Physiol 275: L593–L600, 1998.
 257. Stiebellehner L, Frid MG, Reeves JT, Low RB, Gnanasekharan M, Stenmark KR. Bovine distal pulmonary arterial media is composed of a uniform population of well‐differentiated smooth muscle cells with low proliferative capabilities. Am J Physiol Lung Cell Mol Physiol 285: L819‐L828, 2003.
 258. Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T. Requirement for generation of H2O2 for platelet‐derived growth factor signal transduction. Science 270: 296‐299, 1995.
 259. Takahashi H, Soma S, Muramatsu M, Oka M, Fukuchi Y. Upregulation of ET‐1 and its receptors and remodeling in small pulmonary veins under hypoxic conditions. Am J Physiol Lung Cell Mol Physiol 280: L1104‐L1114, 2001.
 260. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK. Rho‐kinase mediates hypoxia‐induced downregulation of endothelial nitric oxide synthase. Circulation 106: 57‐62, 2002.
 261. Tiktinsky MH, Morin FC III. Increasing oxygen tension dilates fetal pulmonary circulation via endothelium‐derived relaxing factor. Am J Physiol Heart Circ Physiol 265: H376–H380, 1993.
 262. Tolsa J‐F, Gao Y, Raj JU. Magnesium sulphate relaxes newborn rabbit pulmonary arteries by reducing calcium entry. J Appl Physiol 87: 1589‐1594, 1999.
 263. Tolsa J‐F, Gao Y, Sander FC, Souici A‐C, Moessinger A, Raj JU. Differential responses of pulmonary arteries and veins of newborn lamb to atrial and C‐type natriuretic peptides. Am J Physiol Heart Circ Physiol 282: H273‐H280, 2002.
 264. Tucker A, McMurtry IF, Reeves JT, Alexander AF, Will DH, Grover RF. Lung vascular smooth muscle as a determinant of pulmonary hypertension at high altitude. Am J Physiol 228: 762‐767, 1975.
 265. Tucker A, Migally N, Wright ML, Greenlees KJ. Pulmonary vascular changes in young and aging rats exposed to 5,486 m altitude. Respiration 46: 246‐257, 1984.
 266. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 54: S3‐S9, 2009.
 267. Tulloh RM, Hislop AA, Boels PJ, Deutsch J, Haworth SG. Chronic hypoxia inhibits postnatal maturation of porcine intrapulmonary artery relaxation. Am J Physiol 272: 2436‐2445, 1997.
 268. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: Dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 24: 1023‐1030, 2004.
 269. Vicencio AG, Eickelberg O, Stankewich MC, Kashgarian M, Haddad GG. Regulation of TGF‐β ligand and receptor expression in neonatal rat lungs exposed to chronic hypoxia. J Appl Physiol 93: 1123‐1130, 2002.
 270. Villalobo A. Nitric oxide and cell proliferation. FEBS J 273: 2329‐2344, 2006.
 271. Villanueva ME, Zaher FM, Svinarich DM, Konduri GG. Decreased gene expression of endothelial nitric oxide synthase in newborns with persistent pulmonary hypertension. Pediatr Res 44, 338‐43, 1998.
 272. Wagenvoort CA, Wagenvoort N. Pulmonary venous changes in chronic hypoxia. Virchows Arch 372: 51‐56, 1976.
 273. Walsh‐Sukys MC. Persistent pulmonary hypertension of the newborn. The black box revisited. Clin Perinatol 20: 127‐143, 1993.
 274. Walsh‐Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, Verter J, Stoll BJ, Lemons JA, Papile LA, Shankaran S, Donovan EF, Oh W, Ehrenkranz RA, Fanaroff AA. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcomes. Pediatrics 105: 14‐20, 2000.
 275. Walther FJ, Wade AB, Warburton D, Forman HJ. Ontogeny of antioxidant enzymes in the fetal lamb lung. Exp Lung Res 17: 39‐45, 1991.
 276. Wang D, Chang PS, Wang Z, Sutherland L, Richardson JA, Small E, Krieg PA, Olson EN. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105: 851‐862, 2001.
 277. Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL, Shimoda LA. Hypoxia inducible factor 1 mediates hypoxia‐induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circ Res 98: 1528‐1537, 2006.
 278. Wang Y, Coceani F. Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin‐1. Circ Res 71: 320‐330, 1992.
 279. Wang Y, Deng X, Hewavitharana T, Soboloff J, Gill DL. Stim, ORAI and TRPC channels in the control of calcium entry signals in smooth muscle. Clin Exp Pharmacol Physiol 35: 1127‐1133, 2008.
 280. Wang Z, Jin N, Ganguli S, Swartz DR, Li L, Rhoades RA. Rho‐kinase activation is involved in hypoxia‐induced pulmonary vasoconstriction. Am J Respir Cell Mol Biol 25: 628‐635, 2001.
 281. Ward JP. Oxygen sensors in context. Biochim Biophys Acta 1777: 1‐14, 2008.
 282. Ward JP, McMurtry IF. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: New findings for an old problem. Curr Opin Pharmacol 9: 287‐296, 2009.
 283. Waypa GB, Chandel NS, Schumacker PT. Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circ Res 88: 1259‐1266, 2001.
 284. Waypa GB, Schumacker PT. Oxygen sensing in hypoxic pulmonary vasoconstriction: Using new tools to answer an age‐old question. Exp Physiol 93: 133‐138, 2008.
 285. Wedegärtner U, Tchirikov M, Schäfer S, Priest AN, Kooijman H, Adam G, Schröder HJ. Functional MR imaging: Comparison of BOLD signal intensity changes in fetal organs with fetal and maternal oxyhemoglobin saturation during hypoxia in sheep. Radiology 238: 872‐880, 2006.
 286. Wedgwood S, Black SM. Induction of apoptosis in fetal pulmonary arterial smooth muscle cells by a combined superoxide dismutase/catalase mimetic. Am J Physiol Lung Cell Mol Physiol 285: L305‐L312, 2003.
 287. Wedgwood S, Black SM. Molecular mechanisms of nitric oxide‐induced growth arrest and apoptosis in fetal pulmonary arterial smooth muscle cells. Nitric Oxide 9: 201‐210, 2003.
 288. Wedgwood S, Black SM. Combined superoxide dismutase/catalase mimetics alter fetal pulmonary arterial smooth muscle cell growth. Antioxid Redox Signal 6: 191‐197, 2004.
 289. Wedgwood S, Black SM. Endothelin‐1 decreases endothelial NOS expression and activity through ETA receptor‐mediated generation of hydrogen peroxide. Am J Physiol Lung Cell Mol Physiol 288: L480‐L487, 2005.
 290. Wedgwood S, Dettman RW, Black SM. ET‐1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol 281: L1058‐L1067, 2001.
 291. Wilkening RB, Meschia G. Fetal oxygen uptake, oxygenation and acid‐base balance as a function of uterine blood flow. Am J Physiol Heart Circ Physiol 244: H749‐H755, 1983.
 292. Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitors for the treatment of pulmonary hypertension. Eur Respir J 32: 198‐209, 2008.
 293. Wladimiroff JW, Tonge HM, Stewart P. A Doppler ultrasound assessment of cerebral blood flow in the human fetus. Br J Obstet Gynaecol 93: 471‐475, 1986.
 294. Wohrley JD, Frid MG, Moiseeva EP, Orton EC, Belknap JK, Stenmark KR. Hypoxia selectively induces proliferation in a specific subpopulation of smooth muscle cells in the bovine neonatal pulmonary arterial media. J Clin Invest 96: 273‐281, 1995.
 295. Wu‐Wong JR, Chiou WJ, Dickinson R, Opgenorth TJ. Endothelin attenuates apoptosis in human smooth muscle cells. Biochem J 328: 733‐737, 1997.
 296. Xue C, Reynolds PR, Johns RA. Developmental expression of NOS isoforms in fetal rat lung: Implications for transitional circulation and pulmonary angiogenesis. Am J Physiol Lung Cell Mol Physiol 270: L88‐Ll00, 1996.
 297. Xue Q, Ducsay CA, Longo LD, Zhang L. Effect of long‐term high‐altitude hypoxia on fetal pulmonary vascular contractility. J Appl Physiol 104: 1786‐1792, 2008.
 298. Yoshida T, Sinha S, Dandre F, Wamhoff BR, Hoofnagle MH, Kremer BE, Wang DZ, Olson EN, Owens GK. Myocardin is a key regulator of CArG‐dependent transcription of multiple smooth muscle marker genes. Circ Res 92: 856‐864, 2003.
 299. Young KA, Ivester C, West J, Carr M, Rodman DM. BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 290: L841‐L848, 2006.
 300. Young KC, Torres E, Hatzistergos KE, Hehre D, Suguihara C, Hare JM. Inhibition of the SDF‐1/CXCR4 axis attenuates neonatal hypoxia‐induced pulmonary hypertension. Circ Res 104: 1293‐1301, 2009
 301. Yu L, Quinn DA, Garg HG, Hales CA. Deficiency of the NHE1 gene prevents hypoxia‐induced pulmonary hypertension and vascular remodeling. Am J Respir Crit Care Med 177: 1276‐1284, 2008.
 302. Zamora MR, Stelzner TJ, Webb S, Panos RJ, Ruff LJ, Dempsey EC. Overexpression of endothelin‐1 and enhanced growth of pulmonary artery smooth muscle cells from fawn‐hooded rats. Am J Physiol Lung Cell Mol Physiol 270: L101‐L109, 1996.
 303. Zamudio S, Droma T, Norkyel KY, Acharya G, Zamudio JA, Niermeyer SN, Moore LG. Protection from intrauterine growth retardation in Tibetans at high altitude. Am J Phys Anthropol 91: 215‐224, 1993.
 304. Zhao Y, Packer CS, Rhoades RA. Pulmonary vein contracts in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 265: L87‐L92, 1993.
 305. Zheng YM, Wang QS, Liu QH, Rathore R, Yadav V, Wang YX. Heterogeneous gene expression and functional activity of ryanodine receptors in resistance and conduit pulmonary as well as mesenteric artery smooth muscle cells. J Vasc Res 45: 469‐479, 2008.
 306. Zheng YM, Wang QS, Rathore R, Zhang WH, Mazurkiewicz JE, Sorrentino V, Singer HA, Kotlikoff MI, Wang YX. Type‐3 ryanodine receptors mediate hypoxia‐, but not neurotransmitter‐induced calcium release and contraction in pulmonary artery smooth muscle cells. J Gen Physiol 125: 427‐440, 2005.
 307. Zhou W, Dasgupta C, Negash S, Raj JU. Modulation of pulmonary vascular smooth muscle cell phenotype in hypoxia: Role of cGMP‐dependent protein kinase. Am J Physiol Lung Cell Mol Physiol 292: L1459–L1466, 2007.
 308. Zhou W, Ibe BO, Raj JU. Platelet‐activating factor induces ovine fetal pulmonary venous smooth muscle cell proliferation: Role of epidermal growth factor receptor transactivation. Am J Physiol Heart Circ Physiol 292: H2773‐H2781, 2007.
 309. Zhou W, Negash S, Liu J, Raj JU. Modulation of pulmonary vascular smooth muscle cell phenotype in hypoxia: role of cGMP‐dependent protein kinase and myocardin. Am J Physiol Lung Cell Mol Physiol, 296: L780‐L789, 2009.
 310. Ziino AJ, Ivanovska J, Belcastro R, Kantores C, Xu EZ, Lau M, McNamara PJ, Tanswell AK, Jankov RP. Effects of Rho‐kinase inhibition on pulmonary hypertension, lung growth and structure in neonatal rats chronically exposed to hypoxia. Pediatr Res 67: 177‐182, 2010.

Related Articles:

Pulmonary Vascular Disease

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Hypoxic Pulmonary Hypertension of the Newborn
 

How to Cite

Yuansheng Gao, J Usha Raj. Hypoxic Pulmonary Hypertension of the Newborn. Compr Physiol 2010, 1: 61-79. doi: 10.1002/cphy.c090015