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Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction

Bhavisha A. Bakrania, Frank T. Spradley, Heather A. Drummond, Babbette LaMarca, Michael J. Ryan, Joey P. Granger

10.1002/cphy.c200008

Source: Volume 11, Issue 1, January 2021

Published online: December 2020

Full Article on Wiley Online Library



Abstract

Preeclampsia (PE), a hypertensive disorder, occurs in 3% to 8% of pregnancies in the United States and affects over 200,000 women and newborns per year. The United States has seen a 25% increase in the incidence of PE, largely owing to increases in risk factors, including obesity and cardiovascular disease. Although the etiology of PE is not clear, it is believed that impaired spiral artery remodeling of the placenta reduces perfusion, leading to placental ischemia. Subsequently, the ischemic placenta releases antiangiogenic and pro‐inflammatory factors, such as cytokines, reactive oxygen species, and the angiotensin II type 1 receptor autoantibody (AT1‐AA), among others, into the maternal circulation. These factors cause widespread endothelial activation, upregulation of the endothelin system, and vasoconstriction. In turn, these changes affect the function of multiple organ systems including the kidneys, brain, liver, and heart. Despite extensive research into the pathophysiology of PE, the only treatment option remains early delivery of the baby and importantly, the placenta. While premature delivery is effective in ameliorating immediate risk to the mother, mounting evidence suggests that PE increases risk of cardiovascular disease later in life for both mother and baby. Notably, these women are at increased risk of hypertension, heart disease, and stroke, while offspring are at risk of obesity, hypertension, and neurological disease, among other complications, later in life. This article aims to discuss the current understanding of the diagnosis and pathophysiology of PE, as well as associated organ damage, maternal and fetal outcomes, and potential therapeutic avenues. © 2021 American Physiological Society. Compr Physiol 11:1315‐1349, 2021.

Figure 1. Figure 1. Rates of preeclampsia over the past decades. This figure illustrates the rates of preeclampsia (PE) in 1980 and 2010. These rates may be influenced by the change in definition of PE over time but are also certainly affected by the global increase in risk factors for this disease, including obesity and preexisting cardiovascular disease. Notably, rates of severe PE have significantly increased since 1980. Adapted from Ananth CV, et al., 2013 22.
Figure 2. Figure 2. Hemodynamic changes during normal pregnancy. This figure illustrates the gradual increase of cardiac output (CO; circles) and a gradual decrease in mean arterial pressure (MAP; squares) over the first and second trimesters of normal pregnancy. Data are presented as mean ± SEM. Adapted from Moutquin JM, et al., 1985 233.
Figure 3. Figure 3. Uterine artery resistance in humans and an animal model of superimposed preeclampsia. This figure illustrates the difference between Doppler waveforms (velocity) during normal pregnancy and preeclampsia (PE) in (A) humans and (B) rats. In normal pregnancy, resistance in uterine arteries is low as evidenced by high peak during systole followed by a fall during diastole. In contrast, Doppler waveforms from PE pregnancies have a peak during systole followed by a sharp fall during diastole. The arrows in the figure indicate the characteristic notch found in PE and the rat model of superimposed PE (Dahl S Rat). Adapted from McLeod L, 2008 219 and Gillis EE, et al., 2015 119.
Figure 4. Figure 4. Illustrations of mature placenta in rodents and humans. This figure illustrates the differences between the (A) rodent and (B) human placenta. Rodent models of preeclampsia are valuable tools in understanding the pathogenesis of this maternal disorder. The decidua on the “maternal side” can be seen housing the spiral arteries in both placentas. The “fetal side,” closest to the umbilical cord, in the rodent is termed the labyrinth, and the villous layer in the humans. Villi form large surface areas where nutrient/gas exchange can occur between mother and baby. In terms of vascular anatomy, human spiral arteries drain directly into the intervillous space to surround the villi and allow for this nutrient/waste exchange to occur. In rodents, spiral arteries converge into one or more canals that pass through the junctional zone to the base of the villous layer and then branch out to feed the sinusoid/intervillous spaces. Adapted from Rai and Cross, 2014 273.
Figure 5. Figure 5. Illustrations of spiral artery remodeling during normal pregnancy and attenuation of this process in preeclampsia. Spiral arteries are depicted during nonpregnancy (left panel), mid‐to‐late gestation during normal pregnancy (middle panel), and preeclampsia (PE) (right panel). Spiral arteries originate in the myometrium and proceed through the endometrium. Placentation during normal pregnancy is noted by decidualization and significant changes to stromal cells of the uterus, and spiral artery remodeling, which involves invasion of fetal‐derived cytotrophoblast cells. Early trophoblast lineages fuse to form the overlying and multinucleated syncytiotrophoblast layer that progressively invades the uterus and forms the barrier between maternal blood and the fetal capillaries. These capillaries are developed via vasculogenesis and are housed within the placental villi. Villi are floating or anchored to the uterine wall. The cytotrophoblasts within the anchoring villous column break through the syncytium and eventually depolarize into extravillous (interstitial) trophoblast cells. The latter cells invade and replace the vascular smooth muscle and endothelium of the spiral arteries of the endometrium and the first third of the myometrium while becoming endovascular trophoblast cells. The spiral arteries are remodeled to form conduits promoting blood flow toward the intervillous space to surround and deliver oxygen and nutrients to the placental villi. Attenuations in this process promote placental ischemia and PE. Recent research indicates that resident decidual natural killer cells secrete factors that promote trophoblast function and remodel the spiral arteries, which is reduced in PE. SpA, spiral artery; ArcA, arcuate artery; RadA, radial artery; ES, endometrial stroma; EC, endothelial cells; VSMC, vascular smooth muscle cell; UE, uterine epithelium; EVT, extravillous trophoblast; dNK, decidual natural killer cell; EndoT, endovascular trophoblast; SynT, syncytial trophoblast; FC, fetal capillary.
Figure 6. Figure 6. Angiotensin II Type 1 receptor autoantibodies are increased in preeclampsia. Panel (A) illustrates that levels of the agonistic angiotensin II type 1 receptor autoantibody (AT1‐AA) are significantly increased in serum from preeclamptic women. For these data, spontaneous beating of neonatal rat cardiomyocytes in response to serum exposure was used. Panel (B) shows that when the AT1‐AA, which is elevated in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia (PE), is inhibited (with “n7AAc”), mean arterial pressure (MAP) is reduced, suggesting that AT1‐AA has a role in increasing blood pressure in PE. Data are mean + SEM. *P < 0.05. Adapted from Wallukat G, et al., 2008 359 and Cunningham MW, et al., 2018 71.
Figure 7. Figure 7. Role of immune factors in the development of endothelial dysfunction in preeclampsia. This figure illustrates that pro‐inflammatory T‐ and B‐cell activation results in elevated prohypertensive cytokines and the angiotensin II type 1 receptor autoantibody (AT1‐AA). These factors cause endothelial dysfunction by increasing endothelin‐1 (ET‐1) production and reducing nitric oxide (NO) bioavailability.
Figure 8. Figure 8. Endothelial dysfunction in placental ischemic rats. (A) This figure illustrates blunted endothelial‐dependent vasorelaxation in response to increasing concentrations of acetylcholine (Ach) in phenylephrine (Phe)‐constricted aortic tissue isolated from rats with reduced uterine perfusion pressure (RUPP). (B) ACh at these concentrations induces NO production in normal pregnancy, and this effect is attenuated in aortic strips from placental ischemic rats. Data are mean ± SEM. *P < 0.05 versus pregnant. Adapted from Barron LA, et al., 2001 39.
Figure 9. Figure 9. Endothelin type A receptor blockade reduces blood pressure in animal models of preeclampsia. This figure illustrates that endothelin type A (ETA) antagonism reduces mean arterial pressure (MAP) in (A) the reduced uterine perfusion pressure (RUPP) model and (B) the sFlt‐1 infusion (sFlt‐1) model of preeclampsia. Data are mean + SEM. *P < 0.05 versus pregnant. **P < 0.05 versus sFlt‐1/RUPP. Adapted from Murphy S, et al., 2010 236 and Alexander B, et al., 2001 11.
Figure 10. Figure 10. Circulating levels of angiogenic factors in preeclampsia. These data depict the antiangiogenic environment that exists in preeclampsia (PE), whereby (A) sFlt‐1 is increased and (B) free vascular endothelial growth factor (VEGF) and (C) placental growth factor (PlGF) are decreased. Importantly, these changes are exaggerated as the severity of PE increases. Data are mean ± SEM. *P < 0.05 versus Mild. **P < 0.05 versus Severe. Adapted from Maynard SE, et al., 2003 215.
Figure 11. Figure 11. Factors that impact endothelial dysfunction in preeclampsia. This figure illustrates the development of endothelial dysfunction and hypertension in preeclampsia. The release of factors from the ischemic placenta, such as antiangiogenic factors, reactive oxygen species (ROS), matrix metalloproteinases (MMPs), angiotensin II type 1 receptor autoantibody (AT1‐AA), and pro‐inflammatory cytokines, play a central role in depleting nitric oxide (NO) bioavailability and increasing endothelin‐1 (ET‐1) production, which drives this prohypertensive pathway.
Figure 12. Figure 12. The development of renal dysfunction in preeclampsia. This figure illustrates the development of renal injury and dysfunction in preeclampsia, resulting in hypertension and proteinuria. Endothelial cell dysfunction and damage in the kidney leads to increased renal vascular resistance, impaired pressure natriuresis, hypertension, and proteinuria.
Figure 13. Figure 13. Elevated sFlt‐1 induces a preeclampsia‐like phenotype in rats. This figure illustrates that rats injected with sFlt‐1 (via sFlt‐1‐adenovirus construct) develop (A) elevated mean arterial pressure (MAP) and (B) proteinuria, as measured by urine albumin/creatinine, compared to controls (Fc). Data are presented as mean + SEM. *P < 0.05. Adapted from Maynard SE, et al., 2003 215.
Figure 14. Figure 14. Elevated sFlt‐1 causes fibrin deposition in the glomeruli of rats. This figure illustrates fibrin deposition within the glomeruli of rats treated with sFlt‐1 (sFlt‐1) compared to control rats (Fc). Electron microscopy (EM) from an sFlt1‐treated rat confirms glomerular injury. Immunofluorescence (IF) for fibrin shows foci of fibrin deposition in glomeruli of sFlt1 rats. The IF images were collected at 40×, and the EM images were collected at 2400× magnification. Adapted from Maynard SE, et al., 2003 215.
Figure 15. Figure 15. The development of cerebral dysfunction in preeclampsia. Hypertension and placental factors in preeclampsia cause cerebrovascular dysfunction, resulting in impaired cerebral blood flow autoregulation, vessel rupture, and blood brain barrier permeability, leading to hemorrhagic shock and cerebral edema.
Figure 16. Figure 16. Autoregulation in human preeclampsia. This figure illustrates middle cerebral artery blood flow autoregulation in normal and preeclamptic pregnancy at 35 to 37 weeks of gestation and shows that the autoregulatory index is impaired in preeclampsia. Data are mean + SD. *P < 0.05. Adapted from Van Veen TR, et al., 2013 349.
Figure 17. Figure 17. Blood‐brain permeability in placental ischemic rats. This figure illustrates increased blood‐brain permeability in (A) cerebrum and (B) anterior cerebrum of reduced uterine perfusion pressure (RUPP)‐operated rats, as measured by extravasation of Evans blue dye. Data are presented as mean + SEM. *P < 0.05. Adapted from Warrington JP, et al., 2015 363.
Figure 18. Figure 18. Cerebral blood flow and autoregulation index in placental ischemic rats. This figure illustrates that (A) cerebral blood flow (CBF), as measured by laser Doppler flowmetry, and (B) autoregulation are significantly impaired in placental ischemic rats (reduced uterine perfusion pressure; RUPP), as evidenced by increases in blood flow at elevated mean arterial pressures (MAP). Data are mean ± SEM. *P < 0.05 versus pregnant, **P < 0.01 versus pregnant. Adapted from Warrington JP, et al., 2014 365.
Figure 19. Figure 19. Vascular myogenic tone in placental ischemic rats. This figure illustrates that the relationship between middle cerebral artery tone and pressure is blunted in reduced uterine perfusion pressure (RUPP) rats compared to nonpregnant and normal pregnant rats. Data are presented as mean ± SEM. Adapted from Ryan MJ, et al., 2011 291.
Figure 20. Figure 20. Global longitudinal strain in humans and placental ischemic rats. This figure illustrates the development of cardiac global longitudinal strain (GLS) in humans and in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia (PE). Importantly, Panel (A) also shows significantly reduced GLS in PE compared to nonproteinuric hypertension (gestational hypertension), suggesting more than hypertension (potentially placental factors) plays a role. In animal models, cardiac dysfunction typically only emerges after 2 weeks in hypertensive models; therefore, data in the RUPP rat in Panel (B) also suggests that placental factors could play a role in the development of cardiac dysfunction in PE. The lower (25th percentile) and upper (75th percentile) limits of each box represent the interquartile range; the line across the box indicates the median. The lowest and highest values within 1.5 interquartile ranges below and above the interquartile range are indicated by the whiskers. Dots represent values that lie outside this range. *P < 0.05. Adapted from Shahul S, et al., 2012 302 and Bakrania BA, et al., 2019 34.
Figure 21. Figure 21. Factors involved in long‐term cardiovascular risk in offspring from preeclamptic pregnancies. This figure illustrates how fetal programming leads to increased risk of cardiovascular, metabolic, and neurological disease in infants and adults born from preeclamptic pregnancies. SNS, sympathetic nervous system; RAAS, renin angiotensin aldosterone system. Adapted from Alexander BT, et al., 2015 15.
Figure 22. Figure 22. Schematic of the pathogenesis of preeclampsia. This figure illustrates the pathways involved in the pathophysiology of preeclampsia (PE), from abnormal placentation to the development of hypertension and end‐organ dysfunction and injury. Phase 1 of the pathogenesis of PE involves impaired and shallow cytotrophoblast invasion, resulting in impaired spiral artery remodeling, poor placental perfusion, and placental ischemia. Phase 2 is clinical manifestation, which presents >20 weeks of gestation. As a result of placental ischemia, several factors are released into the maternal circulation causing widespread endothelial dysfunction, hypertension, and multiorgan dysfunction. It is important to note that hypertension is the only symptom that occurs in every incidence of PE and is typically coupled with other disturbances/organ dysfunction. NF‐κB, nuclear factor‐kappa B; Th, T helper cell; NK, natural killer cell; dNK, decidual natural killer cell; HLA‐C, human leukocyte antigen‐C; MMP, matrix metalloproteinases; C3, complement 3; SNPs, single nucleotide polymorphisms; FLT‐1, fms‐like tyrosine kinase‐1; sFlt‐1, soluble Flt‐1; sEng, soluble endoglin; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; ROS, reactive oxygen species; AT1‐AA, angiotensin II Type 1 receptor autoantibody; Tregs, T regulatory cells; IL, interleukin; TNF‐α, tumor necrosis factor‐α; ET, endothelin; NO, nitric oxide; IUGR, intrauterine growth restriction.


Figure 1. Rates of preeclampsia over the past decades. This figure illustrates the rates of preeclampsia (PE) in 1980 and 2010. These rates may be influenced by the change in definition of PE over time but are also certainly affected by the global increase in risk factors for this disease, including obesity and preexisting cardiovascular disease. Notably, rates of severe PE have significantly increased since 1980. Adapted from Ananth CV, et al., 2013 22.


Figure 2. Hemodynamic changes during normal pregnancy. This figure illustrates the gradual increase of cardiac output (CO; circles) and a gradual decrease in mean arterial pressure (MAP; squares) over the first and second trimesters of normal pregnancy. Data are presented as mean ± SEM. Adapted from Moutquin JM, et al., 1985 233.


Figure 3. Uterine artery resistance in humans and an animal model of superimposed preeclampsia. This figure illustrates the difference between Doppler waveforms (velocity) during normal pregnancy and preeclampsia (PE) in (A) humans and (B) rats. In normal pregnancy, resistance in uterine arteries is low as evidenced by high peak during systole followed by a fall during diastole. In contrast, Doppler waveforms from PE pregnancies have a peak during systole followed by a sharp fall during diastole. The arrows in the figure indicate the characteristic notch found in PE and the rat model of superimposed PE (Dahl S Rat). Adapted from McLeod L, 2008 219 and Gillis EE, et al., 2015 119.


Figure 4. Illustrations of mature placenta in rodents and humans. This figure illustrates the differences between the (A) rodent and (B) human placenta. Rodent models of preeclampsia are valuable tools in understanding the pathogenesis of this maternal disorder. The decidua on the “maternal side” can be seen housing the spiral arteries in both placentas. The “fetal side,” closest to the umbilical cord, in the rodent is termed the labyrinth, and the villous layer in the humans. Villi form large surface areas where nutrient/gas exchange can occur between mother and baby. In terms of vascular anatomy, human spiral arteries drain directly into the intervillous space to surround the villi and allow for this nutrient/waste exchange to occur. In rodents, spiral arteries converge into one or more canals that pass through the junctional zone to the base of the villous layer and then branch out to feed the sinusoid/intervillous spaces. Adapted from Rai and Cross, 2014 273.


Figure 5. Illustrations of spiral artery remodeling during normal pregnancy and attenuation of this process in preeclampsia. Spiral arteries are depicted during nonpregnancy (left panel), mid‐to‐late gestation during normal pregnancy (middle panel), and preeclampsia (PE) (right panel). Spiral arteries originate in the myometrium and proceed through the endometrium. Placentation during normal pregnancy is noted by decidualization and significant changes to stromal cells of the uterus, and spiral artery remodeling, which involves invasion of fetal‐derived cytotrophoblast cells. Early trophoblast lineages fuse to form the overlying and multinucleated syncytiotrophoblast layer that progressively invades the uterus and forms the barrier between maternal blood and the fetal capillaries. These capillaries are developed via vasculogenesis and are housed within the placental villi. Villi are floating or anchored to the uterine wall. The cytotrophoblasts within the anchoring villous column break through the syncytium and eventually depolarize into extravillous (interstitial) trophoblast cells. The latter cells invade and replace the vascular smooth muscle and endothelium of the spiral arteries of the endometrium and the first third of the myometrium while becoming endovascular trophoblast cells. The spiral arteries are remodeled to form conduits promoting blood flow toward the intervillous space to surround and deliver oxygen and nutrients to the placental villi. Attenuations in this process promote placental ischemia and PE. Recent research indicates that resident decidual natural killer cells secrete factors that promote trophoblast function and remodel the spiral arteries, which is reduced in PE. SpA, spiral artery; ArcA, arcuate artery; RadA, radial artery; ES, endometrial stroma; EC, endothelial cells; VSMC, vascular smooth muscle cell; UE, uterine epithelium; EVT, extravillous trophoblast; dNK, decidual natural killer cell; EndoT, endovascular trophoblast; SynT, syncytial trophoblast; FC, fetal capillary.


Figure 6. Angiotensin II Type 1 receptor autoantibodies are increased in preeclampsia. Panel (A) illustrates that levels of the agonistic angiotensin II type 1 receptor autoantibody (AT1‐AA) are significantly increased in serum from preeclamptic women. For these data, spontaneous beating of neonatal rat cardiomyocytes in response to serum exposure was used. Panel (B) shows that when the AT1‐AA, which is elevated in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia (PE), is inhibited (with “n7AAc”), mean arterial pressure (MAP) is reduced, suggesting that AT1‐AA has a role in increasing blood pressure in PE. Data are mean + SEM. *P < 0.05. Adapted from Wallukat G, et al., 2008 359 and Cunningham MW, et al., 2018 71.


Figure 7. Role of immune factors in the development of endothelial dysfunction in preeclampsia. This figure illustrates that pro‐inflammatory T‐ and B‐cell activation results in elevated prohypertensive cytokines and the angiotensin II type 1 receptor autoantibody (AT1‐AA). These factors cause endothelial dysfunction by increasing endothelin‐1 (ET‐1) production and reducing nitric oxide (NO) bioavailability.


Figure 8. Endothelial dysfunction in placental ischemic rats. (A) This figure illustrates blunted endothelial‐dependent vasorelaxation in response to increasing concentrations of acetylcholine (Ach) in phenylephrine (Phe)‐constricted aortic tissue isolated from rats with reduced uterine perfusion pressure (RUPP). (B) ACh at these concentrations induces NO production in normal pregnancy, and this effect is attenuated in aortic strips from placental ischemic rats. Data are mean ± SEM. *P < 0.05 versus pregnant. Adapted from Barron LA, et al., 2001 39.


Figure 9. Endothelin type A receptor blockade reduces blood pressure in animal models of preeclampsia. This figure illustrates that endothelin type A (ETA) antagonism reduces mean arterial pressure (MAP) in (A) the reduced uterine perfusion pressure (RUPP) model and (B) the sFlt‐1 infusion (sFlt‐1) model of preeclampsia. Data are mean + SEM. *P < 0.05 versus pregnant. **P < 0.05 versus sFlt‐1/RUPP. Adapted from Murphy S, et al., 2010 236 and Alexander B, et al., 2001 11.


Figure 10. Circulating levels of angiogenic factors in preeclampsia. These data depict the antiangiogenic environment that exists in preeclampsia (PE), whereby (A) sFlt‐1 is increased and (B) free vascular endothelial growth factor (VEGF) and (C) placental growth factor (PlGF) are decreased. Importantly, these changes are exaggerated as the severity of PE increases. Data are mean ± SEM. *P < 0.05 versus Mild. **P < 0.05 versus Severe. Adapted from Maynard SE, et al., 2003 215.


Figure 11. Factors that impact endothelial dysfunction in preeclampsia. This figure illustrates the development of endothelial dysfunction and hypertension in preeclampsia. The release of factors from the ischemic placenta, such as antiangiogenic factors, reactive oxygen species (ROS), matrix metalloproteinases (MMPs), angiotensin II type 1 receptor autoantibody (AT1‐AA), and pro‐inflammatory cytokines, play a central role in depleting nitric oxide (NO) bioavailability and increasing endothelin‐1 (ET‐1) production, which drives this prohypertensive pathway.


Figure 12. The development of renal dysfunction in preeclampsia. This figure illustrates the development of renal injury and dysfunction in preeclampsia, resulting in hypertension and proteinuria. Endothelial cell dysfunction and damage in the kidney leads to increased renal vascular resistance, impaired pressure natriuresis, hypertension, and proteinuria.


Figure 13. Elevated sFlt‐1 induces a preeclampsia‐like phenotype in rats. This figure illustrates that rats injected with sFlt‐1 (via sFlt‐1‐adenovirus construct) develop (A) elevated mean arterial pressure (MAP) and (B) proteinuria, as measured by urine albumin/creatinine, compared to controls (Fc). Data are presented as mean + SEM. *P < 0.05. Adapted from Maynard SE, et al., 2003 215.


Figure 14. Elevated sFlt‐1 causes fibrin deposition in the glomeruli of rats. This figure illustrates fibrin deposition within the glomeruli of rats treated with sFlt‐1 (sFlt‐1) compared to control rats (Fc). Electron microscopy (EM) from an sFlt1‐treated rat confirms glomerular injury. Immunofluorescence (IF) for fibrin shows foci of fibrin deposition in glomeruli of sFlt1 rats. The IF images were collected at 40×, and the EM images were collected at 2400× magnification. Adapted from Maynard SE, et al., 2003 215.


Figure 15. The development of cerebral dysfunction in preeclampsia. Hypertension and placental factors in preeclampsia cause cerebrovascular dysfunction, resulting in impaired cerebral blood flow autoregulation, vessel rupture, and blood brain barrier permeability, leading to hemorrhagic shock and cerebral edema.


Figure 16. Autoregulation in human preeclampsia. This figure illustrates middle cerebral artery blood flow autoregulation in normal and preeclamptic pregnancy at 35 to 37 weeks of gestation and shows that the autoregulatory index is impaired in preeclampsia. Data are mean + SD. *P < 0.05. Adapted from Van Veen TR, et al., 2013 349.


Figure 17. Blood‐brain permeability in placental ischemic rats. This figure illustrates increased blood‐brain permeability in (A) cerebrum and (B) anterior cerebrum of reduced uterine perfusion pressure (RUPP)‐operated rats, as measured by extravasation of Evans blue dye. Data are presented as mean + SEM. *P < 0.05. Adapted from Warrington JP, et al., 2015 363.


Figure 18. Cerebral blood flow and autoregulation index in placental ischemic rats. This figure illustrates that (A) cerebral blood flow (CBF), as measured by laser Doppler flowmetry, and (B) autoregulation are significantly impaired in placental ischemic rats (reduced uterine perfusion pressure; RUPP), as evidenced by increases in blood flow at elevated mean arterial pressures (MAP). Data are mean ± SEM. *P < 0.05 versus pregnant, **P < 0.01 versus pregnant. Adapted from Warrington JP, et al., 2014 365.


Figure 19. Vascular myogenic tone in placental ischemic rats. This figure illustrates that the relationship between middle cerebral artery tone and pressure is blunted in reduced uterine perfusion pressure (RUPP) rats compared to nonpregnant and normal pregnant rats. Data are presented as mean ± SEM. Adapted from Ryan MJ, et al., 2011 291.


Figure 20. Global longitudinal strain in humans and placental ischemic rats. This figure illustrates the development of cardiac global longitudinal strain (GLS) in humans and in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia (PE). Importantly, Panel (A) also shows significantly reduced GLS in PE compared to nonproteinuric hypertension (gestational hypertension), suggesting more than hypertension (potentially placental factors) plays a role. In animal models, cardiac dysfunction typically only emerges after 2 weeks in hypertensive models; therefore, data in the RUPP rat in Panel (B) also suggests that placental factors could play a role in the development of cardiac dysfunction in PE. The lower (25th percentile) and upper (75th percentile) limits of each box represent the interquartile range; the line across the box indicates the median. The lowest and highest values within 1.5 interquartile ranges below and above the interquartile range are indicated by the whiskers. Dots represent values that lie outside this range. *P < 0.05. Adapted from Shahul S, et al., 2012 302 and Bakrania BA, et al., 2019 34.


Figure 21. Factors involved in long‐term cardiovascular risk in offspring from preeclamptic pregnancies. This figure illustrates how fetal programming leads to increased risk of cardiovascular, metabolic, and neurological disease in infants and adults born from preeclamptic pregnancies. SNS, sympathetic nervous system; RAAS, renin angiotensin aldosterone system. Adapted from Alexander BT, et al., 2015 15.


Figure 22. Schematic of the pathogenesis of preeclampsia. This figure illustrates the pathways involved in the pathophysiology of preeclampsia (PE), from abnormal placentation to the development of hypertension and end‐organ dysfunction and injury. Phase 1 of the pathogenesis of PE involves impaired and shallow cytotrophoblast invasion, resulting in impaired spiral artery remodeling, poor placental perfusion, and placental ischemia. Phase 2 is clinical manifestation, which presents >20 weeks of gestation. As a result of placental ischemia, several factors are released into the maternal circulation causing widespread endothelial dysfunction, hypertension, and multiorgan dysfunction. It is important to note that hypertension is the only symptom that occurs in every incidence of PE and is typically coupled with other disturbances/organ dysfunction. NF‐κB, nuclear factor‐kappa B; Th, T helper cell; NK, natural killer cell; dNK, decidual natural killer cell; HLA‐C, human leukocyte antigen‐C; MMP, matrix metalloproteinases; C3, complement 3; SNPs, single nucleotide polymorphisms; FLT‐1, fms‐like tyrosine kinase‐1; sFlt‐1, soluble Flt‐1; sEng, soluble endoglin; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; ROS, reactive oxygen species; AT1‐AA, angiotensin II Type 1 receptor autoantibody; Tregs, T regulatory cells; IL, interleukin; TNF‐α, tumor necrosis factor‐α; ET, endothelin; NO, nitric oxide; IUGR, intrauterine growth restriction.
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Further Reading
 1.Alexander BT, Dasinger JH, Intapad S. Fetal programming and cardiovascular pathology. Compr Physiol 5: 997‐1025, 2015.
 2.Granger JP, Spradley FT, Bakrania BA. The endothelin system: A critical player in the pathophysiology of preeclampsia. Curr Hypertens Rep 20: 32, 2018.
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 5.Lu HQ, Hu R. Lasting effects of intrauterine exposure to preeclampsia on oand the underlying mechanism. Am J Perinatol Reports 09: e275‐e291, 2019.
 6.Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, challenges, and perspectives. Circ Res 124: 1094‐1112, 2019.
 7.Wang A, Rana S, Karumanchi SA. Preeclampsia: The role of angiogenic factors in its pathogenesis. Physiology 24: 147‐158, 2009.

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Article Title: Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction
 

How to Cite

Bhavisha A. Bakrania, Frank T. Spradley, Heather A. Drummond, Babbette LaMarca, Michael J. Ryan, Joey P. Granger. Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction. Compr Physiol 2020, 11: 1315-1349. doi: 10.1002/cphy.c200008