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Developmental Conditioning of the Vasculature

Geraldine F. Clough

10.1002/cphy.c140037

Source: Volume 5, Issue 1, January 2015

Published online: December 2014

Full Article on Wiley Online Library



Abstract

There is increasing evidence from epidemiological and experimental animal studies that the early life environment, of which nutrition is a key component, acts through developmental adaptive responses to set the capacity of cardiovascular and metabolic pathways to respond to physiological and pathophysiological challenges in later life. One finding that is consistent to both population studies and animal models is the propensity for such effects to induce endothelial dysfunction throughout the vascular tree, including the microvasculature. Obesity, type 2 diabetes and hypertension are associated with changes in microvascular function affecting multiple tissues and organs. These changes may be detected early, often before the onset of macrovascular disease and the development of end organ damage. Suboptimal maternal nutrition and fetal growth result in reduced microvascular perfusion and functional dilator capacity in the offspring, which together with microvascular rarefaction and remodeling serve to limit capillary recruitment, reduce exchange capacity and increase diffusion distances of metabolic substrates; they also increase local and overall peripheral resistance. This article explores how a developmentally conditioned disadvantageous microvascular phenotype may represent an important and additional risk factor for increased susceptibility to the development of cardio‐metabolic disease in adult life and considers the cell signaling pathways associated with microvascular dysfunction that may be “primed” by the maternal environment. As the microvasculature has been shown to be a potential target for early therapeutic and lifestyle intervention, this article also considers evidence for the efficacy of such strategies in humans and in animal models of the developmental origins of health and disease. © 2015 American Physiological Society. Compr Physiol 5:397‐438, 2015.

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Figure 1. Figure 1. Standardized mortality ratios for coronary heart disease for 15,726 men and women below the age of 65 years in Herefordshire, UK. Adapted from (26) redrawn from Figure 1 with permission.
Figure 2. Figure 2. Vasodilator signaling across the vascular tree. NO mediates vascular relaxation of relatively large, conduit arteries (e.g., aorta and epicardial coronary arteries), whereas EDHF plays an important role in modulating vascular tone in small, resistance arteries (e.g., small mesenteric arteries). Adapted from (437) Figure 9 with permission.
Figure 3. Figure 3. NO as a mediator during the early development of the cardiovascular system in the zebra fish. Influence of chronic exposure to SNP (1 mmol/L) on the formation of (A) the secondary loop and (B) the caudal vasculature that together give rise to the vascular bed in the tail fin in later developmental stages of the zebrafish larvae. Adapted from (359) Fig. 3 and Fig. 4 with permission.
Figure 4. Figure 4. Endothelium‐dependent dilation of rat gracilis muscle arterioles in response to receptor‐dependent and ‐independent agonists before and then after exposure to Nω‐nitro‐L‐arginine methyl ester (L‐NAME). (A) arterioles from 25‐ to 28‐day‐old rats. (B) Arterioles from 42‐ to 46‐day‐old rats. Values are means ± SEM. n = number of vessels. *P < 0.05 versus Control. (45) Figure 1 with permission.
Figure 5. Figure 5. Impact of cardiovascular risk factors on the microvasculature.
Figure 6. Figure 6. Scatter plots for the relationship between microvascular exchange capacity (Kf) and visceral fat, HbA1c and insulin mediated glucose disposal (M/I) from 39 individuals with central obesity. Kf was negatively associated with visceral fat (r = −0.43, P = 0.015) and HbA1c (r = −0.44, P = 0.006) and positively associated with M/I (r = 0.39, P = 0.02). Data Adapted from (93) and (456) with permission.
Figure 7. Figure 7. Effect of diet and activity on skeletal muscle capillarity in mice. Group abbreviations: LFS = low‐fat sedentary, HFS = high‐fat sedentary, LFA = low‐fat active and HFA = high‐fat active. HFS, HFA, and LFA mice had (A) higher capillary density and (B) capillary‐to‐fiber‐ratio in quadriceps femoris muscles than LFS mice. There were no significant differences between HFA and HFS, but the capillary‐to‐fiber‐ratio was higher in the HFA mice, the difference approaching significance (P = 0.08). (C) Fiber cross‐sectional area (CSA) was similar between LFS, LFA, and HFS but CSA was higher in HFA compared to HFS. (D) Representative composite images of muscle fibers and capillaries. Capillaries (green) were visualized by staining with Isolectin‐GSIB4 containing fluorescent Alexa Fluor 488 label. This was combined with antidystrophin staining with Alexa Fluor 555 secondary antibody to visualize muscle fibers (red). Values are mean ± SD. *P < 0.05 versus LFS, **P < 0.01 versus LFS, ***P < 0.001 versus LFS, § = P < 0.05 versus HFS. Adapted from (411) Fig. 1 with permission.
Figure 8. Figure 8. Mechanisms of insulin‐mediated relaxation and constriction. Mechanisms of insulin‐mediated nitric oxide (NO) and endothelin 1 (ET‐1) production leading to vasodilation and vasoconstriction, respectively. Angiotensin II (AngII), tumor necrosis factor α (TNF‐α), and free fatty acids (FFA) inhibit the PI3‐kinase (PI3K) pathway and stimulate the MAPK pathway. IRS‐1, insulin receptor substrate 1; PDK‐1, phosphoinositide‐dependent kinase 1; Akt, protein kinase B; eNOS, endothelial nitric oxide synthase. Adapted from (219) Figure 1.
Figure 9. Figure 9. Impact of maternal low protein (PR) diet on arterial structure in adult male offspring. (A) Representative cross‐section of second‐order mesenteric artery stained with Miller's Elastin and Van Gieson's stain; yellow computer masks of collagen, elastin and smooth muscle staining. (B) Percentage of media + intima thickness of vascular smooth muscle, elastin and collagen in mesenteric arteries from the offspring of control (solid bars, n = 6) and PR (open bars, n = 8) dams, mean ± SEM, **P < 0.01 C versus PR by Student's t test. Modified, with permission, from (387) Figure 1.
Figure 10. Figure 10. Impact of a maternal high fat (HF) diet on arterial NO production in adult male mouse offspring. Dams were assigned to either a high fat (HF) diet or standard chow (C) for 4 weeks before conception and during gestation and lactation. At weaning, offspring were assigned to C or HF to give four dietary groups C/C, HF/C, C/HF, and HF/HF studied at 15 weeks of age. Confocal images of (A) basal and (B) ACh (1 μmol/L) stimulated NO release in femoral arteries measured using DAF‐FM The artery segments were cut longitudinally into two halves and viewed using a Leica SP5 confocal microscope (excitation 488 nm, emission 515‐530 nm). (C) Basal NO production and (D) ACh‐stimulated NO production in femoral arteries as detected by using 4,5‐diaminofluorescein diacetate (DAF‐FM). Data are normalized to NO production by C/C offspring group (n = 3 per group) and expressed as mean ± SEM. Values significantly different between high fat fed offspring groups and control offspring (C/C) at 15 or 30 weeks of age are indicated by *P < 0.05, **P < 0.01. (C) Adapted from (448) parts of Fig. 6, and supplemental material Figure S4 with permission.
Figure 11. Figure 11. Dietary restriction in pregnant rats causes gender‐related vascular dysfunction in offspring. Vasoconstriction to the thromboxane mimetic U46619 was measured in femoral arteries (day 20) and branches of the femoral artery (day 100 and 200) of offspring of control (C) and nutritionally restricted (R) dams. Data are expressed as a percentage of the response to 125 mm KCl. 20 days: C offspring (open circles, n = 7), R offspring (filled circles, n = 6). 100 days: C females (open circles, n = 5), R females (filled circles, n = 6); C males (open squares, n = 6), R males (filled squares, n = 6). 200 days: C females (open circles, n = 5), R females (closed circles, n = 5); C males (open squares, n = 6), R males (closed squares, n = 6). Values are given as mean ± SEM. *P < 0.05 at 20 days of age (ANOVA); *P < 0.05 for maximal constriction R males versus C males at 100 and 200 days of age. Adapted from (348) Fig. 4 with permission.
Figure 12. Figure 12. Relationship between key significant markers of male offspring phenotype measured at 30 weeks of age across the experimental dietary groups. Dams were assigned to either a high fat (HF) diet or standard chow (C) for 4 weeks before conception and during gestation and lactation. At weaning, offspring were assigned to C or HF to give four dietary groups C/C (◯), HF/C (•), C/HF (•), and HF/HF (•). Data are presented for (A) systolic blood pressure, (B) oxidative stress measured by DHE staining in vastus muscle, and (C) antioxidant status measured by HO‐1 staining in liver with relation to body weight and ACh‐mediated endothelium‐dependent vasorelaxation in femoral artery. Data adapted, with permission, from (448).
Figure 13. Figure 13. (A) Relationships between birth weight and the diameters of retinal arterioles, and venules in infants born at term. Retinal image from a newborn infant showing identification and measurement of retinal vessels from 0.5 to 1.0 disk diameters from the margin of the optic disk. Digital images of both the retinas were obtained using a digital retinal camera after pupillary dilation. (B) Relationship between birth weight and vessel diameters. Data are from 7 birth weight (LBW) babies and 17 appropriate for gestational age babies. Babies with low LBW had larger arteriole (113.1 ± 17.9 μm vs. 86.4 ± 14.4 μm; P = 0.0009) and venule diameters (151.7 ± 14.9 μm vs. 128.4 ± 16.9 μm; P = 0.0040). Pearson's coefficient of correlation between retinal arteriole and venule diameter was 0.752 (95% confidence interval 0.50‐0.89; P < 0.0001). Adapted from (226) Figures 1 and 2 with permission.
Figure 14. Figure 14. Impact of birth weight on microvascular function measured in the skin of 3‐month‐old infants. Skin perfusion in response to ACh (an endothelium‐dependent vasodilator) in infants born at term (n = 19) either small (SGA) or average (AGA) for gestational age. The difference between SGA and AGA infants born at term is statistically significant (P < 0.01). Redrawn from (340) Figure 1 with permission.
Figure 15. Figure 15. Schematic illustrating mechanisms by which maternal overnutrition alters the potential for functional dilator capacity via changes in EDH pathways in the offspring and subsequent postweaning diet‐induced obesity (DIO) on this pathway to contribute to microvascular dysfunction. Microvascular dysfunction is primed by altered EDH‐mediated signaling pathways via reduced myoendothelial gap junctions (MEGJ) through holes in the internal elastic lamina (IEL), Ca‐activated K+ channels, and/or diffusible EDHFs that provide a means by which hyperpolarization is transferred between endothelial cells (EC) and vascular smooth muscle cells (SMC) to limit up‐regulation of functional capacity in response to later pathophysiological challenges [after Sandow et al. (400)].
Figure 16. Figure 16. Impact of exercise intervention on microvascular health. (A) Vasodilator capacity (reactive hyperemia, RH) and (B) Microvascular exchange capacity (Kf) (small step venous congestion plethysmography) measured in the calf of healthy older subjects (74 ± 4 years) before and after 14 weeks of lower limb endurance exercise training.*P < 0.05, n = 10. Redrawn from (81) Figure 5 and Figure 3 with permission.


Figure 1. Standardized mortality ratios for coronary heart disease for 15,726 men and women below the age of 65 years in Herefordshire, UK. Adapted from (26) redrawn from Figure 1 with permission.


Figure 2. Vasodilator signaling across the vascular tree. NO mediates vascular relaxation of relatively large, conduit arteries (e.g., aorta and epicardial coronary arteries), whereas EDHF plays an important role in modulating vascular tone in small, resistance arteries (e.g., small mesenteric arteries). Adapted from (437) Figure 9 with permission.


Figure 3. NO as a mediator during the early development of the cardiovascular system in the zebra fish. Influence of chronic exposure to SNP (1 mmol/L) on the formation of (A) the secondary loop and (B) the caudal vasculature that together give rise to the vascular bed in the tail fin in later developmental stages of the zebrafish larvae. Adapted from (359) Fig. 3 and Fig. 4 with permission.


Figure 4. Endothelium‐dependent dilation of rat gracilis muscle arterioles in response to receptor‐dependent and ‐independent agonists before and then after exposure to Nω‐nitro‐L‐arginine methyl ester (L‐NAME). (A) arterioles from 25‐ to 28‐day‐old rats. (B) Arterioles from 42‐ to 46‐day‐old rats. Values are means ± SEM. n = number of vessels. *P < 0.05 versus Control. (45) Figure 1 with permission.


Figure 5. Impact of cardiovascular risk factors on the microvasculature.


Figure 6. Scatter plots for the relationship between microvascular exchange capacity (Kf) and visceral fat, HbA1c and insulin mediated glucose disposal (M/I) from 39 individuals with central obesity. Kf was negatively associated with visceral fat (r = −0.43, P = 0.015) and HbA1c (r = −0.44, P = 0.006) and positively associated with M/I (r = 0.39, P = 0.02). Data Adapted from (93) and (456) with permission.


Figure 7. Effect of diet and activity on skeletal muscle capillarity in mice. Group abbreviations: LFS = low‐fat sedentary, HFS = high‐fat sedentary, LFA = low‐fat active and HFA = high‐fat active. HFS, HFA, and LFA mice had (A) higher capillary density and (B) capillary‐to‐fiber‐ratio in quadriceps femoris muscles than LFS mice. There were no significant differences between HFA and HFS, but the capillary‐to‐fiber‐ratio was higher in the HFA mice, the difference approaching significance (P = 0.08). (C) Fiber cross‐sectional area (CSA) was similar between LFS, LFA, and HFS but CSA was higher in HFA compared to HFS. (D) Representative composite images of muscle fibers and capillaries. Capillaries (green) were visualized by staining with Isolectin‐GSIB4 containing fluorescent Alexa Fluor 488 label. This was combined with antidystrophin staining with Alexa Fluor 555 secondary antibody to visualize muscle fibers (red). Values are mean ± SD. *P < 0.05 versus LFS, **P < 0.01 versus LFS, ***P < 0.001 versus LFS, § = P < 0.05 versus HFS. Adapted from (411) Fig. 1 with permission.


Figure 8. Mechanisms of insulin‐mediated relaxation and constriction. Mechanisms of insulin‐mediated nitric oxide (NO) and endothelin 1 (ET‐1) production leading to vasodilation and vasoconstriction, respectively. Angiotensin II (AngII), tumor necrosis factor α (TNF‐α), and free fatty acids (FFA) inhibit the PI3‐kinase (PI3K) pathway and stimulate the MAPK pathway. IRS‐1, insulin receptor substrate 1; PDK‐1, phosphoinositide‐dependent kinase 1; Akt, protein kinase B; eNOS, endothelial nitric oxide synthase. Adapted from (219) Figure 1.


Figure 9. Impact of maternal low protein (PR) diet on arterial structure in adult male offspring. (A) Representative cross‐section of second‐order mesenteric artery stained with Miller's Elastin and Van Gieson's stain; yellow computer masks of collagen, elastin and smooth muscle staining. (B) Percentage of media + intima thickness of vascular smooth muscle, elastin and collagen in mesenteric arteries from the offspring of control (solid bars, n = 6) and PR (open bars, n = 8) dams, mean ± SEM, **P < 0.01 C versus PR by Student's t test. Modified, with permission, from (387) Figure 1.


Figure 10. Impact of a maternal high fat (HF) diet on arterial NO production in adult male mouse offspring. Dams were assigned to either a high fat (HF) diet or standard chow (C) for 4 weeks before conception and during gestation and lactation. At weaning, offspring were assigned to C or HF to give four dietary groups C/C, HF/C, C/HF, and HF/HF studied at 15 weeks of age. Confocal images of (A) basal and (B) ACh (1 μmol/L) stimulated NO release in femoral arteries measured using DAF‐FM The artery segments were cut longitudinally into two halves and viewed using a Leica SP5 confocal microscope (excitation 488 nm, emission 515‐530 nm). (C) Basal NO production and (D) ACh‐stimulated NO production in femoral arteries as detected by using 4,5‐diaminofluorescein diacetate (DAF‐FM). Data are normalized to NO production by C/C offspring group (n = 3 per group) and expressed as mean ± SEM. Values significantly different between high fat fed offspring groups and control offspring (C/C) at 15 or 30 weeks of age are indicated by *P < 0.05, **P < 0.01. (C) Adapted from (448) parts of Fig. 6, and supplemental material Figure S4 with permission.


Figure 11. Dietary restriction in pregnant rats causes gender‐related vascular dysfunction in offspring. Vasoconstriction to the thromboxane mimetic U46619 was measured in femoral arteries (day 20) and branches of the femoral artery (day 100 and 200) of offspring of control (C) and nutritionally restricted (R) dams. Data are expressed as a percentage of the response to 125 mm KCl. 20 days: C offspring (open circles, n = 7), R offspring (filled circles, n = 6). 100 days: C females (open circles, n = 5), R females (filled circles, n = 6); C males (open squares, n = 6), R males (filled squares, n = 6). 200 days: C females (open circles, n = 5), R females (closed circles, n = 5); C males (open squares, n = 6), R males (closed squares, n = 6). Values are given as mean ± SEM. *P < 0.05 at 20 days of age (ANOVA); *P < 0.05 for maximal constriction R males versus C males at 100 and 200 days of age. Adapted from (348) Fig. 4 with permission.


Figure 12. Relationship between key significant markers of male offspring phenotype measured at 30 weeks of age across the experimental dietary groups. Dams were assigned to either a high fat (HF) diet or standard chow (C) for 4 weeks before conception and during gestation and lactation. At weaning, offspring were assigned to C or HF to give four dietary groups C/C (◯), HF/C (•), C/HF (•), and HF/HF (•). Data are presented for (A) systolic blood pressure, (B) oxidative stress measured by DHE staining in vastus muscle, and (C) antioxidant status measured by HO‐1 staining in liver with relation to body weight and ACh‐mediated endothelium‐dependent vasorelaxation in femoral artery. Data adapted, with permission, from (448).


Figure 13. (A) Relationships between birth weight and the diameters of retinal arterioles, and venules in infants born at term. Retinal image from a newborn infant showing identification and measurement of retinal vessels from 0.5 to 1.0 disk diameters from the margin of the optic disk. Digital images of both the retinas were obtained using a digital retinal camera after pupillary dilation. (B) Relationship between birth weight and vessel diameters. Data are from 7 birth weight (LBW) babies and 17 appropriate for gestational age babies. Babies with low LBW had larger arteriole (113.1 ± 17.9 μm vs. 86.4 ± 14.4 μm; P = 0.0009) and venule diameters (151.7 ± 14.9 μm vs. 128.4 ± 16.9 μm; P = 0.0040). Pearson's coefficient of correlation between retinal arteriole and venule diameter was 0.752 (95% confidence interval 0.50‐0.89; P < 0.0001). Adapted from (226) Figures 1 and 2 with permission.


Figure 14. Impact of birth weight on microvascular function measured in the skin of 3‐month‐old infants. Skin perfusion in response to ACh (an endothelium‐dependent vasodilator) in infants born at term (n = 19) either small (SGA) or average (AGA) for gestational age. The difference between SGA and AGA infants born at term is statistically significant (P < 0.01). Redrawn from (340) Figure 1 with permission.


Figure 15. Schematic illustrating mechanisms by which maternal overnutrition alters the potential for functional dilator capacity via changes in EDH pathways in the offspring and subsequent postweaning diet‐induced obesity (DIO) on this pathway to contribute to microvascular dysfunction. Microvascular dysfunction is primed by altered EDH‐mediated signaling pathways via reduced myoendothelial gap junctions (MEGJ) through holes in the internal elastic lamina (IEL), Ca‐activated K+ channels, and/or diffusible EDHFs that provide a means by which hyperpolarization is transferred between endothelial cells (EC) and vascular smooth muscle cells (SMC) to limit up‐regulation of functional capacity in response to later pathophysiological challenges [after Sandow et al. (400)].


Figure 16. Impact of exercise intervention on microvascular health. (A) Vasodilator capacity (reactive hyperemia, RH) and (B) Microvascular exchange capacity (Kf) (small step venous congestion plethysmography) measured in the calf of healthy older subjects (74 ± 4 years) before and after 14 weeks of lower limb endurance exercise training.*P < 0.05, n = 10. Redrawn from (81) Figure 5 and Figure 3 with permission.
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FURTHER READING

Gluckman P, Hanson M (2006). Mismatch: Why Our World No Longer Fits Our Bodies. Oxford University Press, Oxford

 


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Article Title: Developmental Conditioning of the Vasculature
 

How to Cite

Geraldine F. Clough. Developmental Conditioning of the Vasculature. Compr Physiol 2014, 5: 397-438. doi: 10.1002/cphy.c140037