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Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease

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ABSTRACT

Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 ± 3 vs. 55 ± 3%) and increased vascular short telomere abundance (4.2–1.3 kb) 43.0 ± 1.5 vs. 55.1 ± 3.8%) in aged vs. young offspring of normoxic pregnancy (P < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 ± 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 ± 2.5 vs. 48.2 ± 2.6%) and of plasma proinflammatory chemokine (24.6 ± 2.8 vs. 36.8 ± 5.5 pg/ml, P < 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.—Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.

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Effects of aging and developmental hypoxia on endothelial function and vascular telomere length. Values are means ± sem for the femoral artery maximal dilator response to methacholine (A, endothelial relaxation) expressed as a percentage of the phenylephrine-induced maximal constriction (%PEmax) and for the frequency (%) of aortic telomere length ranges (B, 4.2–1.3 kb; C, 8.6–4.2 kb; D, 48.5–8.6 kb; and E, 145–48.5 kb) in 4- and 15-mo-old offspring of normoxic (white bars) or of hypoxic (black bars) pregnancy. Numbers of animals for each group are in brackets. Bars with different letters are significantly (P < 0.05) different (2-way ANOVA and post hoc Tukey’s test).
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Figure 1: Effects of aging and developmental hypoxia on endothelial function and vascular telomere length. Values are means ± sem for the femoral artery maximal dilator response to methacholine (A, endothelial relaxation) expressed as a percentage of the phenylephrine-induced maximal constriction (%PEmax) and for the frequency (%) of aortic telomere length ranges (B, 4.2–1.3 kb; C, 8.6–4.2 kb; D, 48.5–8.6 kb; and E, 145–48.5 kb) in 4- and 15-mo-old offspring of normoxic (white bars) or of hypoxic (black bars) pregnancy. Numbers of animals for each group are in brackets. Bars with different letters are significantly (P < 0.05) different (2-way ANOVA and post hoc Tukey’s test).

Mentions: Endothelial vasodilator function was investigated using in vitro wire myography of second-order femoral arterial segments. Vascular telomere shortening was investigated by determining aortic telomere length by Southern blot. Femoral arterial segments isolated from aged (15 mo) relative to young adult (4 mo) offspring of normoxic pregnancy had impaired relaxant responses to the acetylcholine analog methacholine following preconstriction with phenylephrine (Fig. 1A). Vascular tissue isolated from aged relative to young adult offspring of normoxic pregnancy also showed an increased frequency of short telomeres (Fig. 1B).


Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease
Effects of aging and developmental hypoxia on endothelial function and vascular telomere length. Values are means ± sem for the femoral artery maximal dilator response to methacholine (A, endothelial relaxation) expressed as a percentage of the phenylephrine-induced maximal constriction (%PEmax) and for the frequency (%) of aortic telomere length ranges (B, 4.2–1.3 kb; C, 8.6–4.2 kb; D, 48.5–8.6 kb; and E, 145–48.5 kb) in 4- and 15-mo-old offspring of normoxic (white bars) or of hypoxic (black bars) pregnancy. Numbers of animals for each group are in brackets. Bars with different letters are significantly (P < 0.05) different (2-way ANOVA and post hoc Tukey’s test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036970&req=5

Figure 1: Effects of aging and developmental hypoxia on endothelial function and vascular telomere length. Values are means ± sem for the femoral artery maximal dilator response to methacholine (A, endothelial relaxation) expressed as a percentage of the phenylephrine-induced maximal constriction (%PEmax) and for the frequency (%) of aortic telomere length ranges (B, 4.2–1.3 kb; C, 8.6–4.2 kb; D, 48.5–8.6 kb; and E, 145–48.5 kb) in 4- and 15-mo-old offspring of normoxic (white bars) or of hypoxic (black bars) pregnancy. Numbers of animals for each group are in brackets. Bars with different letters are significantly (P < 0.05) different (2-way ANOVA and post hoc Tukey’s test).
Mentions: Endothelial vasodilator function was investigated using in vitro wire myography of second-order femoral arterial segments. Vascular telomere shortening was investigated by determining aortic telomere length by Southern blot. Femoral arterial segments isolated from aged (15 mo) relative to young adult (4 mo) offspring of normoxic pregnancy had impaired relaxant responses to the acetylcholine analog methacholine following preconstriction with phenylephrine (Fig. 1A). Vascular tissue isolated from aged relative to young adult offspring of normoxic pregnancy also showed an increased frequency of short telomeres (Fig. 1B).

View Article: PubMed Central - PubMed

ABSTRACT

Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 &plusmn; 3 vs. 55 &plusmn; 3%) and increased vascular short telomere abundance (4.2&ndash;1.3 kb) 43.0 &plusmn; 1.5 vs. 55.1 &plusmn; 3.8%) in aged vs. young offspring of normoxic pregnancy (P &lt; 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 &plusmn; 1%, P &lt; 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 &plusmn; 2.5 vs. 48.2 &plusmn; 2.6%) and of plasma proinflammatory chemokine (24.6 &plusmn; 2.8 vs. 36.8 &plusmn; 5.5 pg/ml, P &lt; 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.&mdash;Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.

No MeSH data available.


Related in: MedlinePlus