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. 2016 May;30(5):1968-75.
doi: 10.1096/fj.201500057. Epub 2016 Mar 1.

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

Beth J Allison  1 , Joepe J Kaandorp  2 , Andrew D Kane  1 , Emily J Camm  1 , Ciara Lusby  1 , Christine M Cross  1 , Rhianon Nevin-Dolan  1 , Avnesh S Thakor  1 , Jan B Derks  2 , Jane L Tarry-Adkins  3 , Susan E Ozanne  3 , Dino A Giussani  4
Affiliations

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

Beth J Allison et al. FASEB J. 2016 May.

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.

Keywords: allopurinol; cell senescence; fetal hypoxia; oxidative stress; xanthine oxidase.

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Figures

Figure 1.
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).
Figure 2.
Figure 2.
Effects of maternal treatment with allopurinol on endothelial function and vascular telomere length in young and aged offspring of normoxic or hypoxic pregnancy. Values are means ± sem for the femoral 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 (stippled bars) or of hypoxic (gray bars) pregnancy following maternal treatment with allopurinol. Numbers of animals for each group are in brackets. Bars with different letters are significantly different (P < 0.05). *P < 0.05 offspring of treated vs. untreated pregnancy (2-way ANOVA and post hoc Tukey’s test).
Figure 3.
Figure 3.
Effects of aging, developmental hypoxia and maternal allopurinol inflammatory markers. Values are means ± sem for the plasma concentration (pg/ml) of the proinflammatory chemokine KC/GRO in 4- and 15-mo-old offspring of untreated normoxic (white bars) or hypoxic (black bars) pregnancy (A) and in 4- and 15-mo-old offspring of normoxic (stippled bars) or hypoxic (dark gray bars) pregnancy treated with allopurinol (B). Bars with different letters are significantly (P < 0.05) different (2-way ANOVA and post hoc Tukey’s test).
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