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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 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).
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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).

Mentions: When comparing treated vs. untreated pregnancy, maternal treatment with allopurinol significantly decreased the magnitude of endothelial relaxation in young adult offspring of normoxic pregnancy (Fig. 1Avs. Fig. 2A; 2-way ANOVA, P < 0.05). When comparing treated vs. untreated normoxic pregnancy, maternal treatment with allopurinol significantly decreased short telomere length in vascular tissue of adult offspring irrespective of age (Fig. 1Bvs. Fig. 2B; 2-way ANOVA, P < 0.05). In contrast to untreated normoxic pregnancy, aged relative to young adult offspring of normoxic pregnancy treated with maternal allopurinol no longer showed a significant impairment in the femoral relaxant response to methacholine (Fig. 2A). Similarly, in contrast to untreated normoxic pregnancy, aged relative to young adult offspring of normoxic pregnancy treated with maternal allopurinol no longer showed a significant increase in the frequency of short telomeres in vascular tissue (Fig. 2B). However, they still showed a modest decrease in the frequency of long telomeres in vascular tissue (Fig. 2E). Compared with untreated hypoxic pregnancy, maternal treatment with allopurinol during hypoxic pregnancy restored femoral endothelial function in aged but not in young adult offspring (Fig. 2A), and this effect was associated with a lack of an increase in the frequency of short telomeres (Fig. 2B) and a significant, albeit modest increase in the frequency of long telomeres (Fig. 2E) in vascular tissue at 15 mo of age.


Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease
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).
© Copyright Policy - open-access
Related In: Results  -  Collection

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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).
Mentions: When comparing treated vs. untreated pregnancy, maternal treatment with allopurinol significantly decreased the magnitude of endothelial relaxation in young adult offspring of normoxic pregnancy (Fig. 1Avs. Fig. 2A; 2-way ANOVA, P < 0.05). When comparing treated vs. untreated normoxic pregnancy, maternal treatment with allopurinol significantly decreased short telomere length in vascular tissue of adult offspring irrespective of age (Fig. 1Bvs. Fig. 2B; 2-way ANOVA, P < 0.05). In contrast to untreated normoxic pregnancy, aged relative to young adult offspring of normoxic pregnancy treated with maternal allopurinol no longer showed a significant impairment in the femoral relaxant response to methacholine (Fig. 2A). Similarly, in contrast to untreated normoxic pregnancy, aged relative to young adult offspring of normoxic pregnancy treated with maternal allopurinol no longer showed a significant increase in the frequency of short telomeres in vascular tissue (Fig. 2B). However, they still showed a modest decrease in the frequency of long telomeres in vascular tissue (Fig. 2E). Compared with untreated hypoxic pregnancy, maternal treatment with allopurinol during hypoxic pregnancy restored femoral endothelial function in aged but not in young adult offspring (Fig. 2A), and this effect was associated with a lack of an increase in the frequency of short telomeres (Fig. 2B) and a significant, albeit modest increase in the frequency of long telomeres (Fig. 2E) in vascular tissue at 15 mo of age.

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