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1 West Virginia University School of Medicine
2 Texas A&M University
3 West Virginia University
* To whom correspondence should be addressed. E-mail: jdelp{at}ufl.edu.
Impairment of flow-induced vasodilation in coronary resistance arterioles may contribute to the decline in coronary vasodilatory reserve that occurs with advancing age. This study investigated the effects of age on flow-induced signaling and activation of nitric oxide (NO)-mediated vasodilation in coronary resistance arterioles. Coronary arterioles were isolated from young (~6 mo) and old (~24 mo) male Fischer-344 rats to assess vasodilation to flow, vascular endothelial growth factor (VEGF), and acetylcholine (ACh). Flow- and VEGF-induced vasodilation of coronary arterioles was impaired with age (P
0.05); however, ACh-induced vasodilation was preserved with age. L-NAME (1x10-5 M) eliminated vasodilation to flow, VEGF, and ACh, indicating dependence of these responses on nitric oxide (NO). SU1498, an inhibitor of vascular endothelial growth receptor 2 (VEGFR, also known as Flk-1), abolished age-related differences in flow-induced vasodilation. Flow induced phosphorylation of Flk-1 in coronary arterioles from young but not old rats, and Flk-1 protein was reduced in coronary arterioles from old rats as compared to those from old rats. Flow stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) in coronary arterioles from both young and old rats. VEGF induced phosphorylation of both Akt and eNOS in coronary arterioles. VEGF-induced phosphorylation of Akt, but not eNOS, was significantly reduced in arterioles from old rats as compared to arterioles from young rats. Wortmannin, an inhibitor of PI3-kinase, eliminated age-related differences in both flow- and VEGF-induced vasodilation. These results indicate that impairment of Flk-1/PI3-kinase signaling contributes to the reduction of flow-induced vasodilation in coronary arterioles with advancing age.
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