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Age impairs Flk-1 signaling and NO-mediated vasodilation in coronary arterioles

¹Center for Interdisciplinary Research in Cardiovascular Sciences, ²Division of Exercise Physiology, and ³Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia; and ⁴Systems Biology and Translational Medicine, Texas A & M University, Temple, Texas

Submitted 22 May 2008 ; accepted in final form 1 October 2008

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 ACh. Flow- and VEGF-induced vasodilation of coronary arterioles was impaired with age (P 0.05); however, ACh-induced vasodilation was preserved with age. N^G-nitro-L-arginine methyl ester (L-NAME) (1 x 10^–5 M) eliminated vasodilation to flow, VEGF, and ACh, indicating dependence of these responses on NO. SU-1498, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR, also known as Flk-1), abolished age-related differences in flow-induced vasodilation. Flow-stimulated 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 compared with those from young rats. Flow stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) in coronary arterioles from both young and old rats. VEGF induced phosphorylation of both protein kinase B (Akt) and eNOS in coronary arterioles. VEGF-induced phosphorylation of Akt, but not eNOS, was significantly reduced in arterioles from old rats compared with arterioles from young rats. Wortmannin, an inhibitor of phosphatidylinositol (PI) 3-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.

phosphatidylinositol 3-kinase; endothelial nitric oxide synthase; acetylcholine; vascular endothelial growth factor; phosphorylated endothelial nitric oxide synthase; phophorylated protein kinase B; vasodilation

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