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

Abstract

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 (approximately 6 mo) and old (approximately 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<or=0.05); however, ACh-induced vasodilation was preserved with age. NG-nitro-L-arginine methyl ester (L-NAME) (1x10(-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.

Aging impairs flow-induced dilation in coronary arterioles: role of NO and H2O2

“…1). These data confirm previous results from our laboratory demonstrating an age-related reduction in NO-mediated endotheliumdependent dilation (21).…”

“…Previous studies have indicated that NO-mediated endothelial function declines with advancing age (26,43,49), and recent reports have shown a similar impairment in endothelium-mediated vasodilation in the coronary microvasculature (7,21). In the present study, we have demonstrated for the first time an age-induced decline in flow-induced NO production, as evidenced by diminished DAF fluorescence in isolated coronary arterioles of aged rats (Fig.…”

“…Vascular resistance increases, leading to impairments in coronary blood flow and flow reserve (15). Endothelial dysfunction similarly progresses with aging (4) and may be mediated by impaired nitric oxide (NO) activity (7,21) or elevated oxidant stress (6,10). Previous studies have demonstrated age-associated declines in flow-mediated dilation in coronary arterioles due to impaired phosphatidylinositol 3-kinase signaling (21) or elevated superoxide (O 2 Ϫ ) production (7).…”

“…Endothelial dysfunction similarly progresses with aging (4) and may be mediated by impaired nitric oxide (NO) activity (7,21) or elevated oxidant stress (6,10). Previous studies have demonstrated age-associated declines in flow-mediated dilation in coronary arterioles due to impaired phosphatidylinositol 3-kinase signaling (21) or elevated superoxide (O 2 Ϫ ) production (7). Because flow-induced vasodilation is inextricably linked to NO-mediated signaling, it is possible that other factors directly involved in the NO pathway may be altered with advancing age.…”

Estrogen replacement restores flow-induced vasodilation in coronary arterioles of aged and ovariectomized rats

“…Although total eNOS was not affected by estrogen status, phosphorylation of eNOS protein (serine 1177) was increased in arterioles from middle-aged and old females after estrogen replacement. In coronary arterioles from male rats, we have previously reported that advancing age impairs flowinduced vasodilation through reductions in Flk-1 activation and PI3-kinase/Akt signaling (23). Similar to our findings in coronary arterioles from old male rats, our current results indicate that basal NO remained constant (Table 2) despite changes in NO-mediated dilation that occurred with advancing age and manipulation of circulating estrogen.…”