Aging and Endothelial Function of Muscle Arterioles

描述：（原文来自应用）骨骼肌灌注和

DESCRIPTION: (Verbatim from application) Skeletal muscle perfusion and endothelium-mediated vasodilation of the skeletal muscle resistance vasculature appear to diminish with advancing age; however, the precise mechanisms that underlie aging-induced decrements in vasodilatory function of the skeletal muscle vasculature are unclear. Our recent work has documented impaired flow-induced vasodilation in 1A arterioles from soleus and gastrocnemius muscles of aged Fischer 344 rats. Although flow-induced vasodilation of skeletal muscle arterioles is known to be an endothelium-dependent response, the mechanisms of the response have not been defined in arterioles from locomotory muscles, such as the soleus and gastrocnemius muscles, and furthermore, the mechanisms which underlie the aging-induced impairment of this response are not known. Therefore, we propose to investigate the contribution of endothelium-dependent vasodilatory pathways to flow-induced vasodilation in soleus and gastronemius muscle arterioles from young and aged Fisher 344 rats. We will test the hypothesis that the aging-induced impairment of flow-induced vasodilation in these resistance arterioles occurs primarily due to a decrease in the ability of the endothelium to produce prostanoid vasodilators. We will use specific inhibitors of key enzymes to determine which component(s) of the flow-induced vasodilation, i.e., endothelial nitric oxide (NO), prostanoid vasodilators, or endothelium-derived hyperpolarizing factor (EDEHF), is downregulated in arterioles from old animals (Aim 1). We will determine whether decreases in protein and mRNA expression for the constitutive form of cyclooxygenase (COX-1) and endothelial nitric synthase (ecNOS) potentially underlie reduced production of No and prostanoid vasodilators in response to flow in arterioles from old rats (Aim2). Finally, because an increased tendency toward more sedentary behavior occurs with advancing age and because exercise training has been shown to improve endothelium-dependent vasodilation of the skeletal muscle vasculature, we propose to determine whether exercise training can ameliorate the impaired flow-induced vasodilation that occurs in skeletal muscle arterioles from aged rats (Aim 3). Although aging has been documented to reduce skeletal muscle vasodilatory responses, these studies will be the first to evaluate the endothelial mechanisms responsible for the loss of vasodilatory function. Furthermore, these studies will determine whether exercise training can counter the aging-associated loss of endothelium-dependent vasodilatory responses in skeletal muscle resistance arterioles.