Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome

Abstract

This study tested the hypothesis that chronically elevated oxidant stress contributes to impaired active hyperemia in skeletal muscle of obese Zucker rats (OZR) vs. lean Zucker rats (LZR) through progressive deteriorations in microvascular structure. Twelve-week-old LZR and OZR were given 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) in the drinking water for approximately 4 wk. Subsequently, perfusion of in situ gastrocnemius muscle was determined during incremental elevations in metabolic demand, while a contralateral skeletal muscle arteriole and the gastrocnemius muscle was removed to determine dilator reactivity, vessel wall mechanics, and microvessel density. Under control conditions, active hyperemia was impaired at all levels of metabolic demand in OZR, and this was correlated with a reduced microvessel density, increased arteriolar stiffness, and impaired dilator reactivity. Chronic tempol ingestion improved perfusion during moderate to high metabolic demand only and was associated with improved arteriolar reactivity and microvessel density; passive vessel mechanics were unaltered. Combined antioxidant therapy and nitric oxide synthase inhibition in OZR prevented much of the restored perfusion and microvessel density. In LZR, treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) hydrochloride and hydralazine (to prevent hypertension) impaired active hyperemia, dilator reactivity, and microvessel density, although arteriolar distensibility was not altered. These results suggest that with the development of the metabolic syndrome, chronic reductions in nitric oxide bioavailability, in part via the scavenging actions of oxidative free radicals, contribute to a loss of skeletal muscle microvessels, leading to impaired muscle perfusion with elevated metabolic demand.

Exercise training blunts microvascular rarefaction in the metabolic syndrome

“…We have previously demonstrated that, with evolution of the metabolic syndrome in the OZR, a progressive reduction in skeletal muscle microvessel density develops that can result in 25% reduction in the total number of microvessels within this tissue compared with levels determined in control animals (14). This rarefaction of the vascular network contributes to an elevation in peripheral vascular resistance in OZR (12,14,15) and appears to be largely independent of any developing increase in mean arterial pressure (13). In contrast, ongoing studies in our laboratory have provided compelling evidence that this reduction in microvessel density may be most accurately predicted by the chronic reduction in nitric oxide (NO) bioavailability that accompanies the developing insulin-resistant state in OZR (12,13).…”

Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

“…The endothelium is a prominent source of nitric oxide (NO) and prostaglandins in the vasculature (3). Several previous studies have emphasized the role of altered NO synthase expression (21) or reduced NO bioavailability (6) in the endothelial dysfunction in metabolic syndrome, which results in an attenuated endothelium-dependent vasodilation (9,12). However, these studies did not test the vasodilatory response during muscle contraction.…”

Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats

“…There is an additional lower rate of microvessel loss after 17 wk of age, but our unpublished work suggests that net microvessel loss develops asymptotic behavior after 17 wk of age. What was most interesting about this observation is that our previous results suggested that the change in skeletal muscle microvessel density would parallel the changes to vascular NO bioavailability (21,23). However, as demonstrated in Figs.…”

“…In OZR, this process plateaus at an ϳ25% reduction in microvessel density compared with control levels in LZR (21,42,48), with clear implications for mass transport/ exchange and muscle fatigue resistance (46). Furthermore, previous results have demonstrated that this response is not dependent on the development of hypertension in OZR (22) and that it is associated with the development of insulin resistance and low bioavailability of nitric oxide (NO) within the microvasculature (23). However, at present we do not have a detailed understanding of either how or why microvessels begin to degrade in skeletal muscle of OZR with the metabolic syndrome, and our understanding of the time course of this evolving rarefaction is superficial at best.…”