Microvascular function and ageing: L‐arginine, tetrahydrobiopterin and the search for the fountain of vascular youth

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Cardiovascular disease remains the most salient killer in the United States and ageing is a primary risk factor. With advancing age, there is pervasive macrovascular and microvascular dysfunction that manifests as stiffening of central elastic arteries, thickening of intimal–medial layers of the vascular wall, and diminished peripheral conduit artery/resistance artery vasodilatory capacity. Reduced endothelium-dependent vasodilatation has been shown in several prospective studies to be an independent predictor of adverse cardiovascular events. In the healthy vasculature, nitric oxide (NO) is released from endothelial cells in response to laminar shear stress and causes vasodilatation. In addition to its vasodilatory properties, NO is antiatherogenic: it inhibits platelet aggregation/adhesion, smooth muscle cell proliferation and lipid oxidation. Depletion of NO has been linked to several pathologies including atherosclerosis and hypertension. Understanding the mechanistic aspects of NO bioavailability, and loss thereof with ageing, has significant clinical relevance. Synthesizing NO requires a precise admixture of substrate and cofactors. Unidirectional laminar shear stress activates endothelial nitric oxide synthase (eNOS) via phosphorylation. l-Arginine is hydroxylated to N-hydroxy-l-arginine and then further oxidized to NO and l-citrulline. NO diffuses into smooth muscle cells, activates guanylate cyclase and induces cyclic GMP-mediated smooth muscle relaxation. Other substrate and cofactors required for this reaction include oxygen, NADPH, flavin, heme and tetrahydrobiopterin (BH4). Altering any one of these variables with ageing may set the reaction awry and attenuate vasodilatation. In an article recently published in The Journal of Physiology, Delp and associates examined several potential mechanisms that may contribute to reduced microvascular vasodilatory capacity with ageing (Delp et al. 2008). Delp et al. harvested arterioles from the soleus muscles of young and old rats and exposed them to graded increases in intraluminal flow in the absence of changes in intraluminal pressure. Results revealed that arterioles from old rats exhibited a 52% reduction in flow-mediated dilatation (FMD) compared to arterioles from young rats. Vessel dilatation was also assessed following administration of the NO donor sodium nitropruside (SNP). There were no group differences in SNP-mediated dilatation suggesting similar endothelial-independent vasodilatation in arterioles from young and old rats. Confirming that the age-associated difference in microvascular vasodilatation was endothelial dependent, Delp and associates proceeded to systematically and eloquently rule out several potential limiting factors regulating the NO signalling pathway.