Role of microvascular rarefaction in the increased arterial pressure in mice lacking for the endothelial nitric oxide synthase gene (eNOS3pt−/−)

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Abstract
Mechanisms involved in hypertension in homozygous mice for the defective endothelial nitric oxide synthase gene (eNOS−/−) have not been fully elucidated. As NO is a potent vasodilator agent and possibly promotes angiogenesis, we investigated whether vasoconstriction and/or microvascular rarefaction could explain hypertension in these mice. Immunohistochemistry with mouse monoclonal smooth muscle α-actin antibody was used to detect arterioles, and quantification of arteriolar density was performed in the left ventricle and in the gracilis muscle of 12-week-old male eNOS+/+ and eNOS−/− mice. Haemodynamic parameters – mean arterial pressure (MAP), cardiac index (CI), total peripheral résistance (TPR), myocardial blood flow, muscular blood flow and corresponding resistances – were measured or calculated using the fluorescent microsphere method in basal conditions and after infusion of sodium nitroprusside (SNP) (5 to 150 μg/kg per min) in eNOS−/− mice, compared with eNOS+/+ mice. We evidenced a significant decrease in arteriolar density in the heart (−16%, P 0.02) and in the gracilis muscle (−22%, P 0.05) in eNOS−/− mice. In basal conditions, eNOS−/− mice developed significant hypertension (MAP = 127 ± 14 versus 77 ± 14 mmHg, P 0.001) associated with decreased CI (−29%, P 0.001) and increased TPR (+ 125%, P 0.001). Coronary and gracilis muscular resistances were increased (by 75 and 89% respectively, P 0.001) compared with eNOS+/+ mice, whereas myocardial and skeletal muscle tissue blood flows were not affected. After SNP administration (10 μg/kg per min), a dose that did not significantly modify haemodynamic parameters in eNOS+/+ mice, MAP, TPR and regional resistances were normalized in eNOS−/− mice, showing that vasodilation may correct hypertension in eNOS−/− mice. However, under maximal vasodilating conditions, TPR and regional resistances remained significantly higher in eNOS−/− mice than those of eNOS+/+ mice.Conclusion Anatomical and functional results show that both vasoconstriction and arteriolar rarefaction are involved in hypertension of eNOS−/− mice. Indeed, under maximal vasodilation, arterial pressure and TPR remained significantly higher in eNOS−/− mice than in eNOS+/+ mice, evidencing a major role of microvascular rarefaction in this model of hypertension. Anatomical and functional results show that both vasoconstriction and arteriolar rarefaction are involved in hypertension of eNOS−/− mice. Indeed, under maximal vasodilation, arterial pressure and TPR remained significantly higher in eNOS−/− mice than in eNOS+/+ mice, evidencing a major role of microvascular rarefaction in this model of hypertension.