Role of endothelial [Ca2+]iin activation of eNOS in pressurized arterioles by agonists and wall shear stress

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Abstract
In cultured endothelial cells, Ca2+-dependent and -independent activation of nitric oxide (NO) synthesis to agonists and flow/wall shear stress (WSS) has been demonstrated. However, the presence and function of these pathways are less well known in microvessels that can be exposed to a high level of WSS. We hypothesized that the role of changes in endothelial intracellular calcium concentration ([Ca2+]i) is different in agonist- and WSS-induced release of NO. Thus changes in endothelial [Ca2+]iand diameter of intact pressurized (∼100 μm at 80 mmHg) gracilis skeletal muscle arterioles of rats were measured by fluorescent videomicroscopy. Acetylcholine (ACh) and increases in WSS (by increasing intraluminal flow) elicited dilations (maximum 91 ± 2% and 34 ± 4%) that could be inhibited by Nω-nitro-l-arginine methyl ester (l-NAME), a NO synthase blocker. In diameter-clamped arterioles, ACh caused substantial increases in the endothelial calcium fluorescence ratio (ERCa, maximum 43 ± 5%), which was significantly greater than changes in ERCa(maximum ∼10%) to increases in WSS. The Ca2+ionophore A-23187 also substantially increased ERCa(maximum 38 ± 5%) and elicited significant l-NAME-sensitive arteriolar dilations (maximum 45 ± 7%). Intraluminal administration of the tyrosine kinase inhibitor genistein had no effect on dilations induced by ACh or the NO donor sodium nitroprusside, whereas it eliminated WSS-induced dilations. Collectively, our data suggest that, in endothelium of skeletal muscle arterioles, NO synthesis is activated by shear stress without a substantial increase in [Ca2+]i, most likely by activation of tyrosine kinase pathways, whereas NO release by ACh and A-23187 is associated with substantial increases in [Ca2+]i.

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