A novel role for spontaneous endothelial cell calcium activity in the vascular myogenic response

Abstract

Although global increases in vascular smooth muscle cell (SMC) calcium are crucial for myogenic tone mainly in resistance arterioles, historically the myogenic response was thought to be independent of endothelial cell (EC) function. We have identified a novel role for ECs in the myogenic response, namely increases in localized spontaneous EC calcium event frequency at low intraluminal pressure activates transient receptor potential, vanilloid 4 channels (TRPV4) and subsequently intermediate conductance calcium‐activated K channels (IKCa), to activate an EC‐dependent vasodilation. Isolated rat cremaster arterioles were cannulated and pressurized (5–80mmHg) at ~34°C. Myogenic tone developed and EC function was assessed. Calcium events were imaged in Oregon Green® 488 BAPTA‐1 loaded ECs and/or SMCs using laser scanning confocal microscopy. Myogenic tone‐pressure response curves were performed in the presence of nitric oxide synthase (L‐NAME, 100 μM), KCa (TRAM‐34, 1 μM, and/or apamin 50 nM) and TRPV4 (RN1734, 30 μM) inhibitors. Calcium event frequency increased in ECs at low pressure versus high, with the reciprocal observed in SMCs. Inhibition of IKCa, TRPV4, but not SKCa at low pressures resulted in a loss of EC‐dependent dilation and a significant increase in myogenic tone. These data support a role for pressure‐dependent TRPV4‐mediated spontaneous EC calcium activity in the modulation of myogenic tone.