Abstract P503: Role of TRPV4 and Endothelial BK Channels in Endothelial-dependent Dilation Following Chronic Hypoxia

Abstract

Following chronic hypoxia (CH) the systemic vasculature exhibits blunted vasoconstriction due to endothelial cell-dependent hyperpolarization (EDH). Previous data demonstrate that after CH, EDH-mediated dilation switches from a reliance on SK ca and IK ca channels to activation of endothelial BK ca channel (eBK). The mechanism by which endothelial cell stimulation activates eBK channels following CH is not known. We hypothesized that following CH, EDH-dependent dilation involves a transient receptor potential V4 (TRPV4)-dependent activation of eBK channels. ACh induced concentration-dependent dilation in pressurized gracilis arteries from normoxic and CH rats. TRPV4 blockade only attenuated ACh-induced vasodilation in arteries from CH rats (Fig. 1). ACh elicited an increase in endothelial TRPV4-dependent Ca 2+ events in arteries from both groups. Direct activation of TRPV4 elicited dilation in arteries from normoxic and CH rats (97 ± 2 % and 95 ± 2 % for normoxic and CH, respectively). In arteries from normoxic rats, inhibition of SK ca and IK ca abolished dilation to TRPV4 activation (6 ± 5 %), whereas, luminal iberiotoxin had no effect (89 ± 7 %). In CH rats, only administration of all three K ca channel inhibitors abolished dilation to TRPV4 activation (3 ± 10%). Disruption of endothelial caveolae with methyl-β-cyclodextrin significantly decreased ACh-induced dilation in arteries from both groups. Using a proximity ligation assay, we observed co-localization between caveolin-1, TRPV4, and eBK channels in the endothelium of gracilis arteries. In conclusion, CH results in functional coupling between muscarinic receptors, TRPV4 and K ca channels in gracilis arteries.