Amplification of EDHF-type vasodilatations in TRPC1-deficient mice

BACKGROUND AND PURPOSE

TRPC1 channels are expressed in the vasculature and are putative candidates for intracellular Ca²⁺ handling. However, little is known about their role in endothelium-dependent vasodilatations including endothelium-derived hyperpolarizing factor (EDHF) vasodilatations, which require activation of Ca²⁺-activated K⁺ channels (K_Ca). To provide molecular information on the role of TRPC1 for K_Ca function and the EDHF signalling complex, we examined endothelium-dependent and independent vasodilatations, K_Ca currents and smooth muscle contractility in TRPC1-deficient mice (TRPC1-/-).

EXPERIMENTAL APPROACH

Vascular responses were studied using pressure/wire myography and intravital microscopy. We performed electrophysiological measurements, and confocal Ca²⁺ imaging for studying K_Ca channel functions and Ca²⁺ sparks.

KEY RESULTS

TRPC1 deficiency in carotid arteries produced a twofold augmentation of TRAM-34- and UCL1684-sensitive EDHF-type vasodilatations and of endothelial hyperpolarization to acetylcholine. NO-mediated vasodilatations were unchanged. TRPC1-/- exhibited enhanced EDHF-type vasodilatations in resistance-sized arterioles in vivo associated with reduced spontaneous tone. Endothelial IK_Ca/SK_Ca-type K_Ca currents, smooth muscle cell Ca²⁺ sparks and associated BK_Ca-mediated spontaneous transient outward currents were unchanged in TRPC1-/-. Smooth muscle contractility induced by receptor-operated Ca²⁺ influx or Ca²⁺ release and endothelium-independent vasodilatations were unaltered in TRPC1-/-. TRPC1-/- exhibited lower systolic blood pressure as determined by tail-cuff blood pressure measurements.

CONCLUSIONS AND IMPLICATIONS

Our data demonstrate that TRPC1 acts as a negative regulator of endothelial K_Ca channel-dependent EDHF-type vasodilatations and thereby contributes to blood pressure regulation. Thus, we propose a specific role of TRPC1 in the EDHF–K_Ca signalling complex and suggest that pharmacological inhibition of TRPC1, by enhancing EDHF vasodilatations, may be a novel strategy for lowering blood pressure.