Ablation of Endothelial TRPV4 Channels Alters the Dynamic Ca(2+) Signaling Profile in Mouse Carotid Arteries

Transient receptor potential vanilloid 4 channels (TRPV4) are pivotal regulators of vascular homeostasis. Altered TRPV4 signaling has recently been implicated in various cardiovascular diseases, including hypertension and atherosclerosis. These versatile nonselective cation channels increase endothelial Ca(2+) influx in response to various stimuli including shear stress and G protein-coupled receptor (GPCR) activation. Recent findings suggest TRPV4 channels produce localized Ca(2+) transients at the endothelial cell plasma membrane that may allow targeted effector recruitment and promote large-scale Ca(2+) events via release from internal stores (endoplasmic reticulum). However, the specific impact of TRPV4 channels on Ca(2+) signaling in the intact arterial intima remains unknown. In the current study, we employ an endothelium-specific TRPV4 knockout mouse model (ecTRPV4(−/−)) to identify and characterize TRPV4-dependent endothelial Ca(2+) dynamics. We find that carotid arteries from both ecTRPV4(−/−) and WT mice exhibit a range of basal and acetylcholine (ACh)-induced Ca(2+) dynamics, similar in net frequency. Analysis of discrete Ca(2+) event parameters (amplitude, duration, and spread) and event composite values reveals that while ecTRPV4(−/−) artery endothelium predominantly produces large Ca(2+) events comparable to and in excess of those produced by WT endothelium, they are deficient in a particular population of small events, under both basal and ACh-stimulated conditions. These findings support the concept that TRPV4 channels are responsible for generating a distinct population of focal Ca(2+) transients in the intact arterial endothelium, likely underlying their essential role in vascular homeostasis.