Loss of Endothelial TRPC1 Induces Aortic Hypercontractility and Hypertension.

Abstract

Background: The increasing prevalence of obesity-related cardiovascular diseases demands a better understanding of the contribution of different cell types to vascular function for developing new treatment strategies. Previous studies have established a fundamental role of TRPC1 (transient receptor potential channel canonical family member 1) in blood vessels. However, little is known about its functional roles within different cell types.

Methods: We generated endothelial-specific TRPC1-deficient and knockin mice and analyzed their changes in vascular function under physiological and pathologically obese state. Wire myography, Ca²⁺ image, blood pressure measurements, RNA-sequencing analysis, liquid chromatography-mass spectrometry, immunoblotting, ELISA, luciferase reporter assay, and morphometric assessments were performed to unravel phenotype and molecular changes in response to the absence or presence of endothelial TRPC1.

Results: Loss of endothelial TRPC1 reduced endothelial-dependent relaxation and exaggerated endothelial-dependent contraction in mouse aorta. As expected, loss of endothelial TRPC1 amplified blood pressure and decreased acetylcholine-induced intracellular Ca²⁺ concentration rise in the aorta. In endothelial-specific TRPC1-deficient mouse arteries, the mRNA profile identified upregulation of c-Fos. Blockade of c-Fos rescued the impaired vasomotor tone in the aorta of mice deficient in endothelial TRPC1. Endothelial TRPC1-regulated nitric oxide/endothelin-1 production is involved in vascular c-Fos expression. Moreover, knockin of endothelial TRPC1 ameliorated enhanced endothelial-dependent contraction and hypertension in obese mice which is related to alleviated endothelial endothelin-1/c-Fos production and smooth muscle contraction.

Conclusions: Our results identify endothelial TRPC1 as a previously unclear regulator of vascular changes and blood pressure in both physiological and pathologically obese state, and it is associated with nitric oxide/endothelin-1/c-Fos signaling.