Loss of Endothelial TRPC1 Induces Aortic Hypercontractility and Hypertension.

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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. 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. 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. 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.