Shear stress-induced endothelial HEG1 signalling regulates vascular tone and blood pressure

Abstract Background and Aims Endothelial cells (ECs) sense flow shear stress for vasodilation, a crucial mechanism for maintaining systemic blood pressure (BP). Impaired shear stress signalling contributes to endothelial dysfunction and hypertension. Heart development protein with EGF-like domain 1 (HEG1), a flow-sensitive, endothelial-derived protein, is inversely associated with cardiovascular risks. This study aimed to elucidate the role of endothelial HEG1 in BP regulation and the underlying mechanisms. Methods Phenome-wide association study, computational fluid dynamics analysis, single-cell RNA sequencing, artery and plasma samples from independent cohorts, and in vitro shear stress analysis were used to assess the association between hypertension, shear stress, and HEG1 levels. Endothelial-specific Heg1 deletion mice, BP monitoring, and vascular function analysis were employed to characterize the roles of EC-HEG1 in endothelial function and hypertension. Proteomics, transcriptomics, and ubiquitination assays were used to identify the regulatory pathways involved. Results Plasma HEG1 levels were down-regulated in hypertensive subjects due to reduced wall shear stress on the endothelium, which diminished HEG1 expression and its release into circulation. Endothelial-specific Heg1 deletion in mice resulted in elevated BP, impaired endothelium-dependent vasodilation, and hypertensive levels especially in an ApoeKO dyslipidaemia background. Mechanistically, HEG1 facilitated CUL3-mediated degradation of PHACTR1. HEG1 deletion led to increased PHACTR1 levels, nuclear translocation, and suppression of SP1-mediated eNOS transcription and NO production. Inhibition of PHACTR1 nuclear localization by CCG-1423 prevented impaired vasodilation and hypertension. Conclusions Our study identifies a novel shear-sensitive endothelial HEG1 signalling pathway in BP regulation, providing potential therapeutic targets for hypertension.