Abstract Background and Aims Endothelial cells (ECs) sensing flow shear stress for vasodilation is essential for maintaining systemic blood pressure (BP), and its impairment leads to EC dysfunction and contributes to hypertension. Heart development protein with EGF like domain 1 (HEG1), a flow-sensitive endothelial-derived circulating protein, has been inversely associated with cardiovascular risks. This study aimed to elucidate the effects and mechanisms of endothelial-HEG1 in BP regulation. Methods and Results Plasma HEG1 levels is negatively associated with hypertension, as identified through a phenome-wide association study (PheWAS) of the UK Biobank population and validated in an independent cohort of hypertensive patients. Single-cell RNA sequencing analysis revealed downregulation of endothelial HEG1 expression in hypertensive rats, which was verified in arteries from hypertensive patients. Fluid shear stress was shown to induce HEG1 expression in ECs in a dose-dependent manner, and EC-specific HEG1 deletion mice (Heg1ECKO) exhibited a gradual elevated BP, reaching hypertensive levels in an ApoeKO background. Mechanistic studies revealed decreased endothelium-dependent vasodilation in the mesenteric arteries of Heg1 ECKO mice, primarily due to downregulated endothelial nitric oxide synthase (eNOS) and reduced nitric oxidate (NO) production. Further studies demonstrated that HEG1’s intracellular domain interacts with E3 ligase Cullin3 (CUL3), promoting ubiquitination and degradation of the phosphatase and actin regulator 1 (PHACTR1). Loss of HEG1 resulted in increased PHACTR1, which bound to phosphatase PP1α for nuclear co-translocation, leading to dephosphorylation and inactivation of the eNOS transcriptional activator SP1, contributing to reduced NO production and EC dysfunction. Finally, the PHACTR1 nuclear translocation inhibitor CCG-1423 reversed the impaired vasodilation and alleviated the endothelial-HEG1 deficiency-mediated hypertension. Conclusions This study identifies a novel shear-sensitive endothelial HEG1 signaling pathway that regulates BP by facilitating CUL3-mediated ubiquitination of PHACTR1, thereby maintaining SP1 phosphorylation, eNOS transcription, and NO production. These findings offer new insights into vascular tone and BP regulation, meanwhile presenting novel therapeutic targets for hypertension.Working model
Wu et al. (Sat,) studied this question.