European heart journal · 2026
Shear stress-induced endothelial HEG1 signalling regulates vascular tone and blood pressure.
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Wu Wenrun, Liu Jun, Chen Xiaoli, Zhu Pengxiong, Xu Jianfei, Yue Jinnan, Liu Xiuxiang, Fang Ji, Chen Xiaohui, Pi Jingjiang, Zheng Liang, Zhang Qi, Zhang Lin, Schneider Carolin Victoria, Schneider Kai Markus, Trautwein Christian, Gao Pingjin, Reilly Muredach P, Zhang Yuzhen, Zheng Xiangjian, Liu Jie
Аннотация
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.
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.