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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study identifies a novel shear-sensitive endothelial HEG1 signalling pathway in BP regulation, providing potential therapeutic targets for hypertension.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf742","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T11:54:33Z","timestamp":1757073273000},"page":"1721-1737","source":"Crossref","is-referenced-by-count":10,"title":["Shear stress-induced endothelial HEG1 signalling regulates vascular tone and blood pressure"],"prefix":"10.1093","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7781-406X","authenticated-orcid":false,"given":"Wenrun","family":"Wu","sequence":"first","affiliation":[{"name":"State 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