Flow-sensitive HEG1 controls eNOS activity to prevent endothelial dysfunction, hypertension, and atherosclerosis.

Area of Science:

• Cardiovascular Biology
• Endothelial Cell Biology
• Molecular Medicine

Background:

• Hypertension (HTN) is a major risk factor for atherosclerotic cardiovascular disease.
• Stable blood flow (s-flow) normally promotes atheroprotective endothelial cell (EC) functions, including nitric oxide (NO) production.
• The role of Heart-of-Glass 1 (HEG1) in EC function and its link to atherosclerosis were previously unknown.

Purpose of the Study:

• To investigate the novel role of HEG1 in endothelial cell (EC) dysfunction, hypertension, and atherosclerosis.
• To elucidate the mechanism by which HEG1 influences these conditions.
• To explore HEG1 as a potential biomarker for cardiovascular disease risk.

Main Methods:

• Utilized endothelial cell-specific knockout (ECKO) mouse models of Heg1.
• Investigated the interaction between HEG1 and endothelial nitric oxide synthase (eNOS).
• Analyzed plasma HEG1 levels in UK BioBank and Swedish cohort studies.

Main Results:

• Endothelial cell-specific knockout of Heg1 (Heg1^ECKO) leads to spontaneous hypertension and exacerbated atherosclerosis.
• HEG1 regulates NO bioavailability through a flow-dependent interaction with eNOS.
• ACE inhibition effectively treated hypertension and atherosclerosis in Heg1^ECKO mice.
• Plasma HEG1 levels are associated with hypertension and cardiovascular disease risk in human cohorts.

Conclusions:

• HEG1 plays a critical role in maintaining endothelial cell function and preventing hypertension and atherosclerosis.
• HEG1 regulates NO bioavailability via interaction with eNOS, modulated by blood flow.
• HEG1 represents a potential biomarker for cardiovascular disease and a target for personalized therapies.