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bioRxiv · 10.1101/2025.06.24.660441

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

Clark, M. D.·Kim, Y.·Romero, C. A.·Kang, D. W.·Baek, K. I.·Song, E. J.·Kellum, C. E.·Bowman-Kirigin, J. A.·Park, C.·Vapoor, V.·Pollock, J. S.·Jo, H.
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Abstract

Hypertension (HTN), the chronic elevation of blood pressure, accounts for more atherosclerotic cardiovascular disease deaths than any other modifiable risk factor.1 In the arteries, stable blood flow (s-flow) drives healthy, atheroprotective endothelial cell (EC) functions including nitric oxide (NO) production, barrier function, and anti-inflammatory programs via the action of flow-sensitive proteins. We showed that s-flow stimulates Heart-of-Glass 1 (HEG1) protein expression, localization to cell-cell junctions, and secretion from ECs.2 We found that conditional, endothelial cell-specific knockout of (Heg1ECKO) exacerbates atherosclerosis2, however the mechanism was unknown. Here, we report a new role of HEG1 in controlling EC dysfunction, hypertension and atherosclerosis. We discover a novel mechanism: HEG1 regulates NO bioavailability via a flow-dependent HEG1-eNOS interaction (endothelial nitric oxide synthase, NOS3). Heg1ECKO develops spontaneous hypertension and severe atherosclerosis, both of which are effectively treated by Angiotensin-Converting Enzyme inhibition (ACEi). UK BioBank and Swedish cohort studies reveal that plasma HEG1 levels are associated with hypertension and cardiovascular disease risk.3,4 Our findings suggest HEG1 may serve as a biomarker to advance personalized therapies for EC dysfunction, hypertension, and atherosclerosis.

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Clark, M. D., Kim, Y., Romero, C. A., Kang, D. W., Baek, K. I., Song, E. J., Kellum, C. E., Bowman-Kirigin, J. A., Park, C., Vapoor, V., Pollock, J. S., Jo, H.. 2025-06-27. Flow-sensitive HEG1 controls eNOS activity to prevent endothelial dysfunction, hypertension, and atherosclerosis. https://doi.org/10.1101/2025.06.24.660441

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