Pollock, J. S. | bioRxiv Science

bioRxiv2025

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

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.

physiology↗

bioRxiv2023

Endothelial Histone Deacetylase 1 Activity Impairs Kidney Microvascular NO Signaling in Rats Fed a High Salt Diet

AimWe aimed to identify new mechanisms by which a high salt diet (HS) decreases NO production in kidney microvascular endothelial cells. Specifically, we hypothesized HS impairs NO signaling through a histone deacetylase 1 (HDAC1)-dependent mechanism. MethodsMale Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or high salt diet (4% NaCl) for two weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. ResultsWe found that HS impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS fed rats to be sufficient to induce dysfunction suggesting a humoral factor, we termed Plasma Derived Endothelial-dysfunction Mediator (PDEM), mediates the endothelial dysfunction. The antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. ConclusionWe conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.

physiology↗