Faculty Collaboration Database

Endothelial TERT drives microvascular phenotype associated with coronary artery disease. Am J Physiol Heart Circ Physiol 2025 Jul 01;329(1):H267-H270

Date

06/14/2025

Pubmed ID

40514200

Pubmed Central ID

PMC12233018

DOI

10.1152/ajpheart.00342.2025

Scopus ID

2-s2.0-105009755634 (requires institutional sign-in at Scopus site)

Abstract

Microvascular endothelial dysfunction is a powerful predictor of future atherosclerotic cardiac events. Our previous studies revealed that under pathological states, such as coronary artery disease (CAD), the dilation mechanism switches from nitric oxide (NO)-mediated [determined by NO synthase (NOS) inhibitor] to mitochondria-derived H₂O₂ (determined by H₂O₂ scavenger). Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, plays a noncanonical role in preventing the increase of mitochondrial reactive oxygen species in arterioles from subjects with CAD. Activation of TERT can reverse the mechanism of flow-induced, endothelium-dependent dilation from H₂O₂ to NO. Previous studies showed that systemic TERT knockout (KO) mice reduced NO synthase (NOS)-mediated dilation, accompanied by increased release of flow-induced mitochondrial H₂O₂ in microcirculations. In this study, we tested the hypothesis that knocking out the endothelial cell (EC)-specific TERT is sufficient to cause endothelial dysfunction in mice. The third/fourth branch of mesenteric arteries from male EC-specific TERT KO mice (3-5-mo old) were isolated, and endothelial-dependent vasodilator response to flow (FMD) and acetylcholine (ACh) was assessed by videomyography. In control animals, FMD was mediated by NOS, whereas in EC-TERT KO mice, dilation was significantly reduced, and the remaining dilation was mediated by both NOS and H₂O₂, suggesting a switch from NO to H₂O₂-mediated dilation. Similarly, ACh-induced dilation was reduced in EC-TERT KO mice compared with control mice, whereas smooth-muscle-dependent dilation to papaverine was not impaired. In conclusion, knocking down EC-TERT is sufficient to cause endothelial dysfunction and triggers a switch from physiological NO-mediated dilation to pathological H₂O₂-mediated dilation.NEW & NOTEWORTHY Previously established by Ait-Aissa et al. (Ait-Aissa K, Kadlec AO, Hockenberry J, Gutterman DD, Beyer AM. Am J Physiol Heart Circ Physiol 314: H1053-H1060, 2018), systemic TERT KO mice have a loss of NO synthase-mediated dilation to flow, accompanied by compensatory increased release of flow-induced H₂O₂ in coronary and peripheral microcirculations. Our study demonstrates that mice with EC-specific TERT KO exhibit phenotypes similar to systemic TERT deficiency and microvascular pathologies observed in patients with CAD. These findings underscore the critical, noncanonical, and likely mitochondrial-mediated regulation of vascular tone and systemic cardio-metabolic changes.

Author List

Birch EC, Nishijima Y, Hader SN, Beyer AM

Author

Andreas M. Beyer PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylcholine
Animals
Coronary Artery Disease
Disease Models, Animal
Endothelial Cells
Endothelium, Vascular
Hydrogen Peroxide
Male
Mesenteric Arteries
Mice
Mice, Inbred C57BL
Mice, Knockout
Microcirculation
Microvessels
Nitric Oxide
Phenotype
Telomerase
Vasodilation
Vasodilator Agents