Endothelial TERT drives microvascular phenotype associated with coronary artery disease

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.