Faculty Collaboration Database

Autophagy modulates the mechanism of flow-mediated dilation upstream of telomerase. Basic Res Cardiol 2025 Dec;120(6):1131-1140

Date

11/15/2025

Pubmed ID

41238787

Pubmed Central ID

PMC12680695

DOI

10.1007/s00395-025-01146-5

Scopus ID

2-s2.0-105021839661 (requires institutional sign-in at Scopus site)

Abstract

The non-canonical functions of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase play a critical role in maintaining microvascular homeostasis utilizing both human and rodent models. Previously, we have demonstrated that intact autophagic flux is necessary for the beneficial effects of TERT to maintain microvascular function and redox status in human resistance arterioles. The purpose of this investigation was to examine (1) whether loss of TERT function in vivo resulted in reductions in autophagy/mitophagy and concomitant changes in the mediator of microvascular FMD; (2) whether restoration of autophagy can reverse this pathological switch in dilator mechanism, reduce shear-induced mitochondrial H₂O₂ production while enhancing NO production. TERT mutant rats were generated and compared to their WT counterparts. Rats were given an autophagy activator (2% trehalose) for 28-days. Isolated mesenteric arteries were used for videomicroscopy, and aortic tissue was collected for immunoblotting. FMD and autophagic flux were measured in arteries in all groups. Loss of TERT function resulted in a switch from NOS-dependent to H₂O₂-dependent FMD, repressed microvascular shear-induced autophagic flux and NO production, and increased mitochondrial H₂O₂ production. Activation of autophagy restored NO-mediated dilation in TERT mutant rats, and enhanced shear-induced autophagic flux. We provide evidence that autophagy is necessary for the beneficial role of TERT within maintaining microvascular function, positioning this pathway as a modifiable target to maintain microvascular health by rescuing the endothelial dysfunction caused by loss of TERT signaling.

Author List

Hughes WE, Hader SN, Astbury K, Brandt L, Ait-Aissa K, Gutterman DD, Beyer AM

Authors

Andreas M. Beyer PhD Professor in the Medicine department at Medical College of Wisconsin
David Gutterman MD Emeritus Professor in the Medicine department at Medical College of Wisconsin
William E. Hughes PhD Assistant Professor in the Anesthesiology department at Medical College of Wisconsin

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

Animals
Autophagy
Hydrogen Peroxide
Male
Mesenteric Arteries
Mitochondria
Nitric Oxide
Rats
Rats, Sprague-Dawley
Telomerase
Vasodilation