Description

Callie Kwartler, Ph.D., Assistant Professor, University of Texas Health Science Center at Houston will present her Springer Award Lecture entitled, "An epigenetic link between metabolism and smooth muscle cell differentiation." Dr. Kwartler gave this talk after receiving NAVBO's Springer Junior Investigator Award at Vascular Biology 2025 in Hyannis, Massachusetts.

Abstract: 

Authors: Jose Emiliano Esparza Pinelo, Jessica Chen, Aminat Dosunmu, Hannah Krenz, Jeison Garcia Serrano, Angie Gonzalez, Dianna M. Milewicz, Callie S. Kwartler

Moyamoya disease (MMD), characterized by occlusive lesions in the distal internal carotid arteries, is a malignant cause of pediatric stroke. Heterozygous ACTA2 p.R179 pathogenic variants cause MMD-like cerebrovascular disease. ACTA2 encodes smooth muscle α-actin (SMA), and the p.R179 variant disrupts nuclear localization of SMA, leading to incomplete differentiation of smooth muscle cells (SMCs). SMCs from a conditional knock-in mouse model (Acta2R179C/+) are incompletely differentiated, leading to enhanced SMC migration and proliferation along with increased glycolysis and reduced oxidative respiration on Seahorse analyses. Nicotinamide riboside (NR) treatment restores oxidative respiration and surprisingly also increases SMC differentiation and decreases migration. Treatment with NR reduces death (Kaplan-Meier p=0.02) and resolves persistent lesions (p<0.05) in Acta2R179C/+ mice after carotid artery ligation injury. The mechanism by which NR treatment increases SMC differentiation is not intuitive. Our data supports that high glycolytic flux in Acta2R179C/+ SMCs leads to increased accumulation of 2-hydroxygluterate (2-HG), which has been previously shown to inhibit TET2, a master regulator of SMC differentiation. TET2 catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to open chromatin, and Acta2R179C/+ SMCs have globally increased 5mC and decreased 5hmC. NR treatment increases 5hmC and reduces 5mC, and exogenous 2-HG prevents NR from promoting SMC differentiation. Thus, the 2-HG/TET2 axis represents a novel link between metabolic reprogramming and SMC phenotype.