RT Journal Article SR Electronic T1 PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.05.26.445830 DO 10.1101/2021.05.26.445830 A1 Shashi Kant A1 Khanh-Van Tran A1 Miroslava Kvandova A1 Amada D. Caliz A1 Hyung-Jin Yoo A1 Heather Learnard A1 Siobhan M. Craige A1 Joshua D. Hall A1 Juan M. Jiménez A1 Cynthia St. Hilaire A1 Eberhard Schulz A1 Swenja Kröller-Schön A1 John F. Keaney, Jr YR 2021 UL http://biorxiv.org/content/early/2021/05/27/2021.05.26.445830.abstract AB Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow that is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. Here we have identified peroxisome proliferator gamma coactivator-1α (PGC-1α) as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared to oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) increased PGC-1α expression and its transcriptional co-activation. PGC-1α was required for laminar FSS-induced expression of telomerase reverse transcriptase (TERT) in vitro and in vivo via its association with ERRα and KLF4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status was heme oxygenase-1 (HMOX1), a gene required for endothelial alignment to laminar FSS. Thus, these data suggest an important role for a PGC-1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.Competing Interest StatementThe authors have declared no competing interest.