PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1

Abstract

Objective: 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, which 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. In this study, we determine the role of PGC1α (peroxisome proliferator gamma coactivator-1α)-TERT (telomerase reverse transcriptase)-HMOX1 (heme oxygenase-1) during shear stress in vitro and in vivo. Approach and Results: Here, we have identified PGC1α as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared with oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) showed increased PGC1α expression and its transcriptional coactivation. PGC1α was required for laminar FSS-induced expression of TERT in vitro and in vivo via its association with ERRα(estrogen-related receptor alpha) and KLF (Kruppel-like factor)-4 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, HMOX1 was required for endothelial alignment to laminar FSS. Conclusions: These data suggest an important role for a PGC1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.

A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells

“…Additionally, components of the pentose phosphate pathway ( Aldoa , Pgd , Tkt ), another REDOX homeostasis pathway, are well represented among the CRISPR screen hits ( Table S1 ). Moreover, recent studies have shown that laminar shear influences mitochondrial-REDOX signaling to confer proper responses, including KLF2 expression ( Kant et al, 2022 ; Yamamoto et al, 2020 ). These data suggest that a delicate balance of pro- and antioxidative stress signaling determines activation of ERK5- Klf2 vs. pro-inflammatory pathways ( Liu et al, 2003 ).…”

Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

“…In various in vitro models, flow-induced shear stress has been shown to affect signaling of ECs and SMCs, either directly or via cellular crosstalk, and to induce SMC phenotype modulation, altered gene expression or re-organization of the cellular cytoskeleton. [50][51][52][53] Laminar flow-induced EC polarization and alignment to the direction of flow is evident, and recently Kant et al 53 demonstrated involvement of PGC1α-TERT-HMOX1 pathway in this response. Also, for example, PGI2 and other factors secreted by ECs under laminar flow can control phenotypic modulation of SMCs towards contractile stage.…”

Investigating the mechanism of Tongqiao Huoxue decotion in the treatment of allergic rhinitis based on network pharmacology and molecular docking: A review

“…[31] Endothelial response to fluid shear stress (FSS) is a critical element of vascular homeostasis. [32] Multi-directional and chaotic FSS caused curved and branched arteries more and this areas with unstable flow were more susceptible to infection and inflammation. [33] The binding mode and binding capacity of active components in THD to potential targets in AR were probed by molecular docking.…”