Transcriptomics

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A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling


ABSTRACT: Vascular remodeling to match arterial diameter to tissue metabolic requirements commonly fails in ischemic disease. Endothelial cells (EC) sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Higher FSS induces vessel outward remodeling to return FSS to physiological levels, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS and suppressed at higher flow. The Smad1/5 pathway opposes activation of Akt, suggesting that inhibiting Smad1/5 may be required for outward remodeling. Here, we report that suppression of Smad1/5 at high FSS is mediated by elevated KLF2, which induces the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces arterial outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both STZ-induced type 1 and HFD-induced type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes. Thus, suppression of Smad1/5 is required for high FSS-mediated outward remodeling and is a potential therapeutic approach for ischemic disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267813 | GEO | 2024/05/24

REPOSITORIES: GEO

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