Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3

Item Type:	Article
Title:	Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3
Creators Name:	Doddaballapur, A. and Michalik, K.M. and Manavski, Y. and Lucas, T. and Houtkooper, R.H. and You, X. and Chen, W. and Zeiher, A.M. and Potente, M. and Dimmeler, S. and Boon, R.A.
Abstract:	OBJECTIVE: Cellular metabolism was recently shown to regulate endothelial cell phenotype profoundly. Whether the atheroprotective biomechanical stimulus elicited by laminar shear stress modulates endothelial cell metabolism is not known. APPROACH AND RESULTS: Here, we show that laminar flow exposure reduced glucose uptake and mitochondrial content in endothelium. Shear stress-mediated reduction of endothelial metabolism was reversed by silencing the flow-sensitive transcription factor Kruppel-like factor 2 (KLF2). Endothelial-specific deletion of KLF2 in mice induced glucose uptake in endothelial cells of perfused hearts. KLF2 overexpression recapitulates the inhibitory effects on endothelial glycolysis elicited by laminar flow, as measured by Seahorse flux analysis and glucose uptake measurements. RNA sequencing showed that shear stress reduced the expression of key glycolytic enzymes, such as 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3), phosphofructokinase-1, and hexokinase 2 in a KLF2-dependent manner. Moreover, KLF2 represses PFKFB3 promoter activity. PFKFB3 knockdown reduced glycolysis, and overexpression increased glycolysis and partially reversed the KLF2-mediated reduction in glycolysis. Furthermore, PFKFB3 overexpression reversed KLF2-mediated reduction in angiogenic sprouting and network formation. CONCLUSIONS: Our data demonstrate that shear stress-mediated repression of endothelial cell metabolism via KLF2 and PFKFB3 controls endothelial cell phenotype.
Keywords:	Angiogenesis, Endothelium, Glycolysis, Hemodynamics, Metabolism, Shear Stress Down Regulated Gene-1 Protein, Human, Animals, Mice
Source:	Arteriosclerosis Thrombosis and Vascular Biology
ISSN:	1079-5642
Publisher:	American Heart Association
Volume:	35
Number:	1
Page Range:	137-145
Date:	January 2015
Official Publication:	https://doi.org/10.1161/ATVBAHA.114.304277
PubMed:	View item in PubMed

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