class=”kwd-title”>Keywords: laminar flow KLF2 endothelial cells metabolism PFKFB3 Copyright notice

class=”kwd-title”>Keywords: laminar flow KLF2 endothelial cells metabolism PFKFB3 Copyright notice and Disclaimer The publisher’s final edited version of this article is available free at Arterioscler Thromb Vasc Biol See other articles in PMC that cite the published article. and Evacetrapib (LY2484595) hypoxia under pathophysiological says. To maintain homeostatic control of ECs gene expression in ECs is usually Evacetrapib (LY2484595) subjected to highly tight regulation at multiple levels including transcriptional and epigenetic control. Exposure of vascular ECs to athero-protective laminar shear stress promotes anti-inflammatory anti-thrombotic and anti-oxidative properties largely through inducing the expression of a cassette of transcriptional regulators including Kruppel-like factor-2 (KLF2).9 Biomechanical stimuli also contribute to a resting quiescent state in ECs.10 However the underlying mechanisms by which biomechanical stimuli such as laminar shear stress regulate cellular metabolism including glycolysis and mitochondrial content to maintain this resting metabolic state in ECs remains poorly understood. In this Evacetrapib (LY2484595) issue of Arteriosclerosis Thrombosis and Vascular Biology Doddaballapur et al.11 present elegant studies addressing the role of laminar shear stress in cellular metabolism of ECs. They report that laminar shear stress reduced EC glycolysis by regulating the expression of KLF2 and phosphofructokinase-2/fructose-2 6 (PFKFB3) an effect that maintained the quiescent metabolic state of ECs and inhibited angiogenesis (Physique). The authors exhibited that laminar shear stress reduced glucose uptake in ECs in a KLF2-dependent manner as supported by siRNA-mediated knockdown studies of KLF2 demonstrating complete abrogation of laminar shear stress-induced reduction of glucose uptake. Overexpression of exogenous KLF2 reduced glucose uptake lactate production glycolysis ATP levels mitochondrial content and basal mitochondrial Evacetrapib (LY2484595) respiration in ECs. Gain- and loss-of-function studies of PFKFB3 exhibited that KLF2 reduced glycolysis at least partially depending on its repressive effect on PFKFB3 expression. To determine how KLF2 inhibits PFKFB3 expression the authors scanned the PFKFB3 promoter region for potential KLF2 binding sites and found KLF2 binds to the PFKFB3 promoter at ~14 bp upstream to the transcription start site which mediated the repressive effect of KLF2. Transducing KLF2 into ECs reduced Rabbit Polyclonal to MRPS33. EC sprouting and network formation a phenotype that is partially rescued by exogenously expressed PFKFB3. These effects appear to be impartial of KLF2’s known regulatory effects on eNOS expression and nitric oxide (NO) production or 5′ adenosine monophosphate-activated protein kinase alpha 1 (AMPK-α1) expression. Furthermore KLF2 does not increase EC senescence or apoptosis in vitro as quantified by β-galactosidase activity p21 expression cell cycle profiling and caspase 3/7 and annexin staining. This study not only adds a new layer of complexity to the growing list of protective functions exerted by the grasp regulator KLF2 but also raises several provocative questions. While KLF2 may Evacetrapib (LY2484595) contribute to maintaining EC metabolic quiescence under laminar flow via PFKFB3 repression is usually loss of KLF2 expression whether by turbulent/disturbed shear stress (ie. as Evacetrapib (LY2484595) observed at vessel branch points) or by biochemical stimuli (ie. cytokines) necessary to increase EC metabolism in vivo? Under more stringent conditions of hyperglycemia hyperlipidemia and/or hypertension is usually this EC resting metabolic state lost in a KLF2-dependent manner? Does KLF2-mediated regulation of PFKFB3 occur in the microvasculature where shear stress forces may not be as dominant as found in the macrovasculature? Given KLF2’s anti-angiogenic effects in ECs would increased KLF2 expression confer deleterious effects in response to ischemic conditions? Conversely will inhibition of KLF2 or overexpression of PFKFB3 expression rescue impaired angiogenesis found in relevant cardiovascular disease states such as myocardial or limb ischemia or diabetic wound healing? Collectively this study paves the way for new directions with considerable scientific interest. Figure The regulation of endothelial cellular metabolism by shear stress through Kruppel-like factor 2 (KLF2) and phosphofructokinase-2/fructose-2 6 (PFKFB3) In this study both laminar shear stress and exogenously.