Regulation of endothelial cell metabolism: just go with the flow.

Abstract

The vascular endothelium, the major interface of the vessel wall between blood and all tissues, must constantly adapt to fluctuations in environmental cues. Cellular metabolism is one mechanism that may contribute to rapid dynamic changes in cell phenotype. For example, glycolysis, one of the major forms of cellular metabolism that converts glucose to pyruvate, is required for immune cell activation, tumor cell proliferation and survival, and the phenotypic switch of endothelial cells (ECs) between quiescent and angiogenic states.1–8 ECs are exposed to a variety of stimuli, such as turbulent/disturbed shear stress and hypoxia under pathophysiological states. To maintain homeostatic control of ECs, gene expression in ECs is subjected to highly tight regulation at multiple levels, including transcriptional and epigenetic control. Exposure of vascular ECs to atheroprotective laminar shear stress promotes anti-inflammatory, antithrombotic, and antioxidative 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. See accompanying article on page 137 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Doddaballapur et al11 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-bisphosphatase-3 (PFKFB3), an effect that maintained the quiescent metabolic state of ECs and inhibited angiogenesis (Figure). The authors demonstrated 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. …