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Cardiovasc. Res., Mar 20 2024, cvae058 | https://doi.org/10.1093/cvr/cvae058 Stem cell factor and cKIT modulate endothelial glycolysis in hypoxia

Hayoung Jeong^a,b†, Ryul-I Kim^a,b†, Hyunwoo Koo^b, Yang Hee Choi^a,b, Minju Kim^a,b, Hyejin Roh^a,b, Sang Gyu Park^c, Jong-Hyuk Sung^d, Koung Li Kim^b*, Wonhee Suh^a,b*

^aDepartment of Global Innovative Drug, Graduate School of Chung-Ang University, Seoul 06974, Korea

^bCollege of Pharmacy, Chung-Ang University, Seoul 06974, Korea

^cCollege of Pharmacy, Ajou University, Suwon 16499, Korea

^dCollege of Pharmacy, Yonsei University, Incheon 21983, Korea.

^†These authors contributed equally to this work.

^*Address for Correspondence: Koung Li Kim, PhD, Wonhee Suh, PhD

Abstract

In hypoxia, endothelial cells proliferate, migrate, and form new vasculature in a process called angiogenesis. Recent studies have suggested that endothelial cells rely on glycolysis to meet metabolic needs for angiogenesis in ischemic tissues and several studies have investigated the molecular mechanisms integrating angiogenesis and endothelial metabolism. Here, we investigated the role of stem cell factor (SCF) and its receptor, cKIT, in regulating endothelial glycolysis during hypoxia-driven angiogenesis. SCF and cKIT signaling increased the glucose uptake, lactate production, and glycolysis in human endothelial cells under hypoxia. Mechanistically, SCF and cKIT signaling enhanced the expression of genes encoding glucose transporter 1 (GLUT1) and glycolytic enzymes via Akt- and ERK1/2-dependent increased translation of hypoxia inducible factor 1A (HIF1A). In hypoxic conditions, reduction of glycolysis and HIF-1α expression using chemical inhibitors significantly reduced the SCF-induced in vitro angiogenesis in human endothelial cells. Compared with normal mice, mice with oxygen-induced retinopathy (OIR), characterized by ischemia-driven pathological retinal neovascularization, displayed increased levels of SCF, cKIT, HIF-1α, GLUT1, and glycolytic enzymes in the retina. Moreover, cKIT-positive neovessels in the retina of mice with OIR showed elevated expression of GLUT1 and glycolytic enzymes. Further, blocking SCF and cKIT signaling using anti-SCF neutralizing IgG and cKIT mutant mice significantly reduced the expression of HIF-1α, GLUT1, and glycolytic enzymes and decreased the pathological neovascularization in the retina of mice with OIR. We demonstrated that SCF and cKIT signaling regulates angiogenesis by controlling endothelial glycolysis in hypoxia and elucidated the SCF/cKIT/HIF-1α axis as a novel metabolic regulation pathway during hypoxia-driven pathological angiogenesis.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-25)
연구진국내 연구진
분야 의약학 > 분자세포의학

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