Stem cell factor and cKIT modulate endothelial glycolysis in hypoxia

Area of Science:

• Cell Biology
• Metabolic Regulation
• Vascular Biology

Background:

• Endothelial cells (ECs) form new vasculature through angiogenesis, a process crucial in hypoxic conditions.
• ECs in ischaemic tissues rely on glycolysis to meet metabolic demands for angiogenesis.
• The molecular links between angiogenesis and endothelial metabolism are under active investigation.

Purpose of the Study:

• To investigate the role of stem cell factor (SCF) and its receptor cKIT in regulating endothelial glycolysis during hypoxia-driven angiogenesis.
• To elucidate the molecular mechanisms by which SCF/cKIT signalling affects endothelial metabolism and angiogenesis.

Main Methods:

• Assessed glucose uptake, lactate production, and glycolysis in human ECs under hypoxia with SCF/cKIT stimulation.
• Utilized chemical inhibitors to reduce glycolysis and HIF-1α expression.
• Examined SCF, cKIT, HIF-1α, GLUT1, and glycolytic enzyme levels in mouse models of oxygen-induced retinopathy (OIR).
• Investigated the effect of blocking SCF/cKIT signalling on neovascularization in OIR mice.

Main Results:

• SCF and cKIT signalling enhanced glucose uptake, lactate production, and glycolysis in human ECs under hypoxia.
• This signalling pathway increased the expression of GLUT1 and glycolytic enzymes via Akt/ERK-dependent HIF-1α translation.
• Inhibition of glycolysis and HIF-1α reduced SCF-induced in vitro angiogenesis.
• OIR mice showed increased SCF, cKIT, HIF-1α, GLUT1, and glycolytic enzymes in the retina, with elevated expression in neovessels.
• Blocking SCF/cKIT signalling reduced HIF-1α, GLUT1, glycolytic enzymes, and pathological neovascularization in OIR mice.

Conclusions:

• SCF and cKIT signalling regulate angiogenesis by controlling endothelial glycolysis in hypoxic conditions.
• The SCF/cKIT/HIF-1α axis represents a novel metabolic regulatory pathway in hypoxia-driven pathological angiogenesis.