Stem cell factor regulates endothelial HIF-2α expression during hypoxia-driven pathological angiogenesis

초록

Hypoxia-inducible factors (HIFs) act as master regulators of hypoxia-induced pathological angiogenesis, a hallmark of various ischemic ocular diseases. Recent evidence highlights the pivotal role of HIF-2α among HIF isoforms in endothelial cells (ECs) undergoing pathological angiogenesis under hypoxic conditions. However, the regulatory mechanisms underlying endothelial HIF-2α expression during hypoxia remain incompletely understood. Here, we demonstrated that stem cell factor (SCF) and its receptor, cKIT, upregulate HIF-2α expression in hypoxic ECs. Using the oxygen-induced retinopathy (OIR) mouse model, we observed that HIF-2α was highly expressed in cKIT-positive pathological neovessels in the retina, and SCF was upregulated mainly at astrocytes in the inner retinal layer. Experiments using cKIT mutant mice and anti-SCF neutralizing antibody demonstrated that inhibition of SCF/cKIT signaling significantly reduced retinal HIF-2α expression and pathological angiogenesis in mice with OIR. Moreover, HIF-2α inhibition abolished the SCF-induced increase in the angiogenic activity of human umbilical vein ECs (HUVECs) under hypoxic conditions. Mechanistic studies in HUVECs revealed that SCF enhanced HIF-2α protein levels without affecting its mRNA levels, through AKT- and ERK1/2-dependent phosphorylation of ribosomal protein S6 kinase β-1 under hypoxia. These findings provide novel insights into the regulatory mechanisms controlling HIF-2α expression in angiogenic ECs during hypoxia and suggest that the SCF/cKIT/HIF-2 axis in hypoxic ECs represents a crucial pathway in the regulation of pathological angiogenesis in ischemic ocular diseases.