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

초록

Hypoxia-inducible factors (HIFs) act as master regulators ofhypoxia-induced pathological angiogenesis, a hallmark of variousischemic ocular diseases. Recent evidence highlights thepivotal role of HIF-2α among HIF isoforms in endothelial cells(ECs) undergoing pathological angiogenesis under hypoxic conditions. However, the regulatory mechanisms underlying endothelialHIF-2α expression during hypoxia remain incompletelyunderstood. Here, we demonstrated that stem cell factor (SCF)and its receptor, cKIT, upregulate HIF-2α expression in hypoxicECs. Using the oxygen-induced retinopathy (OIR) mouse model,we observed that HIF-2α was highly expressed in cKIT-positivepathological neovessels in the retina, and SCF was upregulatedmainly at astrocytes in the inner retinal layer. Experiments usingcKIT mutant mice and anti-SCF neutralizing antibody demonstratedthat inhibition of SCF/cKIT signaling significantly reduced retinalHIF-2α expression and pathological angiogenesis in micewith OIR. Moreover, HIF-2α inhibition abolished the SCF-inducedincrease in the angiogenic activity of human umbilical vein ECs(HUVECs) under hypoxic conditions. Mechanistic studies inHUVECs revealed that SCF enhanced HIF-2α protein levelswithout affecting HIF2A mRNA levels, through AKT- andERK1/2-dependent phosphorylation of ribosomal protein S6kinase β-1 under hypoxia. These findings provide novel insightsinto the regulatory mechanisms controlling HIF-2α expression inangiogenic ECs during hypoxia and suggest that the SCF/cKIT/HIF-2α axis in hypoxic ECs represents a crucial pathwayin the regulation of pathological angiogenesis in ischemicocular diseases.

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