Endothelial USP8 is essential for angiogenesis.

Angiogenesis, the formation of new blood vessels from existing ones, is crucial for both development and disease. Its dysregulation is associated with diseases such as cancer, obesity, and blindness. Vascular endothelial growth factor A (VEGFA) signaling through VEGF receptor 2 (VEGFR2) is the central regulator of angiogenesis. Consequently, there is significant interest in identifying modulators of this pathway to develop targeted therapeutic interventions. Ubiquitination tags proteins for degradation, whereas deubiquitinases counteract this process by removing the attached ubiquitin molecules. Previous studies have shown that the deubiquitinase Ubiquitin-Specific Protease 8 (USP8) regulates VEGFR2 trafficking and activation in vitro, suggesting that USP8 may regulate endothelial cell function. To examine the role of endothelial USP8 in angiogenesis in vivo, we used conditional mouse genetics to delete Usp8 in endothelial cells at different stages: during embryonic development, after birth, and in adulthood. Loss of endothelial Usp8 during embryogenesis resulted in impaired intersomitic vessel angiogenesis and lethality by E10.5. Early postnatal deletion caused severe defects in retinal angiogenesis and abnormal brain vasculature, while adult deletion had no overt vascular effects. Impaired angiogenesis in endothelial Usp8 deficient mice was associated with decreased endothelial cell-cycle activation and increased vessel diameter in capillaries and veins. Mechanistically, we found that loss of endothelial Usp8 led to VEGFR2 accumulation in early endosome aggregates and reduced phospho-ERK signaling. Our findings identify endothelial USP8 as a key regulator of angiogenesis across developmental and postnatal contexts, while dispensable for endothelial homeostasis in adulthood, highlighting its potential as a therapeutic target for anti-angiogenic interventions.