Endothelial von Hippel-Lindau gene deletion causes abnormal blood and lymphatic vasculature through ectopic activation of the HIF-CXCR4 axis

ABSTRACT The von Hippel-Lindau (VHL) protein regulates cellular oxygen sensing by degrading hypoxia-inducible factors (HIFs) under normoxic conditions. VHL mutations show highly vascularized tumor across various organs due to HIF activation and upregulation of HIF-target genes such as VEGF in non-endothelial cells (ECs), influencing neighboring ECs and triggering abnormal angiogenesis. Whether VHL mutations in ECs also contribute to abnormal angiogenesis remains unclear. To address this question, we utilized a well-characterized skin vasculature model that encompasses the processes of vascular patterning and arterial/venous development, to investigate vascular development in mice with an EC-specific Vhl deletion. The mutants exhibited abnormal vascular network formation and embryonic lethal. Mechanistically, the Vhl deletion led to ectopic expression of the chemokine receptor CXCR4 through HIF stabilization in ECs. Treatment with AMD3100, a CXCR4 antagonist, partially restored vascular abnormalities caused by Vhl deletion in ECs. Additionally, publicly available single-cell RNA-sequencing data from ECs of individuals with VHL syndrome supports our findings, indicating that VHL mutations in ECs contribute to abnormal angiogenesis through ectopic activation of the HIF-CXCR4 signaling axis.