NIH Research Festival
The VHL gene, a tumor suppressor gene, plays a vital role in cellular oxygen sensing, by targeting the degradation of hypoxia-inducible factors (HIFs) under normoxic conditions. VHL syndrome is an autosomal dominant genetic disorder resulting from germ line mutations in the VHL gene and patients develop highly vascularized tumors in multiple organs due to the activation of HIFs and their downstream targets, such as VEGF, in non-vascular tissues which affects neighboring endothelial cells and stimulates angiogenesis. Whether VHL mutations in endothelial cells affect angiogenesis, however, remains unclear. To address this question, we investigated skin vascular development in the mutants having the endothelial cell-specific VHL deletion. The mutants exhibit vascular abnormalities and embryonic lethal. At the mechanistic level, the deletion of VHL leads to aberrant expression of the chemokine receptor Cxcr4, a well-known target of HIFs, in endothelial cells. Indeed, the upregulation of Cxcr4 expression observed in VHL knockdown is reversed when HIFs are additional knocked down of HIFs in cultured endothelial cells. Moreover, endothelial cell-specific overexpression of Cxcr4 results in similar vascular abnormalities to those observed in endothelial cell-specific VHL deletion. These findings suggest that VHL deletion induces aberrant expression of Cxcr4 through constitutive stabilization of HIFs, leading to vascular abnormalities. AMD3100, a Cxcr4 antagonist, partially restored vascular abnormalities in endothelial cell-specific VHL deletion. Combined, these studies demonstrate that VHL mutations in endothelial cells lead to vascular abnormalities through the aberrant activation of HIF-Cxcr4 axis. AMD3100 can be serve as an additional therapeutic approach for VHL syndrome, complementing anti-VEGF therapy.
Scientific Focus Area: Developmental Biology
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