The inherited disease Von Hippel-Lindau (VHL) syndrome results from loss-of-function mutations in VHL, which encodes a negative regulator of the hypoxia-inducible transcription factors HIF1α and HIF2α. Individuals with VHL syndrome commonly present with hypervascular tumors, renal cell cancers, and elevated levels of circulating rbc. Targeted therapies for VHL syndrome are currently limited, and surgical removal of tumors is often the only course of action. Ana Metelo and colleagues at Harvard Medical School developed a zebrafish model of VHL and demonstrated that treatment of these animals with a HIF2α inhibitor ameliorates VHL-associated phenotypes. Specific inhibition of HIF2α resulted in downregulation of Hif target genes and decreased vascular growth, circulating erythroid progenitors, and the incidence of heart defects. Moreover, HIF2α inhibition improved survival of vhl-deficient zebrafish. The results of this study indicate that HIF2α-specific inhibitors should be further explored as a therapeutic strategy for VHL syndrome. The accompanying image shows blood vessel development (O-dianisidine staining, brown) in WT zebrafish embryos (top left), vhl-deficient embryos (top right) and vhl-deficient embryos treated with either 1μm (bottom left) of 3.5 μm (bottom right) HIF2α inhibitor. Inhibition of HIF2α decreases the aberrant blood vessel sprouting and erythrocytosis observed in vhl-null embryos.
Patients with a germline mutation in von Hippel-Lindau (
Ana Martins Metelo, Haley R. Noonan, Xiang Li, Youngnam Jin, Rania Baker, Lee Kamentsky, Yiyun Zhang, Ellen van Rooijen, Jordan Shin, Anne E. Carpenter, Jing-Ruey Yeh, Randall T. Peterson, Othon Iliopoulos