The role of von Hippel -Lindau mutation in polycythemia and pulmonary hypertension

Abstract

Adaptation to low oxygen, or hypoxia, is primarily mediated by hypoxia-inducible factor (HIF) proteins, which regulate a wide range of genes involved in processes such as glycolysis, angiogenesis, and erythropoiesis. HIF activity is regulated in an oxygen-dependent manner by the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which promotes ubiquitin-mediated degradation of HIF-α subunits. Most mutations in the VHL gene predispose patients to the formation of highly vascular tumors, due in large part to constitutive HIF signaling. In contrast, germline homozygosity for the unique Chuvash mutation in VHL, 598C\u3eT (R200W in pVHL), results in polycythemia and pulmonary hypertension. To understand the effects of this substitution on pVHL function and to gain insights into the pathogenesis of these diseases, we have generated mice expressing this mutation (VhlR/R). These mice developed polycythemia, with increased hematocrits and elevated serum levels of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) highly similar to the human disease, likely resulting from enhanced erythropoiesis in the spleen. In addition, VhlR/R mice also developed pulmonary hypertension, with elevated pulmonary arterial pressures, hemorrhage, accumulation of extracellular matrix proteins, and macrophage infiltration in the lungs. Therefore, these mice faithfully recapitulate human Chuvash disease and represent a good model for further analysis of the effects of this mutation on both HIF-dependent and HIF-independent pVHL functions. Interestingly, we detected upregulation of many HIF targets in VhlR/R tissues, especially the spleen and lung, and in particular genes preferentially activated by the HIF-2α isoform. These results suggest that increased expression of HIF-2α-regulated genes plays a prominent role in the development of both polycythemia and pulmonary pathology in mice expressing the R200W mutation. Furthermore, these findings offer important insights into the mechanisms underlying these diseases in humans and suggest potential therapeutic implications