Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension

Our understanding of the pathobiology of severe pulmonary hypertension, usu ally a fatal disease, has been hampered by the lack of information of its n atural history. We have demonstrated that, in human severe pulmonary hypert ension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its recept or 2 (VEGFR-2) are involved in proper maintenance, differentiation, and fun ction of endothelial cells. We demonstrate here that VEGFR-2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonar y hypertension associated with precapillary arterial occlusion by prolifera ting endothelial cells. Prior to and concomitant with the development of se vere pulmonary hypertension, lungs of chronically hypoxic SU5416-treated ra ts show significant pulmonary endothelial cell death, as demonstrated by ac tivated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z-A sp-CH2-DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.