The Effects of Antiangiogenic Compound SU5416 in a Rat Model of Pulmonary Arterial Hypertension

Abstract

Several lines of evidence indicate that vascular endothelial growth factor (VEGF) plays a prosurvival and antiapoptotic role in endothelial cells. SU5416 is the first VEGF receptor 2 inhibitor to enter clinical development for cancer therapy. A phase I/II study of SU5416 has been completed, and the results show that SU5416 is well tolerated in patients with terminal cancers. It has been shown that VEGF receptor blockade using SU5416 combined with chronic hypoxia results in severe angioproliferative pulmonary hypertension (PAH) with neointimal changes in adult rats. Although classic animal models of pulmonary hypertension (that is, the monocrotaline and hypoxic models) do not form obstructive intimal lesions in the peripheral pulmonary arteries, the SU5416 model has shown pulmonary arterial changes resembling plexiform lesions. Therefore, the SU5416 model of PAH has been used for some time, and it has thus contributed to a better understanding of the pulmonary hypertensive process. However, the mechanism by which SU5416 combined with chronic hypoxia can result in PAH with plexiform-like lesions in adult rats is complex and still remains to be fully elucidated. The most likely explanation is that there is increased apoptosis of endothelial cells in response to the loss of the survival signaling, creating conditions favoring the emergence of apoptosis-resistant cells with increased growth potential, that is, the endothelial cell hyperproliferation that might characterize the plexiform lesions of human PAH. The aim of the present review is to provide information useful for understanding a potent inhibitor of VEGF receptor tyrosine kinase, SU5416, and to better understand its use for generating animal models of PAH.