Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition.

Abstract

The recognition that angiogenesis is critical for tumor growth has stimulated the development of several agents that interfere with the process of angiogenesis. Of these agents, vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors have gained a prominent role in the treatment of a large variety of cancers. Along with their clinical introduction, treatment with VSP inhibitors appeared to be associated with the development of cardiovascular side effects, particularly hypertension, renal injury, cardiac dysfunction, thrombosis, and hemorrhage. When severe, these side effects are reason to discontinue VSP inhibitor treatment, obviously with repercussions for survival. In this review, we focus on mechanisms underlying the rise in blood pressure (BP) and kidney injury induced by VSP inhibitor treatment. Insight into the mechanisms of these side effects is not only of scientific interest, but may also provide a basis for their prevention with rational treatment. Because for a proportion of clinicians interested in hypertension the VEGF system is not common knowledge, we will start with a short description of this system and ways of its inhibition by pharmacological agents. The mammalian VEGF family includes the glycoproteins VEGF-A,VEGF-B, VEGF-C, VEGF-D, VEGF-E, and the placental growth factor, with VEGF-A, commonly referred to as VEGF, as the most prominent factor. The VEGFs are mainly present as homodimeric polypeptides. Alternative splicing and proteolytic processing increase the complexity of the VEGF system. For instance, alternative splicing of the gene encoding for VEGF-A gives rise to VEGF isoforms exerting antiangiogenic activity.1 VEGF is produced by most parenchymal cells, acting in a paracrine fashion on adjacent endothelial cells (ECs). The induction of VEGF is crucial for the initiation of angiogenesis, with hypoxia-inducible factor 1α and 2α and platelet-derived growth factor B as important positive regulators of its production.2 Genetic deletion experiments in mice have shown that the …