Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor–Associated Hypertension and Vascular Disease
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The VEGF (vascular endothelial growth factor) pathway has emerged as an important target for cancer therapy, with VEGF signaling pathway (VSP) inhibitors having been approved for several different malignancies. Less anticipated has been the multitude of cardiovascular and renal effects of these therapies. Hypertension occurs in at least a quarter of patients starting VSP inhibitors, with virtually every patient having an absolute increase in blood pressure. Patients can also develop proteinuria, renal dysfunction, vascular events, or cardiomyopathy. Although these toxicities have been generally manageable, they have introduced cardiovascular and renal considerations for patient care. On the other hand, these sequelae have provided a growing appreciation for the critical role of VEGF in vascular and renal homeostasis in human biology. Although several recent articles have addressed practical considerations with respect to patient care with this class of drugs,1–4 this review will explore mechanisms associated with the vascular toxicities arising from VEGF signaling inhibition in cancer treatment.
VEGF Signaling and VSP Inhibitors
The human VEGF family consists of 5 related glycoproteins: VEGFA, VEGFB, VEGFC, VEGFD, and PIGF (placental growth factor). These are secreted to form homodimers, which interact with a family of 3 receptor tyrosine kinases: VEGFR1 (VEGF receptor 1), VEGFR2, and VEGFR3 (Figure 1). VEGFA and VEGFB bind to VEGFR1, VEGFA binds to VEGFR2, and VEGFC and VEGFD bind to both VEGFR2 and VEGFR3.1,5 PIGF primarily interacts with VEGFR1. The VEGFRs are found on a wide variety of cell types. VEGFR1, also called Flt-1 (fms-like tyrosine kinase 1), is found on vascular endothelial cells, hematopoietic stem cells, monocytes, and macrophages. VEGFR2, also called KDR (kinase insert domain) or Flk-1 (fetal liver kinase 1), is expressed on vascular and lymphatic endothelial cells; VEGFR3 (also called Flt-4) is restricted to lymphatic endothelial cells.5 On ligand binding, VEGFRs transduce intracellular signals through …