What Type of VEGF Do You Need?

Abstract

Typically considered a mediator of angiogenesis and vascular permeability, vascular endothelial growth factor (VEGF) has emerged as an important modulator of glomerular health and disease. The pleiotropic nature VEGF was dramatically illustrated in cases in which patients who were undergoing chemotherapy with VEGF antibodies ( e.g. , bevacizumab) developed proteinuria1 and thrombotic microangiopathy,2 indicating damage to the glomerular filtration barrier. In addition, individuals with preeclampsia, a condition characterized by excess circulating levels of a soluble form of the VEGF receptor, can likewise develop proteinuria,3 and increased serum levels of sFlt may contribute to endothelial dysfunction in chronic kidney disease.4 These studies suggest that a threshold of VEGF must be met to ensure glomerular health. Accordingly, in this editorial space just 4 years ago, Mathieson asked, “How much VEGF do you need?”5 At the time, the question was prompted by several studies demonstrating that VEGF gene dose is critical to glomerular development, structure, and function. Quaggin's group6,7 was reporting the generation of a series of gene-targeted mice with podocyte-specific VEGF reduction, with expression ranging from 0 to 50% of normal. This exquisite control over VEGF expression yielded a striking variety of phenotypes: When VEGF expression is ablated entirely, glomerular development fails and perinatal lethality ensues; low expression levels (approximately 25% of normal) results in a cascade of glomerular cell attrition beginning with endothelial and proceeding to mesangial cells shortly after birth, and intermediate VEGF levels (approximately 50% of normal) recapitulates …