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Vascular endothelial growth factor A (VEGFA) production by podocytes is critical for glomerular endothelial health. VEGFA is also expressed in tubular epithelial cells in kidney; however, its physiologic role in the tubule has not been established. Using targeted transgenic mouse models, we found that Vegfa is expressed by specific epithelial cells along the nephron, whereas expression of its receptor (Kdr/Vegfr2) is largely restricted to adjacent peritubular capillaries. Embryonic deletion of tubular Vegfa did not affect systemic Vegfa levels, whereas renal Vegfa abundance was markedly decreased. Excision of Vegfa from renal tubules resulted in the formation of a smaller kidney, with a striking reduction in the density of peritubular capillaries. Consequently, elimination of tubular Vegfa caused pronounced polycythemia because of increased renal erythropoietin (Epo) production. Reducing hematocrit to normal levels in tubular Vegfa-deficient mice resulted in a markedly augmented renal Epo production, comparable with that observed in anemic wild-type mice. Here, we show that tubulovascular cross-talk by Vegfa is essential for maintenance of peritubular capillary networks in kidney. Disruption of this communication leads to increased renal Epo production and resulting polycythemia, presumably to counterbalance microvascular losses.

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SignificanceReducing vascular leakage and stabilizing the endothelium through activation of the angiopoietin (ANGPT)–TIE2 receptor tyrosine kinase pathway is a promising therapeutic strategy for vascular diseases. ANGPT2 is one of two major ligands for the TIE2 receptor. Uniquely, ANGPT2 possesses an agonistic role in lymphatic endothelium, but acts as a competitive antagonist in blood endothelium. The molecular basis for the opposing actions of ANGPT2 in these two vascular beds is poorly understood. Here we demonstrate that the absence of VEPTP expression in the lymphatic endothelium confers an agonist function of ANGPT2 on TIE2 receptor, but VEPTP expression in blood endothelium abrogates its activity. Our findings provide mechanistic insights needed to advance therapeutic targeting of this pathway.