In the microvessels that deliver nutrients to and remove wastes from tissues, a single layer of endothelial cells separates the blood from the parenchyma. This endothelial barrier consists of a sheet of polarized cells, with the apical surface of the cells facing the vessel lumen (luminal) and the basal side facing the parenchyma (abluminal). Vascular endothelial growth factor A (VEGF-A) typically promotes vessel permeability. However, Hudson et al. found that VEGF-A did not promote permeability of microvessels in the brain or eye when intravenously injected into mice, but did increase permeability when injected directly into the brain or eye. This suggested that VEGF-A induced permeability only when presented to the abluminal side of neural microvessels. Primary neural microvessel endothelial cells (MVECs) retain their intercellular junctions, apicobasal polarity, and barrier function in culture. In neural MVECs isolated from the retina or brain of rat, mouse, or pig, VEGF-A induced permeability only when administered to the basal side of the MVEC monolayer. Whereas VEGF receptor 1 (VEGFR1) was distributed predominantly on the apical surface of rat brain MVECs, VEGFR2 was distributed predominantly on the basal surface. Intact mouse hippocampal microvessels also exhibited this polarized distribution of VEGFR1 and VEGFR2. In contrast, both receptors were abundant on the luminal surface of lung microvessels. A VEGFR2-specific inhibitor blocked VEGF-A–induced permeability in cultured brain MVECs. The kinases Akt and p38 are two of the many downstream signaling components activated by VEGF signaling in endothelial cells. Basal, but not apical, application of VEGF-A induced phosphorylation (activation) of p38 in cultured rat brain MVECs. In contrast, apical, but not basal, application of VEGF-A or a VEGFR1-specific ligand induced phosphorylation (activation) of Akt. Neither apical nor basal application of a ligand selective for VEGFR2 induced phosphorylation of Akt. In vivo, intravenous injection of VEGF-A induced phosphorylation of Akt in retinal lysates, but injection directly into the retina (abluminal application) did not. Intravenous injection of VEGF-A induced the accumulation of phosphorylated p38 in lung microvessels, but not in microvessels of the membrane surrounding the spinal cord. Additional experiments indicated that apical application of VEGF-A protected cultured rat brain MVECs from staurosporine-induced apoptosis. These results imply a model in which VEGF-A at the basal surface of neural microvessel endothelia signals through VEGFR2 to induce vascular permeability, whereas VEGF-A at the apical surface signals through VEGFR1 to promote cell survival.
N. Hudson, M. B. Powner, M. H. Sarker, T. Burgoyne, M. Campbell, Z. K. Ockrim, R. Martinelli, C. E. Futter, M. B. Grant, P. A. Fraser, D. T. Shima, J. Greenwood, P. Turowski, Differential apicobasal VEGF signaling at vascular blood-neural barriers. Dev. Cell 30, 541–552 (2014). [PubMed]