In addition to its role in blood vessel morphogenesis, VEGF has been implicated as being mitogenic for other cell types, which include lymphocytes, retina pigment epithelial cells, and Schwann cells. VEGF can act as a neuron survival factor. Nerves and blood vessels are both branched structures, forming intricate networks that are often associated with each other in the same anatomic space. However, it is unknown if they form their patterns in an independent or coordinated fashion. Arteries, but not veins, specifically align with peripheral nerves. VEGF is expressed by peripheral nerves and can induce expression of arterial markers (including ephrinB2) when added to primary embryonic endothelial cells in vitro . A similar effect was seen when neural cells were cocultured with endothelial cells, suggesting that neurons and Schwann cells induce ephrinB2 in primary embryonic endothelial cells by secretion of VEGF. In erbB3-/- mutant mice, Schwann cells are absent and blood vessels fail to arterialize. This is correlated with reduced nerve-associated VEGF levels, suggesting that VEGF from nerves is an arterializing factor in vivo . VEGF has also been found to promote arterial fate in zebrafish . Genetic studies demonstrated that VEGF acts downstream from the hedgehog signaling pathway, but upstream of Notch to specify arterial endothelial cell fate.
Use of VEGF antisense morpholinos resulted in loss of arterial markers from trunk vessels and ectopic venous marker expression in arterial vessels. This was similar to the phenotypes observed in animals with defective Notch signaling. Activated Notch induces arterial specification in the absence of VEGF, a further indication that VEGF is active upstream of the Notch pathway.
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