Vascular Endothelial Growth Factor

In this issue of Circulation Research , D’Arcangelo et al1 report highly interesting and unexpected results in that acidosis inhibits proliferation and migration of cultured endothelial cells, inhibits the formation of capillary tubes, but simultaneously increases expression of the endothelial growth factors vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2. In addition, VEGF expression was caused neither by hif-1 activation nor increased mRNA stability. In line with the latter observation may be that VEGF transgenic mice in which a reporter gene is controlled by the VEGF promoter missing the VEGF mRNA stabilizing downstream 3′ sequences2 still show expression in the periphery of tumors but restricted to non–tumor fibroblast-like cells.3 However, a word of caution should be permitted with regard to the interpretation of results. A 2-fold overexpression detected by a semiquantitative polymerase chain reaction method may not be extremely convincing, and the unorthodox mechanism of expression may be the result of simply no significant induction. Perhaps these findings may not have attracted so much attention were it not for the special relevance to tumor angiogenesis. In tumors, acidosis is the expected metabolic event, because most tumors prefer anaerobic glycolysis above the aerobic pathway even in the presence of oxygen, as we know from the pioneering work of Warburg et al.4 Another reason for acidosis in tumors is the hypoxia due to deficient capillarization.The failing capillarization of growing tumors, which ultimately leads to a necrotic core, may have to do with the acidosis that apparently counteracts the hypoxic angiogenic growth stimulus. Also, the fact that tumor vessels are immature, leaky, and inferior blood conductors may be related …