VEGF non-angiogenic functions in adult organ homeostasis: therapeutic implications

Vascular endothelial growth factor (VEGF) is best known as an angiogenic factor essential for embryonic vasculogenesis and postnatal angiogenesis. Considerable evidence has accumulated that VEGF also has non-angiogenic functions. Early studies demonstrated that VEGF transcripts are ubiquitously expressed, and the phosphorylation of VEGF receptor is detectable in adult organs that have no feature of angiogenesis. Recent clinical studies showed that the inhibition of VEGF signaling results in diverse angiogenesis-irrelevant side effects involving the dysfunctions of many organs, suggesting non-angiogenic roles of VEGF in the regulation of organ homeostasis. On the other hand, VEGF stimulates endothelial cells (ECs) to express intercellular adhesion molecules that mediate physical interactions with adjacent tissue cells, or secreted various multifunctional substances that affect the functions of surrounding organs. Furthermore, very recent studies including ours have revealed VEGF as a potent agonist for endothelial exocytosis of Weibel-Palade bodies in which thrombogenic and inflammatory factors are stored. In this brief review, we highlight the importance of VEGF non-angiogenic functions in the modulation of tissue repair and organ regeneration, vascular homeostasis, and inflammation, and propose that the non-angiogenic functions are primarily mediated through the substances released from ECs.