Vascular endothelial growth factors and angiogenesis.

VEGF was discovered in 1989. Research -conducted over the past 10 years has -demonstrated that VEGF is a major regulator of angiogenesis and vasculogenesis. This paper reviews the molecular data on the multiple forms of VEGF, their signalling and accessory receptors. Five genes encoding VEGF-like proteins have been identified; the different isoforms of each VEGF molecule are generated by alternative splicing mechanisms. The different VEGF's recognize signalling tyrosine kinase receptors (Flt-1, Flk-1 and Flt-4) and accessory receptors. VEGF expression is stimulated by hypoxia-dependent and -independent mechanisms. Hypoxic responses are mediated by specific transcription factors that are expressed in a tissue dependent fashion and that are developmentally regulated. VEGF is thought to play a role in tumor angiogenesis and may contribute to cardioprotection in ischemic heart -diseases. Its role in pulmonary hypertension induced by chronic hypoxia is discussed. This review also stresses the difficulty of applying results from in vitro -studies to in vivo situations.