The proliferation of blood vessels is crucial for a wide variety of physiological processes, such as embryonic development, normal growth and differentiation, wound healing, and reproductive functions.
During embryonic development, VEGF expression is first detected within the first few days following implantation in the giant cells of the trophoblast (79,111). At later devel opmental stages in mouse or rat embryos, the VEGF mRNA is expressed in several organs, including heart, vertebral column, kidney, and along the surface of the spinal cord and brain. In the developing mouse brain, the highest levels of mRNA expression are associated with the choroid plexus and the ventricular epithelium (111). In the human fetus (16-22 wk), VEGF mRNA expression is detectable in virtually all tissues, and is most abundant in lung kidney and spleen (112).
In situ hybridization studies have shown that the Flk-1 mRNA is expressed in the yolk sac and intraembryonic mesoderm, and later in angioblasts, endocardium, and small- and large-vessel endothelium (113,114). These findings strongly suggested a role for Flk-1 in the regulation of vasculogenesis and angiogenesis. Other studies have demonstrated that expression of Flk-1 mRNA is first detected in the proximal-lateral embryonic mesoderm, which gives rise to the heart (115). Flk-1 is then detectable in endocardial cell of heart primordia, and subsequently in the major embryonic and extraembryonic vessels (115). These studies have indicated that Flk-1 may be the earliest marker of endothelial cell precursors. The Flt-1 mRNA is selectively expressed in vascular endothelial cells, both in fetal and adult mouse tissues (116). Like the high-affinity VEGF binding, the Flt-1 mRNA is expressed in both proliferating and quiescent endothelial cells, suggesting a role for Flt-1 in the maintenance of endothelial cells (116).
VEGF expression is also detectable around microvessels in areas where endothelial cells are normally quiescent, such as kidney glomerulus, pituitary, heart, lung, and brain (117,118). These findings raised the possibility that VEGF may be required not only to induce active vascular proliferation, but, at least in some circumstances, also for the maintenance of the differentiated state of blood vessels (117). In agreement with this hypothesis, Alon et al. (119) have shown that VEGF acts as a survival factor, at least for the developing retinal vessels. They propose that hyperoxia-induced vascular regression in the retina of neonatal animals is a consequence of inhibition of VEGF production by glial cells.
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