Human PL and GH are remarkably similar in amino acid sequence, and disulde bond number and position, whereas human PRL has amino acids and disulde bonds and shares only sequence identity with the other two hormones, but only GH activates the GH receptor. GH receptors have been detected in blood vessels from different vascular beds, where GH stimulates endothelial cell proliferation. The proangiogenic effects of GH have also been demonstrated in vivo.Indeed, IGFI is necessary for maximal VEGF activation of the mitogenactivated protein kinase, and IGFI induces the expression of retinal VEGF by activating the phosphatidylinositol kinase. IGFI may also mediate the proangiogenic actions of GH at other sites, as IGFI receptors are widely expressed in endothelial cells, and IGFI has been shown to stimulate angiogenesis in vivo and in vitro. However, some actions of GH on endothelial cells may be independent of IGFI.For example, GH is unable to increase the transcription of IGFI in endothelial cells.Instead, it promotes the expression and activity of endothelial NOS. In addition, systemic acutely increase forearm blood ow and NO release in healthy humans without signicantly raising plasma IGFI levels or muscle IGFI mRNA expression.While these observations argue in favor of an autonomous GH action mediated by NO, IGFI is also vasoactive due to its activation of eNOS, and more information is required to clarify this issue.The relevance of the vascular actions of GH is emphasized by clinical data showing that patients with GH deciency have increased risk of cardiovascular death. Loss of GH production in humans leads to increased peripheral resistance, reduced cardiac output, decreased blood ow in response to vasodilators, and reduced systemic NO levels, whereas GH replacement restores these responses to normal. Interestingly, some vasoconstrictive effects of GH via NO inhibition have also been reported in experimental settings. The complexity of GH vascular effects is further illustrated by the fact that elevated GH levels are not always associated with angiogenesis.Overexpression of GH in transgenic mice, acromegaly has no correlation with retinopathy, and longterm GH replacement therapy does not appear to increase the risk of retinopathy in children or adults. Interestingly, in the chick embryo chorioallantoic membrane, GH is proangiogenic only during the more differentiated, nongrowing state of blood vessels. Furthermore, treatment with GH does not stimulate the proliferation of some endothelial cells in culture. The retina has been considered a major target for the proangiogenic actions of the GHIGFI axis. Proliferative diabetic retinopathy is rare in dwarfs who are decient for GH and IGFI. Lowering circulating GH with a somatostatin analog alanine decreases ischemiainduced retinal neovascularization in mice or by genetic silencing of the GH receptor in transgenic dwarf mice. GH action on retinal angiogenesis is mediated primarily Flumazenil through circulating or locally produced IGFI. Therefore, the lack of action of exogenous GH may relate to endothelial cell GH receptors being already occupied by the endogenous hormone.Other important factors affecting GH actions on angiogenesis include its local proteolysis to vasoinhibins and the relative contribution of other related hormones.During pregnancy, PRL receptor deciency interferes with the vascularization of the corpus luteum null mice can be associated, in part, with subnormal neovascularization.