Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis

Abstract

Prolactin, growth hormone and placental lactogen are members of a family of polypeptide hormones which share structural similarities and biological activities. Numerous functions have been attributed to these hormones, among which stand out their recently discovered effects on angiogenesis, the process by which new blood vessels are formed from the pre-existing microvasculature. Prolactin, growth hormone and placental lactogen, along with two non-classical members of the family, proliferin and proliferin-related protein, can act both as circulating hormones and as paracrine/autocrine factors to either stimulate or inhibit various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, migration, protease production and apoptosis. Such opposing actions can reside in similar but independent molecules, as is the case of proliferin and proliferin-related protein, which stimulate and inhibit angiogenesis respectively. The potential to exert opposing effects on angiogenesis can also reside within the same molecule as the parent protein can promote angiogenesis (i.e. prolactin, growth hormone and placental lactogen), but after proteolytic processing the resulting peptide fragment acquires anti-angiogenic properties (i.e. 16 kDa prolactin, 16 kDa growth hormone and 16 kDa placental lactogen). The unique properties of the peptide fragments versus the full-length molecules, the regulation of the protease responsible for specific protein cleavage, the selective expression of specific receptors and their associated signal transduction pathways are issues that are being investigated to further establish the precise contribution of these hormones to angiogenesis under both physiological and pathological situations. In this review article, we summarize the known and speculative issues underlying the effects of the prolactin, growth hormone and placental lactogen family of proteins on angiogenesis, and address important remaining enigmas in this field of research.

The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings

“…Additionally, hPRL has a very weak affinity for the GH receptor, whereas GH, PL, and PRL each bind with high affinity to the PRL receptor [9] ; moreover, we demonstrated that both GH and PL induced their relaxation effects via the GHR and PRLR, respectively. In addition to these findings, we observed that following Phe-induced contraction, a relaxation effect of approximately 50% occurred, an effect that stabilized after 50 min, in the aortic rings that were preincubated with either anti-GHR or PRLR antibodies.…”

“…These findings are indicative of the controversial roles played by PRL family members in the regulation of vascular function, roles that depend on the experimental models used, as well as the microenvironment surrounding the blood vessels, as each of these parameters may be key factors in the regulation of vascular responses [9,[33][34][35] . Therefore, the aim of this study is to investigate the roles played by GH, PL, and PRL in the regulation of vascular tone, as well as the roles of the mediators involved in this process, using both isolated rat aortic rings and cultured aortic endothelial cells.…”

“…The luteal hormone, relaxin, which is increased during pregnancy, also induces vasodilation, although this effect is mediated via increased NO production through the phosphorylation of www.chinaphar.com Gonzalez C et al Acta Pharmacologica Sinica npg endothelial NO synthase (eNOS) [7] . Among the reproductive hormones, the prolactin (PRL) family also exerts controversial vascular effects; the members of the PRL family include growth hormone (GH), placental lactogen (PL) and PRL, hormones that share structural and biological similarities [8][9][10][11][12][13] . GH and PRL are produced primarily in the pituitary gland but may also be locally produced by endothelial cells [1,9,14] .…”

Thrombotic thrombocytopenic purpura associated with a prolactin‐producing pituitary adenoma

“…Recent studies indicate an important role for PRL in various biologic processes and have changed the views on PRL production and function [20][21][22][23]. It became evident that PRL is produced not only in pituitary lactotrophs but also in the brain, spinal cord, immune system, uterus, placenta, and decidua.…”

“…PRL may stimulate or inhibit various stages of formation and remodelling of new blood vessels as well as affect endothelial cell proliferation, migration, protease production, and apoptosis [23]. Endothelial cells can express PRL mRNA, synthesize and release PRL, and have PRL receptors, raising the question whether, in addition to its systemic effect, PRL can act locally via an autocrine/paracrine mechanism [23]. PRL can disrupt the actin cytoskeleton, induce changes in cell shape, reduce cell adhesion, regulate transendothelial leukocyte trafficking, act on endothelial D 2 receptors, and inhibit VEGF-induced angiogenesis.…”