Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology?

Abstract

Prolactin is best known as the polypeptide anterior pituitary hormone, which regulates the development of the mammary gland. However, it became clear over the last decade that prolactin contributes to a broad range of pathologies, including breast cancer. Prolactin is also involved in angiogenesis via the release of pro-angiogenic factors by leukocytes and epithelial cells. However, whether prolactin also influences endothelial cells, and whether there are functional consequences of prolactin-induced signalling in the perspective of angiogenesis, remains so far elusive. In the present study, we show that prolactin induces phosphorylation of ERK1/2 and STAT5 and induces tube formation of endothelial cells on Matrigel. These effects are blocked by a specific prolactin receptor antagonist, del1-9-G129R-hPRL. Moreover, in an in vivo model of the chorioallantoic membrane of the chicken embryo, prolactin enhances vessel density and the tortuosity of the vasculature and pillar formation, which are hallmarks of intussusceptive angiogenesis. Interestingly, while prolactin has only little effect on endothelial cell proliferation, it markedly stimulates endothelial cell migration. Again, migration was reverted by del1-9-G129R-hPRL, indicating a direct effect of prolactin on its receptor. Immunohistochemistry and spectral imaging revealed that the prolactin receptor is present in the microvasculature of human breast carcinoma tissue. Altogether, these results suggest that prolactin may directly stimulate angiogenesis, which could be one of the mechanisms by which prolactin contributes to breast cancer progression, thereby providing a potential tool for intervention.

STAT5 and Prolactin Participate in a Positive Autocrine Feedback Loop That Promotes Angiogenesis

“…PRL is also secreted by various ECs (15)(16)(17), a cell type that also expresses PRLR (6,15,39,40) and thus might be subject to autocrine stimulation by this hormone. Some reports describe an effect of PRL on EC proliferation (9), whereas we and others have failed to observe this activity (6). This discrepancy may be due to different EC types used in the experiments or different functional states of the target cells.…”

“…Work by a number of investigators indicates that these hormones along with proliferin (PLF) and proliferin-related protein (PRP), the murine members of this family, can regulate angiogenesis (5)(6)(7). The classical textbook model suggests that PRL is secreted by the pituitary gland into the circulation and exerts its effects systemically primarily on the mammary gland.…”

“…One of the proposed local activities of PRL is the regulation of angiogenesis (5). The intact human PRL molecule, with a molecular mass of 23 kDa, has proangiogenic activity and reportedly stimulates endothelial cell (EC) proliferation (9), migration, and tube formation (6). Conversely, proteolytically generated fragments of PRL, typically displaying a molecular mass of 16 kDa, inhibit angiogenesis and block EC proliferation (7, 10 -14).…”

A microRNA links prolactin to peripartum cardiomyopathy

“…The investigators linked this vascular phenotype to PPCM through the hormone prolactin (PRL), which is secreted from the anterior pituitary gland. PRL has multiple effects in addition to stimulating milk production, one of which is the promotion of angiogenesis (11). However, the serum of patients with PPCM contains increased levels of a 16-kDa N-terminal PRL cleavage fragment (16K PRL) that is strongly antiangiogenic.…”

Role of Notch, SDF-1 and Mononuclear Cells Recruitment in Angiogenesis

“…These data suggest that sprouting angiogenesis is not needed for the incipient growth of cerebral metastases and that tumor growth in this model is a result of incorporation of host vessels. Prolactin was found to directly stimulate angiogenesis in breast cancer progression, enhancing vessel density and the tortuosity of the vasculature by pillar formation, which are hallmarks of intussusceptive angiogenesis [23]. It is a preferred mode of angiogenesis in oral squamous cell carcinoma [24] and in hepatocellular carcinoma [25,26].…”