Prolactin in Ovarian Follicular Fluid Stimulates Endothelial Cell Proliferation

Abstract

Angiogenesis is essential for the growth and maturation of the ovarian follicle and its transition into the corpus luteum. In addition to the main proangiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), follicular fluid (FF) contains the hormone prolactin (PRL), which is known to promote angiogenesis in vivo. Here, we show that FF from large follicles, which contains twice the PRL level of FF from small follicles, stimulates endothelial cell proliferation to a greater extent than the latter, and that immunoneutralization of PRL prevents FF from stimulating endothelial cell proliferation. Notably, the FF increases the expression of the short and long PRL receptor isoforms in endothelial cells, and a purified PRL standard stimulates endothelial cell proliferation but only after the cells have been pretreated with FF. However, purified PRL activates the JAK2/STAT3 pathway in endothelial cells in the absence of pretreatment with FF. In summary, PRL present in the FF stimulates the proliferation of endothelial cells. This effect likely involves the upregulation of the short and long PRL receptor isoforms and is independent of PRL-induced JAK2/STAT3 signaling.

A Positive Feedback Loop Between Prolactin and Stat5 Promotes Angiogenesis

“…The mitogenic effect of PRL on endothelial cells is controversial. While some reports describe the induction of endothelial cell proliferation by PRL [27], we and other investigators have failed to observe this activity [26,28]. This apparent discrepancy may be due to different endothelial cells types studied or different functional states of the target cells.…”

“…As circulating hormone and as paracrine/autocrine factor, PRL can either stimulate or inhibit various stages of angiogenesis, including migration, proteolytic matrix remodeling, apoptosis, and possibly endothelial cell proliferation [27,28,34,36,51,57]. PRL binds to endothelial cells and affects endothelial cell adhesion [40], stimulates endothelial cell proliferation [27,53] and improves engraftment and function of transplanted pancreatic islets [58]. PRL also promotes angiogenesis in vivo [51,54].…”

Regulation of Blood Vessels by Prolactin and Vasoinhibins

“…PRL actions may be limited by underexpressed PRL receptors in endothelial cells. Exposure to ovarian follicular fluid stimulates the expression of the long and short PRL receptor isoforms in bovine umbilical vein endothelial cells (BUVEC), and PRL does not stimulate BUVEC proliferation unless the cells are pretreated with ovarian follicular fluid [44]. In addition, vascular endothelial cells produce and release PRL, so the locally produced hormone may limit the effects of exogenous PRL by occupying its receptors in endothelial cells.…”

JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer

“…STAT3 is an oncogenic transcription factor that is constitutively active in many human cancers and regulates the several genes that are involved in angiogenesis, such as VEGF, bFGF [17,[33][34][35]. Here, of the total number of cases, 50/68 (73.5%) were positive for VEGF and 55/68 (80.9%) for bFGF.…”