Relaxin Gene and Protein Expression and Its Regulation of Procollagenase and Vascular Endothelial Growth Factor in Human Endometrial Cells1

Abstract

Extensive evidence demonstrates pronounced effects of relaxin on the differentiation of human endometrial cells in vitro. In vivo data in rhesus monkeys suggest a role for relaxin in the development of endometrial vascular architecture. In women, pregnancy can be established and maintained in the absence of circulating relaxin. Thus, local synthesis by the endometrium is necessary if relaxin plays a physiological role in human endometrial function. Although relaxin protein and the prorelaxin C peptide have been localized to human endometrium, no data for relaxin synthesis have been provided to date. We therefore assessed relaxin mRNA and protein levels in cultured, defined human endometrial cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques were used to demonstrate the presence of relaxin mRNA in human stromal and glandular epithelial cells. Secretion of the protein into the media of cultured cells of both types was also detected. Relaxin stimulated the expression of vascular endothelial growth factor in glandular epithelial and stromal cells that were isolated from tissue that had been taken during the secretory phase of the cycle. Relaxin inhibited the expression of procollagenase from both glandular epithelial cells, with a more marked inhibition demonstrated from cells that were isolated from tissue that had been taken during the secretory phase, and from stromal cells. These data demonstrate that human endometrial cells synthesize relaxin, and they support the concept that relaxin fosters endometrial conditions that are required for implantation in women.

H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis

“…Other investigators have observed that the effect of relaxin on MMP regulation appears to be cell-type specific. For example, the upregulation, 10,28 downregulation 39,40 and biphasic regulation 27 of MMPs by relaxin have been reported before. In tumor biology, MMPs have been implicated in a variety of processes: a) the degradation of the ECM allowing for cell migration; 41 b) the alteration of the ECM microenvironment resulting in changes of cellular behaviour; 41 and c) the modulation of biologically active molecules by direct cleavage, release from bound stores or modulation of the activity of tissue inhibitors of MMPs (TIMPs).…”

“…46,47 The switch towards an angiogenic phenotype facilitates tumor expansion by allowing the tumor to maximize surface area for oxygen transport and nutrient diffusion. 48 Relaxin has been shown to upregulate both transcript and protein of the proangiogenic VEGF 39,49 and NOS species. 50 Therefore, considering that the upregulation of VEGF and NO are implicated in prostate tumor angiogenesis, microcirculation and neovascularization, 7,51 it is possible that relaxin may play an indirect role in this axis during tumor growth.…”

Relaxin regulation of endometrial structure and function in the rhesus monkey

“…Results from various studies provide abundant evidence that relaxin is a potent regulator of the differentiated function of human endometrial cells in vitro (14,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Relaxin stimulates the production of prolactin (16,17,19), insulin-like growth factor (18), and insulin-like growth factor binding protein 1 (IGFBP-1) (19), in progestin-primed endometrial stromal cells.…”

“…Relaxin-specific mRNA is detected in human endometrial stromal and glandular epithelial cells, and relaxin protein is secreted into the medium taken from primary cultures of these cell types (14). A role for relaxin in human endometrial function is also supported by findings that relaxin binds specifically and with high affinity to human endometrial cells (15).…”

“…A role for relaxin in human endometrial function is also supported by findings that relaxin binds specifically and with high affinity to human endometrial cells (15). In addition, a large body of evidence exists to demonstrate that relaxin has definitive effects on human endometrial cells in vitro (14,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Relaxin stimulates production of several endometrial products including prolactin, glycodelin, insulin-like growth factor binding protein 1 (IGFBP-1) and vascular endothelial growth factor in progestin-primed human endometrial cells in vitro.…”