Potential role of follicle‐stimulating hormone (FSH) and transforming growth factor (TGFβ1) in the regulation of ovarian angiogenesis

Abstract

Angiogenesis occurs during ovarian follicle development and luteinization. Pituitary secreted FSH was reported to stimulate the expression of endothelial mitogen VEGF in granulosa cells. And, intraovarian cytokine transforming growth factor (TGF)β1 is known to facilitate FSH-induced differentiation of ovarian granulosa cells. This intrigues us to investigate the potential role of FSH and TGFβ1 regulation of granulosa cell function in relation to ovarian angiogenesis. Granulosa cells were isolated from gonadotropin-primed immature rats and treated once with FSH and/or TGFβ1 for 48 h, and the angiogenic potential of conditioned media (granulosa cell culture conditioned media; GCCM) was determined using an in vitro assay with aortic ring embedded in collagen gel and immunoblotting. FSH and TGFβ1 increased the secreted angiogenic activity in granulosa cells (FSH + TGFβ1 > FSH ≈ TGFβ1 >control) that was partly attributed to the increased secretion of pro-angiogenic factors VEGF and PDGF-B. This is further supported by the evidence that pre-treatment with inhibitor of VEGF receptor-2 (Ki8751) or PDGF receptor (AG1296) throughout or only during the first 2-day aortic ring culture period suppressed microvessel growth in GCCM-treated groups, and also inhibited the FSH + TGFβ1-GCCM-stimulated release of matrix remodeling-associated gelatinase activities. Interestingly, pre-treatment of AG1296 at late stage suppressed GCCM-induced microvessel growth and stability with demise of endothelial and mural cells. Together, we provide original findings that both FSH and TGFβ1 increased the secretion of VEGF and PDGF-B, and that in turn up-regulated the angiogenic activity in rat ovarian granulosa cells. This implicates that FSH and TGFβ1 play important roles in regulation of ovarian angiogenesis during follicle development.

Vascular endothelial growth factor induces anti-Müllerian hormone receptor 2 overexpression in ovarian granulosa cells of in vitro fertilization/intracytoplasmic sperm injection patients

“…AMH mRNA levels were decreased in response to FSH and/or VEGF treatment. Furthermore, TGFβ is important in controlling cell proliferation and exerts a regulatory role in ovarian angiogenesis (25). TGFβ expression levels were increased in response to VEGF treatment in the current study.…”

Immunohistochemical detection of follicle stimulating hormone receptor (FSHR) in neuroendocrine tumours

“…The functionality of these receptors remains unknown and needs further study. It is known that the ovary stimulation of FSHR by FSH leads to the enhanced proliferation of granulosa cells, increased secretion of vascular endothelial growth factor (VEGF), and increased angiogenesis [6]. A similar observation was made with ovarian cancer cells SK-OV-3 [6].…”

“…It is known that the ovary stimulation of FSHR by FSH leads to the enhanced proliferation of granulosa cells, increased secretion of vascular endothelial growth factor (VEGF), and increased angiogenesis [6]. A similar observation was made with ovarian cancer cells SK-OV-3 [6]. FSH also inhibits ovarian cancer cell apoptosis by up-regulating survivin and downregulating programmed cell death gene 6 (PDCD6) and death receptor 5 (DR5) [7,8].…”

Immunohistochemical detection of FSH receptors in pituitary adenomas and adrenal tumors

“…If FSHR expressed in endocrine and other tumors are functional, they may exhibit a similar action to that occurring in normal gonads and gonadal tumors. It is known that FSH, acting via its receptors, stimulates the proliferation of ovarian granulosa cells and increases vascular endothelial growth factor (VEGF) secretion within the ovary, leading to enhanced angiogenesis [13]. A similar observation was made with ovarian cancer cells SK-OV-3) [14].…”