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.
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ABSTRACT: In normal conditions FSHR are expressed in granulosa cells of the ovary and Sertoli cells of the testis. They can be expressed also in gonadal tumours. However, recently the expression of FSHR was found in tumoral cells and intra-tumoral blood vessels of many other tumours, including thyroid tumours. Aim of this study was to see whether the expression of FSHR can be useful in the differentiation of benign and malignant thyroid lesions. 44 samples of surgically excised thyroids were immunostained with anti- FSHR antibody raised against 1-190 amino acid sequence from the human FSHR. Non-neoplastic thyroid follicles (i.e. the follicles situated outside the tumour) do not show the immunostaining for FSHR. The same concerns the majority of follicular adenomas. In contrast, 87.5% of follicular cancers, the same percentage of papillary cancers and all the examined undifferentiated cancers showed the FSHR immunopositivity of tumoral cells. A tendency towards the higher frequency of FSHR - positive blood vessels also concerns malignant thyroid tumours. The ectopic FSHR immunostaining seems to be useful to differentiate malignant from benign lesions, especially follicular cancers from follicular adenomas. However, the further studies on larger material are needed.Thyroid Research 12/2015; 8(1):1. DOI:10.1186/s13044-015-0014-6
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ABSTRACT: In our earlier study, we found that pituitary adenomas, like other human tumours, express ectopically follicle stimulating hormone receptors (FSHR) in intratumoural blood vessels endothelia and/or tumoural cells. The aim of the present paper was to provide more detailed data on FSHR expression in different subtypes of pituitary adenomas and to evaluate its possible role as a prognostic and/ or predictive biomarker in these tumours. Forty two pituitary adenomas, surgically removed, were immunostained with antibodies against the pituitary hormones, antigen Ki-67 and 1-190 fragment of FSHR. The positive FSHR immunostaining was found in blood vessels endothelia of 88% of adenomas and in tumoural cells of 40% adenomas. In tumoural cells, the incidence of at least moderate FSHR immunostaining is significantly higher in invasive tumours (68%) compared to non-invasive (12%) ones, and higher (albeit not statistically significantly) in invasive-proliferating adenomas (Ki-67 > 3%, grade 2b) compared to invasive but non-proliferating (Ki-67 < 3%, grade 2a) ones. The present study confirms that pituitary adenomas ectopically express FSHR in intratumoural blood vessels endothelia and tumoural cells. Moreover, the expression in tumoural cells is prevalent in invasive and proliferating adenomas vs. non-invasive and non-proliferating tumours. (Endokrynol Pol 2014; 65 (6): 469-471).Endokrynologia Polska 01/2014; 65(6):469-71. DOI:10.5603/EP.2014.0065 · 1.21 Impact Factor
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ABSTRACT: Smad7 has a key role in apoptosis of mammalian ovarian granulosa cells (GCs), as it antagonizes and fine-tunes transforming growth factor β (TGFβ) signaling. This study demonstrates that miR-92a regulates GC apoptosis in pig ovaries by targeting Smad7 directly. The expression level of miR-92a was down-regulated in atretic porcine follicles, whereas miR-92a expression led to inhibition of GC apoptosis. The Smad7 gene was identified as a direct target of miR-92a using a dual-luciferase reporter assay. Transfection of GCs with miR-92a mimics decreased Smad7 mRNA and protein levels, whereas expression of an miR-92a inhibitor in GCs had the opposite effect. In addition, knockdown of Smad7 prevented GC apoptosis in cells that expressed the miR-92a inhibitor. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.FEBS Letters 10/2014; 588(23):4497-4503. DOI:10.1016/j.febslet.2014.10.021 · 3.34 Impact Factor