Stimulation of cell proliferation of the receptor for PDGF has been implicated in atherogenesis and in cell
transformation by the SIS oncogene. Gronwald et al. (1988) found that the PDGF receptor clone expressed a high
affinity receptor specific for the BB isoform of PDGF, i.e., PDGF dimers composed of 2 B chains. Thereis a
separate class of PDGF receptor that binds both the homodimers and the heterodimer.
The PDGFRB gene and the CSF1 receptor gene encode proteins that belong to the same subfamily of receptor
tyrosine kinases Yarden and Ullrich, 1988 .
NCBI Summary:
This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. This gene is flanked on chromosome 5 by the genes for granulocyte-macrophage colony-stimulating factor and macrophage-colony stimulating factor receptor; all three genes may be implicated in the 5-q syndrome. A translocation between chromosomes 5 and 12, that fuses this gene to that of the translocation, ETV6, leukemia gene, results in chronic myeloproliferative disorder with eosinophilia. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Steroid metabolism, Luteinization
Comment
PDGFR Inhibition Results in Pericyte Depletion and Hemorrhage into the Corpus Luteum of the Rat Ovary. Hall AP et al. (2015) The growth plate, ovary, adrenal gland, and rodent incisor tooth are sentinel organs for antiangiogenic effects since they respond reliably, quantitatively, and sensitively to inhibition of the vascular endothelial growth factor receptor (VEGFR). Here we report that treatment of rats with platelet-derived growth factor receptor beta (PDGFRβ) inhibitors that target pericytes results in severe ovarian hemorrhage with degeneration and eventual rupture of the corpus luteum. Evaluation of the growth plate, adrenal gland, and incisor tooth that are typical target organs for antiangiogenic treatment in the rodent revealed no abnormalities. Histologically, the changes in the ovary were characterized by sinusoidal dilatation, increased vessel fragility, and hemorrhage into the corpus luteum. Immunocytochemical staining of vessels with alpha smooth muscle actin and CD31 that recognize pericytes and vascular endothelium, respectively, demonstrated that this effect was due to selective pericyte deficiency within corpora lutea. Further experiments in which rats were treated concurrently with both PDGFRβ and VEGFR inhibitors ablated the hemorrhagic response, resulting instead in corpus luteum necrosis. These changes are consistent with the notion that selective pericyte loss in the primitive capillary network resulted in increased vessel fragility and hemorrhage, whereas concomitant VEGFR inhibition resulted in vessel regression and reduced vascular perfusion that restricted development of the hemorrhagic vessels. These results also highlight the utility of the rodent ovary to respond differentially to VEGFR and PDGFR inhibitors, which may provide useful information during routine safety assessment for determining target organ toxicity.//////////////////
Expression regulated by
FSH, LH, tgfb
Comment
Potential role of follicle-stimulating hormone (FSH) and transforming growth factor (TGF?) in the regulation of ovarian angiogenesis. Kuo SW et al. 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 TGFb1 is known to facilitate FSH-induced differentiation of ovarian granulosa cells. This intrigues us to investigate the potential role of FSH and TGFb1 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 TGF? for forty-eight hours, and the angiogenic potential of conditioned media (GCCM) was determined using an in vitro assay with aortic ring embedded in collagen gel and immunoblotting. FSH and TGF? increased the secreted angiogenic activity in granulosa cells (FSH+TGF? > FSH ? TGFb1 > 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 pretreatment with inhibitor of VEGF receptor-2 (Ki8751) or PDGF receptor (AG1296) throughout or only during the first two-day aortic ring culture period suppressed microvessel growth in GCCM-treated groups, and also inhibited the FSH+TGF?-GCCM-stimulated release of matrix remodeling-associated gelatinase activities. Interestingly, pretreatment 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 TGF? increased the secretion of VEGF and PDGF-B, and that in turn upregulated the angiogenic activity in rat ovarian granulosa cells. This implicates that FSH and TGF? play important roles in regulation of ovarian angiogenesis during follicle development. J. Cell. Physiol. ? 2010 Wiley-Liss, Inc.
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Platelet-derived growth factor BB and DD and angiopoietin1 are altered in follicular fluid from polycystic ovary syndrome patients. Scotti L 2014 et al.
Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age, and is characterized by abnormalities in ovarian angiogenesis, among other features. Consistent with this association, follicular fluid (FF) concentration and ovarian expression of vascular endothelial growth factor (VEGF) are increased in PCOS patients. In this study, we examined the protein levels of platelet-derived growth factor (PDGF) BB and DD (PDGFBB and PDGFDD), angiopoietin 1 and 2 (ANGPT1 and ANGPT2), and their soluble receptor sTIE2 in FF from PCOS and control patients undergoing assisted reproductive techniques. We also analyzed the effect of FF from PCOS and control patients on tight and adherens junction protein expression0] in an endothelial cell line. PDGFBB and PDGFDD were significantly whereas ANGPT1 concentration was significantly higher in FF from PCOS patients than from control patients. No changes were found in the concentration of ANGPT2 or sTIE2. Expression of claudin-5 was significantly increased in endothelial cells incubated for 24?h in the presence of FF from PCOS versus from control patients, while vascular-endothelial cadherin, -catenin, and zonula occludens 1 expression were unchanged. The changes observed in the levels of PDGF isoforms and ANGPT1 may prevent VEGF-induced vascular permeability in the PCOS ovary by regulating endothelial-cell-junction protein levels. Restoring the levels of angiogenic factors may provide new insights into PCOS treatment and the prevention of ovarian hyperstimulation syndrome in affected women. Mol. Reprod. Dev. 2014 Wiley Periodicals, Inc.
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[Taylor et al 2000 reported that Platelet-Derived Growth Factor Activates Porcine Thecal Cell
Phosphatidylinositol-3-Kinase-Akt/PKB and Ras-Extracellular Signal-Regulated
Kinase-1/2 Kinase Signaling Pathways via the Platelet-Derived Growth Factor Receptor.
Duleba AJ, et al 1999 reported that that differentiated/steroidogenically active cells divide; furthermore,
PDGF and IGF-I may selectively stimulate proliferation of individual
subpopulations of theca-interstitial (T-I) cells, thereby providing a mechanism for development of
structural and steroidogenically active components of the T-I compartment.
Dabrow MB, 1998 reported the effects of platelet-derived growth factor and receptor on normal and
neoplastic human ovarian surface epithelium.
Liebermann J, et al 1996 studied effects of local growth factors on the secretory function of
bovine corpus luteum during the oestrous cycle and pregnancy in
vitro.
PDGF was effective in stimulating P4 release
particularly during late pregnancy.
May et al 1992 studied the regulation of porcine theca cell proliferation in vitro and suggest that PDGF is
a major mitogen toward porcine theca cells and that EGF greatly enhances its
activity.
Mondschein JS, et al reported the efects of partially and more highly purified platelet-derived growth factor
preparations on luteinizing hormone receptor induction in granulosa cell cultures.
Cell-Type Localization of Platelet-Derived Growth Factors and Receptors in the Postnatal Rat Ovary and Follicle. Sleer LS et al. Intraovarian growth factors play a significant role in the regulation of follicular selection and growth. In this study, the presence and localization of all members of the family of platelet derived growth factors (PDGF) and receptors (PDGFR) were identified and characterized in the rat ovary and a role in contributing towards growth of preantral follicles was identified. Real-time polymerase chain reaction revealed the presence of mRNA for all platelet derived growth factors (Pdgfa, Pdgfb, Pdgfc and Pdgfd) and receptors (Pdgfra and Pdgfrb) in the rat ovary from birth until four weeks. In situ hybridization and immunohistochemistry were utilized to identify cell-type expression of PDGFs and PDGFRs in rat ovaries from birth until four weeks. Shortly after birth, expression of PDGFRA and PDGFC was observed in and around oocyte clusters, and PDGFRB in stromal cells surrounding oocyte clusters. All members were identified in oocytesof primordial and primary follicles, and in cells of the theca layer of primordial to antral follicles. PDGFRA and PDGFA were also localized to some granulosa cells of secondary and antral follicles in ovaries from rats at days 20 and 24. Thus, localization data suggest both theca-theca and theca-granulosa cell interactions of PDGFs and receptors. Preantral follicles cultured in vitro over five days in serum-free medium plus recombinant PDGFAA, PDGFAB or PDGFBB increased in follicle diameter by 18.32 +/- 2.18%, 17.72 +/- 2.3% and 17.6 +/- 1.81% respectively, representing significantly greater increases than for follicles incubated in serum-free medium alone (11 +/- 1.57%), and suggesting a role for these growth factors in positively influencing early follicle growth.
Follicle stages
Primordial, Follicular fluid
Comment
Hammadeh ME et al 2000 reported that PDGF is present in pre-ovulatory follicular fluid in
patients undergoing ovarian hyperstimulation.
Expression of c-ABL, c-KIT, and platelet-derived growth factor receptor-beta in ovarian serous carcinoma and normal ovarian surface epithelium.
Schmandt RE, et al
Tyrosine kinases, such as c-KIT, c-ABL, and platelet-derived growth factor-beta (PDGFR-beta), are important regulators of cell growth. Highly potent and selective inhibitors of tyrosine kinases are being investigated as alternatives to standard chemotherapy. One such inhibitor, imatinib mesylate, is being used to treat gastrointestinal stromal tumors and chronic myelogenous leukemia. Ovarian carcinomas frequently develop resistance to conventional chemotherapeutic agents. Immunohistochemical expression of c-ABL, PDGFR-beta, and c-KIT was evaluated in ovarian carcinomas to determine whether treatment with imatinib mesylate might be feasible. The expression of c-ABL, c-KIT, and PDGFR-beta in tumors was evaluated by immunohistochemical analysis of 52 ovarian serous carcinomas, including 21 low-grade (well differentiated) and 31 high-grade (poorly differentiated) tumors. Fourteen normal ovaries were also evaluated. In normal ovarian surface epithelium, c-ABL was expressed universally. PDGFR-beta was expressed in the majority (93%) of samples of normal ovarian epithelium, whereas the c-KIT protein was undetectable in normal ovarian surface epithelium. Overall, c-ABL was expressed in 71% of serous carcinomas. c-ABL was expressed more frequently in the low-grade serous carcinomas (81%) compared with the high-grade serous carcinomas (65%). PDGFR-beta expression was observed in 81% of serous carcinomas overall and was observed more frequently in higher-grade tumors. c-KIT immunohistochemical staining was absent in low-grade tumors but was present in 26% of high-grade serous carcinomas. The majority of ovarian serous carcinomas express one or more of the kinases targeted by the tyrosine kinase inhibitor, imatinib mesylate, suggesting the potential usefulness of this drug in the treatment of ovarian carcinoma.
Herrera L et al reported mouse ovary developmental RNA and protein markers from gene expression profiling.
To identify genes involved in morphogenetic events during mouse ovary development, we started with microarray analyses of whole organ RNA. Transcripts for 60% of the 15,000 gene NIA panel were detected, and about 2000 were differentially expressed in nascent newborn compared to adult ovary. Highly differentially expressed transcripts included noncoding RNAs and newly detected genes involved in transcription regulation and signal transduction. The phased pattern of newborn mouse ovary differentiation allowed us to (1) extend information on activity and stage specificity of cell type-specific genes; and (2) generate a list of candidate genes involved in primordial follicle formation, including podocalyxin (Podxl), PDGFR-beta, and a follistatin-domain-encoding gene Flst1. Oocyte-specific transcripts included many (e.g., Deltex2, Bicd2, and Zfp37) enriched in growing oocytes, as well as a novel family of untranslated RNA's (RLTR10) that is selectively expressed in early stage follicles. The results indicate that global expression profiling of whole organ RNA provides sensitive first-line information about ovarian histogenesis for which no in vitro cell models are currently available.