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. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, Mar 2012]
General function
Receptor
Comment
Involvement of Bone Marrow-Derived Vascular Progenitor Cells in Neovascularization During Formation of the Corpus Luteum in Mice. Kizuka F et al. Neovascularization is necessary for formation of the corpus luteum (CL) and includes angiogenesis and vasculogenesis. Vasculogenesis is the formation of new blood vessels by bone marrow-derived endothelial progenitor cells. Here we investigated whether vasculogenesis occurs in neovascularization during CL formation. Mice transplanted with bone marrow from transgenic mice expressing GFP were injected with equine chorionic gonadotropin and human chorionic gonadotropin (hCG) to induce ovulation and subsequent CL formation. Immunohistochemistry was performed on the ovaries obtained before hCG injection and 6, 12, and 24 h after hCG injection using antibodies for CD34 or CD31 (an endothelial cell marker), platelet-derived growth factor receptor beta (PDGFR-beta,a pericyte marker), F4/80 (a macrophage marker), and GFP (a bone marrow-derived cell marker). Cells immunostained for CD34, PDGFR-beta, F4/80, and GFP were present in the theca cell layer of the preovulatory follicle before hCG injection. Each of these cell types invaded the granulosa cell layer after hCG injection, and a number of them were observed in the CL 24 h after hCG injection. Fluorescence-based immunohistochemistry or double immunohistochemical staining revealed that a few CD34/CD31-positive cells and PDGFR-beta-positive cells were also positive for GFP in the preovulatory follicle and CL, and that many of the GFP-positive cells recruited to the CL during CL formation were F4/80 positive macrophages. In conclusion, bone marrow-derived vascular progenitor cells and macrophages contribute to neovascularization during CL formation.
Cellular localization
Plasma membrane
Comment
Ovarian function
Initiation of primordial follicle growth, Preantral follicle growth
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.//////////////////
"Inhibition of platelet-derived growth factor (PDGF) receptor affects follicular development and ovarian proliferation, apoptosis and angiogenesis in prepubertal eCG-treated rats". Pascuali N et al. (2015) The platelet-derived growth factor (PDGF) system is crucial for blood vessel stability. In the present study, we evaluated whether PDGFs play a critical intraovarian survival role in gonadotropin-dependent folliculogenesis. We examined the effect of intrabursal administration of a selective platelet-derived growth factor receptor (PDGFR) inhibitor (AG1295) on follicular development, proliferation, apoptosis and blood vessel formation and stability in ovaries from rats treated with equine chorionic gonadotropin (eCG). The percentages of preantral follicles (PAFs) and early antral follicles (EAFs) were lower in AG1295-treated ovaries than in control ovaries (p<0.01-0.05). The percentage of atretic follicles (AtrFs) increased in AG1295-treated ovaries compared to control (p<0.05). The ovarian weight and estradiol concentrations were lower in AG1295-treated ovaries than in the control group (p<0.01 and p<0.05, respectively), whereas progesterone concentrations did not change. AG1295 decreased the proliferation index in EAFs (p<0.05) and increased the percentage of nuclei positive for cleaved caspase-3 and apoptotic DNA fragmentation (p<0.01-0.05). AG1295 increased the expression of Bax (p<0.05) without changes in the expression of Bcl-2 protein. AG1295-treated ovaries increased the cleavage of caspase-8 (p<0.05) and decreased AKT and BAD phosphorylation compared with control ovaries (p<0.05). AG1295 caused a decrease not only in the endothelial cell area but also in the area of pericytes and vascular smooth muscle cells (VSMCs) in the ovary (p<0.05). Our findings suggest that the local inhibition of PDGFs causes an increase in ovarian apoptosis through an imbalance in the ratio of antiapoptotic to proapoptotic proteins, thus leading a larger number of follicles to atresia. PDGFs could exert their mechanism of action through an autocrine/paracrine effect on granulosa and theca cells mediated by PDGFRs. In conclusion, these data clearly indicate that the PDGF system is necessary for follicular development induced by gonadotropins.//////////////////
Platelet-derived growth factor modulates the primordial to primary follicle transition. Nilsson EE et al. Primordial follicles steadily leave the arrested pool and undergo a primordial to primary follicle transition during the female reproductive lifespan. When the available pool of primordial follicles is depleted reproduction ceases and humans enter menopause. The present study was designed to investigate the actions of several growth factors previously identified as candidate regulatory factors for the primordial to primary follicle transition with a microarray analysis. Ovaries from 4-day-old rats were placed into culture and treated for 2 weeks with platelet-derived growth factor (PDGF), anti-PDGF neutralizing antibody, vascular endothelial growth factor (VEGF), neuregulin (NRG), or kit ligand (KITL) as a positive control. PDGF-treatment resulted in a significant decrease in the percentage of primordial follicles and a concomitant increase in the percentage of developing primary follicles compared to controls. In contrast, ovaries treated with an anti-PDGF neutralizing antibody had a significant increase in the percentage of primordial follicles demonstrating an inhibition of endogenous follicle development. Ovaries incubated in the presence of VEGF or NRG had no change in follicle development. Observations indicate that PDGF, but not VEGF or NRG, promotes the primordial to primary follicle transition. Immunohistochemical localization indicated that the PDGF protein was present in the oocytes of both primordial and developing follicles. PDGF-treatment of cultured ovaries resulted in an increase in KITL mRNA expression. KITL has been previously shown to promote the primordial to primary follicle transition. KITL-treatment of ovaries had no effect on expression of Pdgf or any PDGF homologs or receptors. Therefore, PDGF appears to be produced by the oocyte and acts as one of several extracellular signaling factors that regulate the primordial to primary follicle transition. These observations provide insight into the cell-cell interactions involved in the regulation of primordial follicle development and can be used in the future development of therapies for some forms of infertility.
Expression Levels of mRNA-Encoding PDGF Receptors in Goat Ovaries and the Influence of PDGF on the In Vitro Development of Caprine Pre-Antral Follicles. Brito I et al. The aims of this study were to investigate the expression levels of mRNA for platelet-derived growth factor (PDGF) receptors (PDGFR-a and -? in caprine follicles at different developmental stages and to evaluate the influence of PDGF on the in vitro development of pre-antral follicles. For this, goat primordial, primary and secondary follicles, as well as small (1-3 mm) and large (3-6 mm) antral follicles, were obtained, and PDGFR-a and -?mRNA levels were quantified by real-time PCR. Furthermore, pre-antral follicles (=200 ?m) were isolated from goat ovaries and cultured for 18 days in a- minimum essential medium supplemented with PDGF at 50 or 100 ng/ml, containing or not FSH. Real-time PCR showed highest PDGFR-a mRNA levels in secondary follicles, while PDGFR-?mRNA levels were highest in primary follicles onwards. Both receptors showed higher mRNA levels in granulosa/theca cells from small and large antral follicles than in their corresponding cumulus-oocyte complexes. In culture, the percentage of antrum formation was significantly higher in 100 ng/ml PDGF compared with the same PDGF concentration associated with FSH. After 18 days, PDGF in both concentrations associated with FSH promoted follicular growth significantly higher than the control. Moreover, the addition of FSH to 50 ng/ml PDGF positively influenced the follicular growth when compared with the same PDGF concentration in the absence of FSH. In conclusion, PDGF is important for early goat folliculogenesis, because the presence of PDGFR-a and -?mRNA was detected in all follicular categories, and PDGF associated with FSH stimulated the growth of goat pre-antral follicles isolated and cultured in vitro.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa, Theca
Comment
Gene expression profiling of early follicular development in primordial, primary, and secondary follicles. Yoon SJ et al. OBJECTIVE: To study global gene expression profiles of early folliculogenesis in primordial, primary, and secondary follicles. DESIGN: A cDNA microarray study using amplified RNAs from isolated follicles. SETTING: Experimental animal study. ANIMAL(S): Female ICR strain mice (12 days old). INTERVENTION(S): Isolation of follicles at each stage, RNA isolation and amplification, microarray hybridization, and statistical analysis for microarray. MAIN OUTCOME MEASURE(S): Gene lists of various functional groups with an estimated false discovery rate of 5%. Among them, platelet-derived growth factors (PDGFs) and receptors were localized by immunohistochemistry in mouse ovaries. RESULT(S): We analyzed a list of genes according to function, such as apoptosis, cell cycle, cell proliferation and maintenance, cytoskeleton, extracellular matrix, and signal transduction, as well as according to frequency. Among the list of genes, we found all PDGFs (A, B, C, and D) and receptors (alpha and beta) are expressed with differential expression patterns in the oocytes and ovarian cells according to stage of follicular development. CONCLUSION(S): The present report suggests that genome-wide expression profiling using microarray after RNA amplification may become a useful tool to better understand the molecular mechanism(s) involved in early ovarian folliculogenesis.
Differential expression and distribution of alternatively spliced transcripts of PDGF-A and of PDGF receptor-alpha in mouse reproductive tissues Li SH, et al .
Platelet-derived growth factor-A (PDGF-A) affects cellular activities such as proliferation, differentiation, and development by way of paracrine or autocrine interaction with PDGF-A receptor alpha (PDGFR-alpha). Two forms of alternatively spliced PDGF-A mRNA, a long and a short isoform, have been found in several mammalian species. Expression of PDGF-A and its cognate receptor PDGFR-alpha has been well studied in various tissues. However, these investigations did not distinguish between the individual isoforms of PDGF-A. In the present investigation, we identified the differential cellular expression patterns of the two isoforms of PDGF-A and of PDGFR-alpha in mouse reproductive tissues by using laser capture microdissection coupled with reverse transcriptase polymerase chain reaction. The long PDGF-A mRNA isoform was primarily detected in the epithelium, while the short isoform was ubiquitously distributed in epithelium, stroma, and muscle cells, although it was still more prominent in epithelium. PDGFR-alpha was mainly detected in stromal and muscle cells. Also, it was found in the epididymal epithelium, mucosal folds of the seminal vesicle, and ovarian granulosa cells. Thus, the complete PDGF-A/PDGFR-alpha signaling system is present in murine reproductive tissues, but the distribution of the long and short isoforms of PDFG-A differs.
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
Comment
Platelet-derived growth factors (PDGF-A and B) and their receptors in human fetal and adult ovaries. Pinkas H et al. There is no information regarding the presence of platelet-derived growth factors (PDGFs) and their receptors in human ovaries. The expression of PDGF-A, PDGF-B, and their two receptors, PDGFR-alpha and PDGFR-beta, was investigated in ovarian samples from women/girls and from human fetuses, at the protein and mRNA levels. The samples were prepared for immunohistochemical staining for PDGF-A and PDGF-B and their two receptors and in situ hybridization for the detection of the mRNA transcripts of the receptors. Total RNA was extracted from frozen ovarian samples, and the expression of PDGF-A and PDGF-B was investigated by reverse transcription polymerase chain reaction. The proteins for PDGF-A and PDGF-B were detected in oocytes, and in granulosa cells (GC) of 50% of the follicles from women/girls. The proteins and mRNA transcripts for the two receptors were detected in oocytes (mRNA for PDGFR-beta only in 25% of the oocytes). PDGFR-alpha mRNA was expressed in GC of a minority of the samples from women/girls, whereas PDGFR-beta protein and mRNA were identified in over 50% of the GC from this source. PDGF-A and -B transcripts were identified in all the extracts. The presence of the receptors in GC suggests that PDGFs might be involved in the activation of primordial follicles.