Platelet glycoprotein IV is immunologically related to the leukocyte differentiation antigen CD36. It is alternatively known as GP IIIb and is the fourth major glycoprotein of the platelet surface, the others being GP Ib, the platelet for thrombin, and von Willebrand factor (231200); whereas the complex of GP IIb (273800) and GP IIIa (173470) is the platelet-binding site for fibrinogen and fibronectin (134820), GP IV is the receptor for thrombospondin (see 188060) in platelets and various cell lines. Since thrombospondins are adhesive proteins widely distributed and involved in a variety of adhesive processes, GP IV may have important functions as a cell adhesion molecule .
NCBI Summary:
The protein encoded by this gene is the fourth major glycoprotein of the platelet surface and serves as a receptor for thrombospondin in platelets and various cell lines. Since thrombospondins are widely distributed proteins involved in a variety of adhesive processes, this protein may have important functions as a cell adhesion molecule. It binds to collagen, thrombospondin, anionic phospholipids and oxidized LDL. It directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and it binds long chain fatty acids and may function in the transport and/or as a regulator of fatty acid transport. Mutations in this gene cause platelet glycoprotein deficiency. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2014]
General function
Receptor, Cell adhesion molecule
Comment
Cellular localization
Plasma membrane
Comment
Correlation between local hormones and CD36 transcription level in women with polycystic ovary]. [Yao LQ et al. (2004) To detect CD(36) expressions in polycystic ovary (PCO), and to explore its correlation with local androgen and insulin at transcription level. From August 2002 to February 2003, 12 patients with asymmetric PCO, 15 primary or secondary infertile patients without endocrine disorders and 8 polycystic ovary syndrome (PCOS) with bilateral PCO were recruited. Extraction of follicular fluid and detection of testosterone (T), dehydroepiandrosterone sulfate (DHEAS), insulin (INS) and androstenedione (A(2)) were performed. Relative CD(36) mRNA expression level of human ovarian inner thecal cells was analyzed by auto image analysis system (IAS) after RT-PCR. The level of CD(36) mRNA expression in thecal cells was 0.24 +/- 0.07 in polycystic ovary of PCO group and 0.21 +/- 0.05 in bilateral ovaries of PCOS group, respectively, which were significantly lower than 0.83 +/- 0.13 in normal ovaries (P < 0.01). T and INS levels of follicle fluid in PCO were significantly higher than that in normal ovaries (P < 0.01). T and INS levels of follicle fluid were negatively related to CD(36) mRNA expression of follicular theca interna (r = -0.6810, r = -0.6708, P < 0.01). Decrease of scavenger receptor gene CD(36) mRNA may play a role in the pathogenesis of PCO by increasing the level of T and INS in follicular fluid.//////////////////
Zhang X, et al reported the expression of CD36/fatty acid translocase in rats: distribution, isolation from hepatocytes, and comparison with the scavenger receptor SR-B1.
The new mAb UA009 recognizes an antigen expressed by microvascular endothelium, by lymphatic endothelium, and by some epithelia in a number of organs, including the small intestine, lactating mammary gland, kidney, lung, sebaceous glands, and circumvallate papillae of the tongue. This antigen is also expressed abundantly in the splenic red pulp and marginal zone and by monocytes, macrophages, and erythrocytes (but not by platelets). Among tissues that store or metabolize fatty acids, the antigen is expressed by adipocytes, cardiomyocytes, and red skeletal muscle. Importantly, it is expressed by steroidogenic cells in the adrenal gland, testis, and ovary, whereas in the liver it is expressed by hepatocytes in a pattern that is dependent on gender and genetic background. mAb UA009 immunoprecipitated a mol wt 85-kDa surface protein from detergent extracts of hepatocytes from Dark Agouti female rats. The N-terminal amino acid sequence of this protein was identical to fatty acid translocase (FAT), the rat cluster of differentiation 36 (CD36) ortholog. The mAb also reacted with COS-7 cells transfected with cDNA encoding FAT. cDNAs encoding a CD36/FAT-like polypeptide were prepared from both liver and heart RNA by RT-PCR. The nucleotide sequences obtained from these cDNAs (Dark Agouti rats) revealed identity and 99% similarity, respectively, with the published sequences of Cd36/Fat in rats of the Wistar and Sprague-Dawley strains. The absence of the UA009 antigen in CD36/FAT-deficient SHR/N rats confirmed the identity of the UA009 antigen and CD36/FAT. We suggest that CD36/FAT might function in the liver as a sex-regulated accessory molecule, either in reverse cholesterol transport and/or in fatty acid uptake.
Expression regulated by
LH, Eicosanoids
Comment
Regulation of Angiogenesis-Related Prostaglandin F2alpha-Induced Genes in the Bovine Corpus Luteum. Zalman Y et al. We recently compared prostaglandin F2alpha (PG)-induced global gene expression profiles in PG-refractory, bovine corpus luteum (CL) collected on day (d) 4 of the estrous cycle, versus PG-responsive, d11 CL. Transcriptome analyses led us to study the regulation of angiogenesis-related genes by PG and their functions in luteal endothelial cells (ECs). We found that PG regulated angiogenesis-modulating factors in a luteal stage-dependent way. A robust increase in FGF2 expression (mRNA and protein) occurred in the PG-refractory d4 CL promoting CL survival and function. Inhibitors of FGF2 action, thrombospondin 1 and 2, their receptor (CD36), and PTX3 were upregulated by PG specifically in d11 CL undergoing luteolysis. VEGF mRNA decreased 4h post PG in both d4 and d11 CL. The resulting destabilization of blood vessels in d11 CL is expected to weaken the gland and reduce its hormonal output. These genes were expressed in dispersed luteal ECs and steroidogenic cells, however, thrombospondin 1 and FGF2 were more abundant in luteal ECs. Expression of such genes and their ability to modulate FGF2 actions were investigated. Similarly to its in vivo effect, PG stimulated in vitro the expression of thrombospondins and PTX3 genes in several luteal cell models. Importantly, these factors influenced the angiogenic properties of luteal ECs. FGF2 dose-dependently enhanced cell migration and proliferation, whereas thrombospondin 1 and PTX3 inhibited FGF2 actions in luteal ECs. Collectively, the data presented here suggest that by tilting the balance between pro- and anti-angiogenic factors, PG can potentially control the ability of the CL to resist or advance toward luteolysis.
Ovarian localization
Cumulus, Granulosa, Theca, Luteal cells
Comment
Expression and localization of members of the thrombospondin family during final follicle maturation and corpus luteum formation and function in the bovine ovary. Berisha B et al. (2016) The aim of this study was to characterize the expression patterns and localization of the thrombospondin family members (THBS1, THBS2) and their receptors (CD36 and CD47) in bovine ovaries. First, the antral follicles were classified into 5 groups based on the follicle size and estradiol-17beta (E2) concentration in the follicular fluid (< 0.5, 0.5-5, 5-40, 40-180 and >180 E2 ng/ml). Second, the corpus luteum (CL) was assigned to the following stages: days 1-2, 3-4, 5-7, 8-12, 13-16 and >18 of the estrous cycle and of pregnancy (month 1-2, 3-4, 6-7 and > 8). Third, the corpora lutea were collected by transvaginal ovariectomy before and 0.5, 2, 4, 12, 24, 48 and 64 h after inducing luteolysis by injecting a prostaglandin F2alpha analog. The mRNA expression of examined factors was measured by RT-qPCR, steroid hormone concentration by EIA, and localization by immunohistochemistry. The mRNA expression of THBS1, THBS2, CD36, and CD47 in the granulosa cells and theca interna was high in the small follicles and reduced in the preovulatory follicles. The mRNA expression of THBS1, THBS2, and CD47 in the CL during the estrous cycle was high, but decreased significantly during pregnancy. After induced luteolysis, thrombospondins increased significantly to reach the maximum level at 12 h for THBS1, 24 h for THBS2, and 48 h for CD36. The temporal expression and localization pattern of the thrombospondins and their specific receptors in the antral follicles and corpora lutea during the different physiological phases of the estrous cycle and induced luteolysis appear to be compatible with their inhibitory role in the control of ovarian angiogenesis.//////////////////
Expression and localization of members of the thrombospondin family during final follicle maturation and corpus luteum formation and function in the bovine ovary. Berisha B et al. (2016) The aim of this study was to characterize the expression patterns and localization of the thrombospondin family members (THBS1, THBS2) and their receptors (CD36 and CD47) in bovine ovaries. First, the antral follicles were classified into 5 groups based on the follicle size and estradiol-17beta (E2) concentration in the follicular fluid (< 0.5, 0.5-5, 5-40, 40-180 and > 180 E2 ng/ml). Second, the corpus luteum (CL) was assigned to the following stages: days 1-2, 3-4, 5-7, 8-12, 13-16, and > 18 of the estrous cycle and of pregnancy (month 1-2, 3-4, 6-7, > 8). Third, the corpora lutea were collected by transvaginal ovariectomy before and 0.5, 2, 4, 12, 24, 48 and 64 h after inducing luteolysis by injecting a prostaglandin F2alpha analog. The mRNA expression of examined factors was measured by RT-qPCR, steroid hormone concentration by EIA, and localization by immunohistochemistry. The mRNA expression of THBS1, THBS2, CD36, and CD47 in the granulosa cells and theca interna was high in the small follicles and reduced in the preovulatory follicles. The mRNA expression of THBS1, THBS2, and CD47 in the CL during the estrous cycle was high, but decreased significantly during pregnancy. After induced luteolysis, thrombospondins increased significantly to reach the maximum level at 12 h for THBS1, 24 h for THBS2, and 48 h for CD36. The temporal expression and localization pattern of the thrombospondins and their specific receptors in the antral follicles and corpora lutea during the different physiological phases of the estrous cycle and induced luteolysis appear to be compatible with their inhibitory role in the control of ovarian angiogenesis.//////////////////
MALDI Mass Spectrometry Imaging of Lipids and Gene Expression Reveals Differences in Fatty Acid Metabolism between Follicular Compartments in Porcine Ovaries. Uzbekova S et al. (2015) In mammals, oocytes develop inside the ovarian follicles; this process is strongly supported by the surrounding follicular environment consisting of cumulus, granulosa and theca cells, and follicular fluid. In the antral follicle, the final stages of oogenesis require large amounts of energy that is produced by follicular cells from substrates including glucose, amino acids and fatty acids (FAs). Since lipid metabolism plays an important role in acquiring oocyte developmental competence, the aim of this study was to investigate site-specificity of lipid metabolism in ovaries by comparing lipid profiles and expression of FA metabolism-related genes in different ovarian compartments. Using MALDI Mass Spectrometry Imaging, images of porcine ovary sections were reconstructed from lipid ion signals for the first time. Cluster analysis of ion spectra revealed differences in spatial distribution of lipid species among ovarian compartments, notably between the follicles and interstitial tissue. Inside the follicles analysis differentiated follicular fluid, granulosa, theca and the oocyte-cumulus complex. Moreover, by transcript quantification using real time PCR, we showed that expression of five key genes (including CD36) in FA metabolism significantly varied between somatic follicular cells (theca, granulosa and cumulus) and the oocyte. In conclusion, lipid metabolism differs between ovarian and follicular compartments.//////////////////
Functions and Transcriptional Regulation of Thrombospondins and Their Interrelationship with Fibroblast Growth Factor-2 in Luteal Cells. Farberov S 2014 et al.
Previously we showed luteal stage-specific regulation of angiogenesis modulating factors by prostaglandin F2 alpha (PGF2a). Fibroblast growth factor 2 (FGF2) and thrombospondins (THBSs) exhibited the most divergent profile of induction by PGF2a. We therefore examined the transcriptional regulation and roles of THBSs in luteal cells and studied their interaction with FGF2. THBSs and their receptors exhibited cell specific expression: THBS1 was the predominant form in luteal endothelial cells (LEC), whereas luteinized granulosa cells (LGC) expressed mostly THBS2. CD36 was confined to LGC, but CD47 did not exhibit preferential expression between LEC and LGC. THBS1 and THBS2 were both stimulated in vitro by PGF2a and its analog in LGC. Contrarily, luteinizing signals (LH and insulin) decreased the expression of THBS1, THBS2, and CD36. Importantly, LH increased FGF2 expression, suggesting that THBSs and FGF2 are conversely regulated. We found that FGF2 inhibited THBS1 and vice versa, and that THBS1 treatment decreased FGF2 expression, suggesting reciprocal inhibition. In agreement, ablation of THBS1 by specific siRNAs elevated FGF2 levels. THBS1 reduced LEC numbers and promoted apoptosis by activation of caspase-3. In contrast, FGF2 reduced basal and THBS1-induced caspase-3 levels. Consistent with these findings, siRNA silencing of THBS1 in luteal cells reduced the levels of active caspase-3 and improved the survival of cells when challenged with staurosporine. Taken together, these studies suggest that THBSs are suppressed during luteinization but are induced by PGF2a in luteolysis. THBS1 has antiangiogenic, proapoptotic properties; these, together with its ability to inhibit FGF2 expression and activity, can promote luteolysis.
/////////////////////////
Resveratrol and desferoxamine protect human oxLDL-treated granulosa cell subtypes from degeneration. Schube U 2013 et al.
Context: Obese women suffer from anovulation and infertility, which are driven by oxidative stress caused by increased levels of lipid peroxides and circulating oxidised low-density lipoprotein (oxLDL). OxLDL binds to lectin-like oxLDL receptor 1 (LOX-1), CD36, and toll-like receptor 4 (TLR4) and causes cell death in human granulosa cells (GCs). Objective: To reveal whether treatment with antioxidants: resveratrol (RES) and/or desferoxamine (DFO) protect GCs from oxLDL-induced damage. Design and Setting: Basic research at the Institute of Anatomy and the Clinic of Reproductive Medicine. Patients: Women undergoing in vitro fertilization (IVF) therapy. Main Outcome Measures: Granulosa cell cultures were treated with oxLDL alone or with resveratrol (RES) or desferoxamine (DFO) under serum-free conditions for up to 36 h. Dead cells were determined by propidium iodide uptake, cleaved caspase-3 expression, and electron microscopy. Mitosis was detected by Ki-67 immunostaining. LOX-1, TLR4, CD36 and Hsp60 were examined by Western blots. Measurement of oxidative stress markers (8-iso-PGF2a, advanced glycation end products, protein carbonyl-content) was conducted by ELISA-Kits. Results: Different subtypes of human GCs exposed to RES or DFO were protected as evidenced by lack of cell death, enhanced mitosis, reduced expression of LOX-1, TLR4, CD36, and Hsp-60, induction of protective autophagy, and reduction of oxidative stress markers. Importantly, RES could restore steroid-biosynthesis in cytokeratin-positive GCs which exhibited significant induction of steroidogenic acute regulatory protein. Conclusions: RES and DFO exert a protective effect on human GCs. Thus, RES and DFO may help improving the treatment of obese women or PCOS patients undergoing IVF-therapy.
/////////////////////////
Growth Factor are Cyclically Expressed in an Inverse Pattern During Bovine Ovarian Follicle Development Greenaway J, et al .
Angiogenesis does not normally occur in most adult tissues. However, in the ovary, there are cyclical vascular changes including angiogenesis that involve the interaction of numerous cytokines and growth factors. Angiogenic processes are regulated by a balance between pro- and anti-angiogenic factors. The purpose of this study was to determine the expression of the anti-angiogenic thrombospondin family and pro-angiogenic vascular endothelial growth factor (VEGF) in various sizes of healthy bovine follicles. Ovaries were collected from slaughterhouse animals and healthy follicles were sorted based on size (<0.5cm - small, 0.5-1.0cm - medium, >1.0cm - large). Thrombospondin protein levels were significantly higher in small follicles. Immunohistochemistry confirmed the granulosa layer as the primary area within the follicle involved in TSP generation, and that small follicles had the highest proportion of immunopositive cells. TSP-1 and -2 mRNA levels were significantly higher in small follicles than either medium or large follicles. TSP co-localized with CD36 on granulosa cells (GC) in the follicle and in cultured cells. In contrast to TSP, VEGF expression increased during growth and development of the follicle. FSH stimulated GC expression of TSP, while LH had no effect. In summary, TSP-1 and -2 were coordinately expressed in the extravascular compartment of the ovary during early follicle development. VEGF was inversely expressed, with expression increasing as follicles developed. Regulated expression and Localization of these proteins suggests that they may be involved in regulating growth and development of the follicle in a novel fashion.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Induced expression of pattern recognition receptors (PRRs) in cumulus oocyte complexes (COCs): Novel evidence for innate immune-like functions during ovulation. Shimada M et al. Ovulation is the complex, inflammatory-like process by which the cumulus oocyte complex (COC) is released from a mature, preovulatory (PO) follicle through a rupture site at the ovarian surface and requires expression of genes that generate and stabilize the expanded extracellular COC matrix. Gene profiling analyses of COCs at selected time intervals during ovulation revealed that many genes associated with immune related surveillance functions were also induced in cumulus cells. Specifically, cell surface signaling molecules known as pattern recognition receptors (PRRs) that act as sensors of the external environment important for the innate immune system to detect 'self' from 'non-self' or 'altered self' are induced and/or expressed in cumulus cells as well as granulosa cells. These include the complement factor C1q, CD14 and the Toll-like receptors (TLRs) 4, 8 and 9 as well as mediators of TLR activation, MYD88 and IRF3. COCs exposed to bacterial LPS exhibit enhanced phosphorylation of p38MAPK, ERK1/2 and NF-kB and increased expression of Il6 and Tnfa target genes, documenting that the TLR pathway is functional. Cumulus cells and granulosa cells also express the scavenger receptors CD36 and SCARBI and exhibited phagocytic uptake of fluorescently-tagged bacterial particles. Collectively, these results provide novel evidence that cumulus cells as well as granulosa cells express innate immune related genes that may play critical roles in surveillance and cell survival during the ovulation process.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: The thrombospondin-1 receptor CD36 is an important mediator of ovarian angiogenesis and folliculogenesis. Osz K 2014 et al.
BACKGROUND
Ovarian angiogenesis is a complex process that is regulated by a balance between pro- and anti-angiogenic factors. Physiological processes within the ovary, such as folliculogenesis, ovulation, and luteal formation are dependent upon adequate vascularization and anything that disrupts normal angiogenic processes may result in ovarian dysfunction, and possibly infertility. The objective of this study was to evaluate the role of the thrombospondin-1 (TSP-1) receptor CD36 in mediating ovarian angiogenesis and regulating ovarian function.
METHODS
The role of CD36 was evaluated in granulosa cells in vitro and ovarian morphology and protein expression were determined in wild type and CD36 null mice.
RESULTS
In vitro, CD36 inhibition increased granulosa cell proliferation and decreased apoptosis. Granulosa cells in which CD36 was knocked down also exhibited an increase in expression of survival and angiogenic proteins. Ovaries from CD36 null mice were hypervascularized, with increased expression of pro-angiogenic vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. Ovaries from CD36 null mice contained an increase in the numbers of pre-ovulatory follicles and decreased numbers of corpora lutea. CD36 null mice also had fewer number of offspring compared to wild type controls.
CONCLUSIONS
The results from this study demonstrate that CD36 is integral to the regulation of ovarian angiogenesis by TSP-1 and the expression of these family members may be useful in the control of ovarian vascular disorders.
/////////////////////////