Thrombospondin was originally discovered as a secretory product of platelet alpha-granules (Baenziger et al., 1971). Since that time it has been detected as a product of a great variety of cells. It is a multifunctional protein that contains binding sites for thrombin, fibrinogen, heparin, fibronectin, plasminogen, plasminogen activator, collagen, laminin, etc. It functions in many cell adhesion and migration events including platelet aggregation.
NCBI Summary:
The protein encoded by this gene belongs to the thrombospondin family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration. [provided by RefSeq, Jul 2008]
General function
Cell adhesion molecule
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Cellular localization
Secreted
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Ovarian function
Follicle development
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Expression regulated by
FSH, Eicosanoids, PGF2a
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.
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.
Ovarian localization
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, > 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.//////////////////
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.
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Danik et al. (1999) reported that most endocrine tissues (adrenal cortex, testis, ovary, and placenta) appeared to express thrombospondin 2 (TSP2), as determined by Western blot analysis. The highest levels of TSP2 protein were found in the adrenal cortex, followed by the heart, spleen, brain, and kidney.
Follicle stages
Secondary, Corpus luteum
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment:Kyriakides et al. (1998) disrupted the thrombospondin 2 (designated TSP2) gene in order to generate homozyous
tsp2-null mice. Mutant mice were fertile and overtly normal. However, they displayed abnormalities in connective tissue structure and function. The skin was fragile and had reduced tensile strength, and the tail was unusually flexible. Mutant mice displayed increased cortical bone thickness and density, a significant increase in density in small blood vessels in skin and other tissues, and had abnormally long bleeding times.