Aburima, A, Berger, M, Spurgeon, BEJ et al. (5 more authors) (2021) Thrombospondin-1 promotes haemostasis through modulation of cAMP signaling in blood platelets. Blood, 137 (5). pp. 678-689. ISSN 0006-4971
Abstract
Thrombospondin-1 (TSP-1) is released by platelets upon activation and can promote platelet activation, but its role in haemostasis in vivo is unclear. We show that TSP-1 is a critical mediator of haemostasis that promotes platelet activation by modulating inhibitory cAMP signaling. Genetic deletion of TSP-1 did not affect platelet activation in vitro, but in vivo models of haemostasis and thrombosis demonstrated that TSP-1 deficient mice had prolonged bleeding, defective thrombosis and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild type (WT), but not TSP-1-/- platelets, ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1-deficient platelets showed an increased sensitivity to cAMP signaling, inhibition of platelet aggregation and arrest under flow by PGI2. Plasma swap experiments showed that plasma TSP-1 did not correct PGI2 hypersensitivity in TSP-1-/- platelets. By contrast, incubation of TSP-1-/- platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1-/- platelets, reduced the inhibitory effects of PGI2. Activation of WT platelets resulted in diminished cAMP accumulation and downstream signaling, which was associated with increased activity of the cAMP hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A activity and cAMP accumulation were unaffected in platelets from TSP-1-/- mice. Platelets deficient in CD36, a TSP-1 receptor, showed increased sensitivity to PGI2/cAMP signaling and diminished PDE3A activity, which was unaffected by platelet-derived or purified TSP-1. This suggests that the release of TSP-1 regulates haemostasis in vivo through modulation of platelet cAMP signaling at sites of vascular injury.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 American Society of Hematology. This is an author produced version of a paper published in Blood. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | blood platelets; cyclic amp; signal transduction; thrombospondin 1; hemostatic function; cd36 antigens; mice; thrombosis |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 24 Sep 2020 15:20 |
Last Modified: | 21 Jun 2023 15:37 |
Status: | Published |
Publisher: | American Society of Hematology |
Identification Number: | 10.1182/blood.2020005382 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:165667 |