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Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling.
- Source :
-
Blood [Blood] 2008 Jan 15; Vol. 111 (2), pp. 613-23. Date of Electronic Publication: 2007 Sep 21. - Publication Year :
- 2008
-
Abstract
- Platelet alpha-granules constitute the major rapidly releasable reservoir of thrombospondin-1 in higher animals. Although some fragments and peptides derived from thrombospondin-1 stimulate or inhibit platelet aggregation, its physiologic function in platelets has remained elusive. We now show that endogenous thrombospondin-1 is necessary for platelet aggregation in vitro in the presence of physiologic levels of nitric oxide (NO). Exogenous NO or elevation of cGMP delays thrombin-induced platelet aggregation under high shear and static conditions, and exogenous thrombospondin-1 reverses this delay. Thrombospondin-1-null murine platelets fail to aggregate in response to thrombin in the presence of exogenous NO or 8Br-cGMP. At physiologic concentrations of the NO synthase substrate arginine, thrombospondin-1-null platelets have elevated basal cGMP. Ligation of CD36 or CD47 is sufficient to block NO-induced cGMP accumulation and mimic the effect of thrombospondin-1 on aggregation. Exogenous thrombospondin-1 also reverses the suppression by NO of alphaIIb/beta3 integrin-mediated platelet adhesion on immobilized fibrinogen, mediated in part by increased GTP loading of Rap1. Thrombospondin-1 also inhibits cGMP-mediated activation of cGMP-dependent protein kinase and thereby prevents phosphorylation of VASP. Thus, release of thrombospondin-1 from alpha-granules during activation provides positive feedback to promote efficient platelet aggregation and adhesion by overcoming the antithrombotic activity of physiologic NO.
- Subjects :
- Animals
Arginine genetics
Arginine metabolism
Blood Platelets cytology
CD36 Antigens genetics
CD36 Antigens metabolism
CD47 Antigen genetics
CD47 Antigen metabolism
Cell Adhesion Molecules genetics
Cell Adhesion Molecules metabolism
Cyclic GMP antagonists & inhibitors
Cyclic GMP genetics
Cyclic GMP pharmacology
Fibrinolytic Agents pharmacology
Immunologic Capping drug effects
Immunologic Capping physiology
Mice
Mice, Knockout
Microfilament Proteins genetics
Microfilament Proteins metabolism
Nitric Oxide antagonists & inhibitors
Nitric Oxide genetics
Peptides genetics
Peptides metabolism
Peptides pharmacology
Phosphoproteins genetics
Phosphoproteins metabolism
Platelet Adhesiveness drug effects
Platelet Adhesiveness genetics
Platelet Aggregation drug effects
Platelet Glycoprotein GPIIb-IIIa Complex genetics
Platelet Glycoprotein GPIIb-IIIa Complex metabolism
Secretory Vesicles genetics
Secretory Vesicles metabolism
Shear Strength
Thrombin genetics
Thrombin metabolism
Thrombin pharmacology
Thrombospondin 1 genetics
Thrombospondin 1 pharmacology
rap1 GTP-Binding Proteins genetics
rap1 GTP-Binding Proteins metabolism
Blood Platelets metabolism
Cyclic GMP metabolism
Fibrinolytic Agents metabolism
Nitric Oxide metabolism
Platelet Aggregation physiology
Thrombospondin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 111
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 17890448
- Full Text :
- https://doi.org/10.1182/blood-2007-06-098392