Platelet PECAM-1 inhibits thrombus formation in vivo

Abstract

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a cell surface glycoprotein receptor expressed on a range of blood cells, including platelets, and on vascular endothelial cells. PECAM-1 possesses adhesive and signaling properties, the latter being mediated by immunoreceptor tyrosine-based inhibitory motifs present on the cytoplasmic tail of the protein. Recent studies in vitro have demonstrated that PECAM-1 signaling inhibits the aggregation of platelets. In the present study we have used PECAM-1-deficient mice and radiation chimeras to investigate the function of this receptor in the regulation of thrombus formation. Using intravital microscopy and laserinduced injury to cremaster muscle arterioles, we show that thrombi formed in PECAM-1-deficient mice were larger, formed more rapidly than in control mice, and were more stable. Larger thrombi were also formed in control mice that received transplants of PECAM-1-deficient bone marrow, in comparison to mice that received control transplants. A ferric chloride model of thrombosis was used to investigate thrombus formation in carotid arteries. In PECAM-1-deficient mice the time to 75% vessel occlusion was significantly shorter than in control mice. These data provide evidence for the involvement of platelet PECAM-1 in the negative regulation of thrombus formation. IntroductionPlatelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a 130-kDa membrane glycoprotein that is expressed on a range of blood cells including platelets, monocytes, neutrophils, B lymphocytes, some T lymphocyte subsets, and also on vascular endothelial cells. [1][2][3][4] This member of the immunoglobulin superfamily has been reported to be associated with a wide range of functions, depending on the cell of interest. These include transendothelial migration of leukocytes, 5-7 integrin regulation, [8][9][10][11][12][13][14][15][16] modulation of T-and Blymphocyte antigen receptor signaling, 17,18 B-lymphocyte development, 19 vasculogenesis, 20 apoptosis, 21,22 and protection against endotoxic shock. 23 Several lines of investigation have recently determined that PECAM-1 is involved in the negative regulation of platelet function in vitro. The activation of PECAM-1 prior to the stimulation of platelets results in the inhibition of platelet aggregation and the inhibition of activatory signaling mechanisms. 24,25 Of particular note, therefore, are the observations that mouse platelets deficient in PECAM-1 are hyperresponsive to stimulation with collagen and demonstrate enhanced aggregation, secretion, and adhesion to this agonist. 26 Platelets from PECAM-1-deficient mice have also been shown to form larger thrombi in vitro under physiologic flow conditions. 25 PECAM-1 participates in homophilic ligand-binding interactions [27][28][29] ; indeed, such interactions between PECAM-1 molecules on the same cell and between cells are believed to underlie most of its identified functions. Additional potential ligand-binding interactions have been reported, such as with integrin ␣ v ␤ 3 ...

Platelet power: sticky problems for sticky parasites?

“…Furthermore, although not primary receptors involved in binding, the recruitment of other receptors after initial tethering could nonetheless be important for stabilization of the platelet-infected erythrocyte complex or for triggering functions from them, as is known for other immunological synapses. PECAM-1 is particularly interesting in this respect because it is known to be a ligand for the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of variant surface antigens [9], binds glycosaminoglycans [10] and has been shown to inhibit platelet responses [11,12], suggesting that PECAM-1 triggering might be advantageous to the parasite.…”

“…Furthermore, although not primary receptors involved in binding, the recruitment of other receptors after initial tethering could nonetheless be important for stabilization of the platelet-infected erythrocyte complex or for triggering functions from them, as is known for other immunological synapses. PECAM-1 is particularly interesting in this respect because it is known to be a ligand for the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of variant surface antigens [9], binds glycosaminoglycans [10] and has been shown to inhibit platelet responses [11,12], suggesting that PECAM-1 triggering might be advantageous to the parasite.These issues certainly need to be explored, and the availability of increasing numbers of mice deficient in various platelet-adhesion receptors and ligands might provide novel insights into the role of platelets in protection from malaria, especially under hydrodynamic shear flow in the bloodstream [13]. In addition, many of these receptors (including CD36 and gC1qR/HABP1/p32) are expressed by other important immune cells, including dendritic cells, neutrophils and B cells.…”

CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo

“…43 The mean occlusion rate in pecam-1 Ϫ/Ϫ mice was shorter than in wild-type control mice. However, the magnitude of difference was only very modest.…”

“…A more noticeable difference was observed in the kinetics of platelet thrombus formation using the laser-induced injury model that requires tissue factor generated platelet/fibrin thrombus and not type I collagen exposure. 43 Therefore, it appears that Figure 7. ceacam1 ؊/؊ mice are more susceptible to type I collageninduced pulmonary thromboembolism.…”

Imaging of Structural Changes in Endothelial Cells and Thrombus Formation at the Site of FeCl₃-Induced Injuries in Mice Cremasteric Arteries

“…It is well known that endothelial cells release many bioactive substances known to inhibit local activation of platelets, such as nitric oxide (NO) 2,3) , prostaglandin (PG)-I2 [4][5][6] , tissue type plasminogen activators (t-PA) 7) etc. In clinical els [13][14][15][16][17] . These stimulations are presumed to produce free radicals to injure endothelial cell function [18][19][20] ; however, the detailed physiological mechanism resulting in formation of arterial occlusive thrombi is yet to be clarified.…”