Integrin alpha(6)beta(1) Is the Main Receptor for Vascular Laminins and Plays a Role in Platelet Adhesion, Activation, and Arterial Thrombosis

Article

关键词: VON-WILLEBRAND-FACTOR;    GLYCOPROTEIN-IB;    EXTRACELLULAR DOMAIN;    VONWILLEBRAND-FACTOR;    MOUSE MODEL;    CELLS;    BINDING;    CHAINS;    GPIB;    ALPHA-5-BETA-1-GAMMA-1;   

DOI  :  10.1161/CIRCULATIONAHA.112.000799

来源: SCIE

【 摘 要 】

Background-Laminins are major components of basement membranes, well located to interact with platelets upon vascular injury. Laminin-111 (alpha(1)beta(1)gamma(1)) is known to support platelet adhesion but is absent from most blood vessels, which contain isoforms with the alpha(2), alpha(4), or alpha(5) chain. Whether vascular laminins support platelet adhesion and activation and the significance of these interactions in hemostasis and thrombosis remain unknown. Methods and Results-Using an in vitro flow assay, we show that laminin-411 (alpha(4)beta(1)gamma(1)), laminin-511 (alpha(5)beta(1)gamma(1)), and laminin-521 (alpha(5)beta(2)gamma(1)), but not laminin-211 (alpha(2)beta(1)gamma(1)), allow efficient platelet adhesion and activation across a wide range of arterial wall shear rates. Adhesion was critically dependent on integrin alpha(6)beta(1) and the glycoprotein Ib-IX complex, which binds to plasmatic von Willebrand factor adsorbed on laminins. Glycoprotein VI did not participate in the adhesive process but mediated platelet activation induced by alpha(5)-containing laminins. To address the significance of platelet/laminin interactions in vivo, we developed a platelet-specific knockout of integrin alpha(6). Platelets from these mice failed to adhere to laminin-411, laminin-511, and laminin-521 but responded normally to a series of agonists. alpha(6)beta(1)-Deficient mice presented a marked decrease in arterial thrombosis in 3 models of injury of the carotid, aorta, and mesenteric arterioles. The tail bleeding time and blood loss remained unaltered, indicating normal hemostasis. Conclusions-This study reveals an unsuspected important contribution of laminins to thrombus formation in vivo and suggests that targeting their main receptor, integrin alpha(6)beta(1), could represent an alternative antithrombotic strategy with a potentially low bleeding risk.

【 授权许可】

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