Integrin α6β1 Is the Main Receptor for Vascular Laminins and Plays a Role in Platelet Adhesion, Activation, and Arterial Thrombosis
Integrin α6β1 Is the Main Receptor for Vascular Laminins and Plays a Role in Platelet Adhesion, Activation, and Arterial Thrombosis
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DOI：
10.1161/circulationaha.112.000799
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发表时间：
2013-07-30
期刊：
影响因子：
37.8
通讯作者：
Mangin, Pierre H.
中科院分区：
文献类型：
--
作者：
Schaff, Mathieu;Tang, ChaoJun;Mangin, Pierre H.
背景-层粘连蛋白是基底膜的主要成分，在血管损伤时与血小板相互作用。已知层粘连蛋白-111（alpha（1）beta（1）gamma（1））可支持血小板粘附，但大多数血管中不存在，其中含有α（2）、α（4）或α（5）链的亚型。血管层粘连蛋白是否支持血小板粘附和活化以及这些相互作用在止血和血栓形成中的意义仍然未知.方法和结果-使用体外流动测定，我们表明层粘连蛋白-411（α（4）β（1）γ（1）），层粘连蛋白-511（α（5）β（1）γ（1）），和层粘连蛋白-521（α（5）β（2）γ（1）），而不是层粘连蛋白-211（α（2）β（1）γ（1）），允许在宽范围的动脉壁剪切速率下有效的血小板粘附和活化。粘附主要依赖于整合素α（6）β（1）和糖蛋白Ib-IX复合物，该复合物与吸附在层粘连蛋白上的血浆血管性血友病因子结合。糖蛋白VI不参与粘附过程，但介导含α（5）层粘连蛋白诱导的血小板活化。为了解决体内血小板/层粘连蛋白相互作用的重要性，我们开发了血小板特异性敲除整合素α（6）。这些小鼠的血小板不能粘附层粘连蛋白-411、层粘连蛋白-511和层粘连蛋白-521，但对一系列激动剂反应正常。在颈动脉、主动脉和肠系膜小动脉损伤的3种模型中，α（6）β（1）缺陷小鼠的动脉血栓形成显著减少。尾部出血时间和失血量保持不变，表明正常止血。结论-这项研究揭示了层粘连蛋白在体内血栓形成的一个意料之外的重要贡献，并表明靶向其主要受体整合素α（6）β（1），可能代表一种潜在的低出血风险的替代抗血栓形成策略。
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.