Byzova T V, Plow E F
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
J Cell Biol. 1998 Dec 28;143(7):2081-92. doi: 10.1083/jcb.143.7.2081.
Regulation of vascular homeostasis depends upon collaboration between cells of the vessel wall and blood coagulation system. A direct interaction between integrin alphaVbeta3 on endothelial cells and smooth muscle cells and prothrombin, the pivotal proenzyme of the blood coagulation system, is demonstrated and activation of the integrin is required for receptor engagement. Evidence that prothrombin is a ligand for alphaVbeta3 on these cells include: (a) prothrombin binds to purified alphaVbeta3 via a RGD recognition specificity; (b) prothrombin supports alphaVbeta3-mediated adhesion of stimulated endothelial cells and smooth muscle cells; and (c) endothelial cells, either in suspension and in a monolayer, recognize soluble prothrombin via alphaVbeta3. alphaVbeta3-mediated cell adhesion to prothrombin, but not to fibrinogen, required activation of the receptor. Thus, the functionality of the alphaVbeta3 receptor is ligand defined, and prothrombin and fibrinogen represent activation- dependent and activation-independent ligands. Activation of alphaVbeta3 could be induced not only by model agonists, PMA and Mn2+, but also by a physiologically relevant agonist, ADP. Inhibition of protein kinase C and calpain prevented activation of alphaVbeta3 on vascular cells, suggesting that these molecules are involved in the inside-out signaling events that activate the integrin. The capacity of alphaVbeta3 to interact with prothrombin may play a significant role in the maintenance of hemostasis; and, at a general level, ligand selection by alphaVbeta3 may be controlled by the activation state of this integrin.
血管稳态的调节依赖于血管壁细胞与血液凝固系统之间的协作。已证实内皮细胞和平滑肌细胞上的整合素αVβ3与凝血系统的关键前体酶凝血酶原之间存在直接相互作用，且受体结合需要整合素的激活。凝血酶原是这些细胞上αVβ3的配体的证据包括：(a) 凝血酶原通过RGD识别特异性与纯化的αVβ3结合；(b) 凝血酶原支持αVβ3介导的受刺激内皮细胞和平滑肌细胞的黏附；(c) 悬浮和单层培养的内皮细胞均通过αVβ3识别可溶性凝血酶原。αVβ3介导的细胞与凝血酶原而非纤维蛋白原的黏附需要受体的激活。因此，αVβ3受体的功能由配体决定，凝血酶原和纤维蛋白原分别代表激活依赖性和激活非依赖性配体。αVβ3的激活不仅可由模型激动剂佛波酯（PMA）和锰离子（Mn2+）诱导，还可由生理相关激动剂二磷酸腺苷（ADP）诱导。蛋白激酶C和钙蛋白酶的抑制可阻止血管细胞上αVβ3的激活，表明这些分子参与激活整合素由内向外的信号转导事件。αVβ3与凝血酶原相互作用的能力可能在维持止血中起重要作用；一般而言，αVβ3的配体选择可能受该整合素激活状态的控制。
