English D, Garcia J G, Brindley D N
Experimental Cell Research Program, Methodist Research Institute, 1701 N. Senate, Rm. 1417 MPC, Indianapolis, IN 46202, USA.
Cardiovasc Res. 2001 Feb 16;49(3):588-99. doi: 10.1016/s0008-6363(00)00230-3.
Considerable attention has focused on identifying mediators of neovascularization at sites of growth and abnormal tissue development. By contrast, mediators of angiogenesis at sites of injury and wound repair are not well defined but factors generated during blood coagulation (haemostasis) are attractive candidates. In addition to proteins generated, activated and released during the activation of clotting cascades, platelet-derived lipid mediators are now known to play a key role in many aspects of the angiogenic response. The first indication of lipid mediator involvement in angiogenesis was the discovery that lysophosphatidate (LPA), phosphatidic acid (PA) and sphingosine 1-phosphate (SPP) are high affinity agonists for G-protein coupled EDG (endothelial differentiation gene) receptors. The prototype for this family, EDG-1, was cloned from genes expressed when endothelial cells were activated to assume an angiogenic phenotype in vitro. The subsequent finding that SPP is a high affinity ligand for EDG-1 led Spiegel, Hla and associates (Lee et al., Science 1998;279:1552-1555) to hypothesize that platelet-released phospholipids play an important role in angiogenesis. These investigators and others demonstrated that SPP, LPA and phosphatidate (PA) induce many important endothelial cell responses associated with angiogenesis, including liberation of endothelial cells from established monolayers, chemotactic migration, proliferation, adherens junction assembly and morphogenesis into capillary-like structures. Although these studies indicated the potential involvement of platelet-derived phospholipids in angiogenesis, their physiological importance was not established. However, recent work demonstrates that >80% of the potent endothelial cell chemoattractive activity generated in human serum during clotting--an activity necessary for optimal angiogenesis--results from platelet-derived SPP. Other factors released from platelets during clotting, including LPA and PA, exert profound effects on endothelial cells that contribute unique aspects to the angiogenic response. These combined studies establish that SPP and other platelet-derived lipid mediators provide a novel link between haemostasis and angiogenesis.
相当多的注意力集中在识别生长和异常组织发育部位新生血管形成的介质上。相比之下，损伤和伤口修复部位血管生成的介质尚未明确界定，但凝血（止血）过程中产生的因子是有吸引力的候选者。除了在凝血级联激活过程中产生、激活和释放的蛋白质外，现在已知血小板衍生的脂质介质在血管生成反应的许多方面发挥关键作用。脂质介质参与血管生成的第一个迹象是发现溶血磷脂酸（LPA）、磷脂酸（PA）和鞘氨醇-1-磷酸（SPP）是G蛋白偶联的EDG（内皮分化基因）受体的高亲和力激动剂。该家族的原型EDG-1是从体外激活内皮细胞以呈现血管生成表型时表达的基因中克隆出来的。随后发现SPP是EDG-1的高亲和力配体，这使得Spiegel、Hla及其同事（Lee等人，《科学》，1998年；279:1552-1555）推测血小板释放的磷脂在血管生成中起重要作用。这些研究者和其他人证明，SPP、LPA和磷脂酸（PA）诱导许多与血管生成相关的重要内皮细胞反应，包括使内皮细胞从已建立的单层中释放、趋化性迁移、增殖、黏附连接组装以及向毛细血管样结构的形态发生。尽管这些研究表明血小板衍生的磷脂可能参与血管生成，但其生理重要性尚未确定。然而，最近的研究表明，人类血清在凝血过程中产生的>80%的强效内皮细胞趋化活性——这是最佳血管生成所必需的活性——来自血小板衍生的SPP。凝血过程中从血小板释放的其他因子，包括LPA和PA，对内皮细胞产生深远影响，为血管生成反应贡献独特的方面。这些综合研究表明，SPP和其他血小板衍生的脂质介质在止血和血管生成之间提供了一种新的联系。
