Department for Radiobiology and Molecular Genetics, Vinča Institute, University of Belgrade, P.O. Box 522, 11001, Belgrade, Serbia.
J Thromb Thrombolysis. 2012 Feb;33(2):160-72. doi: 10.1007/s11239-011-0662-x.
Vascular endothelium, as a key regulator of hemostasis, mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. Endothelial dysfunction caused by acute or chronic inflammation, such as in atherosclerosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites, and at the same time promotes coagulation, thrombin generation, and fibrin deposition in an attempt to close the wound. Life-long persistent infection with human cytomegalovirus (HCMV) has been associated with atherosclerosis. In vivo studies have revealed that HCMV infection of the vessel wall affects various cells including monocytes/macrophages, smooth muscle cells (SMCs) and endothelial cells (ECs). HCMV-infected SMCs within vascular lesions display enhanced proliferation and impaired apoptosis, which contribute to intima-media thickening, plaque formation and restenosis. Monocytes play a central role in the process of viral dissemination, whereas ECs may represent a viral reservoir, maintaining persistent infection in HCMV-infected atherosclerotic patients following the primary infection. Persistent infection leads to dysfunction of ECs and activates proinflammatory signaling involving nuclear factor κB, specificity protein 1, and phosphatidylinositol 3-kinase, as well as expression of platelet-derived growth factor receptor. Activation of these pathways promotes enhanced proliferation and migration of monocytes and SMCs into the intima of the vascular wall as well as lipid accumulation and expansion of the atherosclerotic lesion. Moreover, HCMV infection induces enhanced expression of endothelial adhesion molecules and modifies the proteolytic balance in monocytes and macrophages. As a consequence, infected endothelium recruits naive monocytes from the blood stream, and the concomitant interaction between infected ECs and monocytes enables virus transfer to migrating monocytes. Endothelial damage promotes thrombin generation linking inflammation and coagulation. HCMV, in turn, enhances the thrombin generation. The virus carries on its surface the molecular machinery necessary to initiate thrombin generation, and in addition, may interact with the prothrombinase protein complex thereby facilitating thrombin generation. Thus, infection of endothelium may significantly increase the production of thrombin. This might not only contribute to thrombosis in patients with atherosclerosis, but might also induce thrombin-dependent proinflammatory cell activation. This review summarizes the existing evidence on the role of HCMV in vascular inflammation.
血管内皮作为止血的关键调节者，介导血管扩张、防止血小板黏附并抑制凝血酶生成。急性或慢性炎症（如动脉粥样硬化）导致的内皮功能障碍会产生促炎环境，支持白细胞向炎症部位迁移，同时促进凝血、凝血酶生成和纤维蛋白沉积，试图封闭伤口。人巨细胞病毒（HCMV）的终身持续感染与动脉粥样硬化有关。体内研究表明，血管壁的 HCMV 感染会影响多种细胞，包括单核细胞/巨噬细胞、平滑肌细胞（SMCs）和内皮细胞（ECs）。血管病变中的 HCMV 感染 SMCs 表现出增强的增殖和受损的凋亡，这导致内膜-中膜增厚、斑块形成和再狭窄。单核细胞在病毒传播过程中起核心作用，而 ECs 可能代表病毒库，在 HCMV 感染的动脉粥样硬化患者原发性感染后维持持续性感染。持续性感染导致 ECs 功能障碍，并激活涉及核因子 κB、特异性蛋白 1 和磷脂酰肌醇 3-激酶的促炎信号，以及血小板衍生生长因子受体的表达。这些途径的激活促进单核细胞和 SMCs 向血管壁内膜的增强增殖和迁移以及脂质积累和动脉粥样硬化病变的扩张。此外，HCMV 感染诱导内皮黏附分子的表达增强，并改变单核细胞和巨噬细胞中的蛋白水解平衡。结果，受感染的内皮细胞从血流中招募幼稚单核细胞，受感染的 ECs 和单核细胞之间的协同作用使病毒转移到迁移的单核细胞。内皮损伤促进炎症和凝血的凝血酶生成。反过来，HCMV 增强了凝血酶生成。病毒在其表面携带启动凝血酶生成所需的分子机制，并且还可以与凝血酶原酶蛋白复合物相互作用，从而促进凝血酶生成。因此，内皮感染可能显著增加凝血酶的产生。这不仅可能导致动脉粥样硬化患者的血栓形成，而且可能诱导依赖凝血酶的促炎细胞激活。本综述总结了 HCMV 在血管炎症中的作用的现有证据。
