Naito M
Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan.
Nihon Ronen Igakkai Zasshi. 2000 Jun;37(6):458-63. doi: 10.3143/geriatrics.37.458.
The transition of fibrinogen to fibrin and to their degradation products within the arterial wall has been reported to be accompanied by atherosclerotic progression. A major step in the pathogenesis of atherosclerosis is the vectorial migration of vascular smooth muscle cells (SMCs) from the arterial media through the internal elastic lamina into the intima and their subsequent proliferation in the intima. I have been studying the effects of fibrinogen, fibrin and their degradation products on the behaviour, particularly migration, of SMCs. Fibrinogen/fibrin stimulates the adhesion and migration of SMCs and their effects are mediated by both the RGD-containing region of the alpha chain of fibrinogen/fibrin and integrin alpha v beta 3 on the cell surface. SMCs migrate into fibrin gel even with no other chemotactic stimuli. SMCs displayed two-fold increase in migration into crosslinked fibrin gels compared to non-crosslinked gels, suggesting the importance of fibrin crosslinking by factor XIIIa on its three-dimensional structure for the migration of SMCs. Fibrin gels prepared with batroxobin, which cleaves only fibrinopeptide A, with ACTE, which cleaves only fibrinopeptide B, and with protamine sulfate, which cleaves nothing, but forms a fibrin-like gel, induce migration of SMCs in a manner similar to the gel prepared with thrombin, suggesting that the cleavage of fibrinopeptides is not involved in the migration of SMCs. Both anti-fibrinogen fragment D and E antibodies inhibit the migration of SMCs into fibrin gel, suggesting that both D and E regions of fibrin are involved in the migration of SMCs into fibrin gel. The migration of SMCs into fibrin gel also depends on the RGD-containing region and integrin alpha v beta 3. Both fibrinogen fragments D and E inhibit the migration of SMCs into fibrin gels, suggesting that these fragments may be involved in the regulation of SMC migration into fibrin gel as the result of fibrinolysis. Although subcultured SMCs usually show a synthetic phenotype, the behaviour of contractile SMCs may be crucial for the subsequent migration of the cells. We employed an in vitro assay system to evaluate the effects of fibrin gels on the migration of SMCs from explants taken from rabbit aorta. alpha v beta 3 integrin and the RGD-containing region are involved in the migration of SMCs into the fibrin gels. SMCs which migrated from the explants showed positive staining with monoclonal antibodies against SMC myosin heavy chain isoforms, SMemb, SM1 and SM2, suggesting that they are in an intermediate state changing from a contractile to synthetic state. These findings show that fibrin (ogen) itself induces adhesion and migration of SMCs without other chemotactic or chemokinetic substances, suggesting a crucial role for fibrin (ogen) in the development and progression of such vascular diseases as atherosclerosis, thrombosis and restenosis following balloon angioplasty.
据报道，纤维蛋白原在动脉壁内转变为纤维蛋白及其降解产物的过程伴随着动脉粥样硬化的进展。动脉粥样硬化发病机制中的一个主要步骤是血管平滑肌细胞（SMCs）从动脉中膜通过内弹性膜向内膜的定向迁移以及随后在内膜中的增殖。我一直在研究纤维蛋白原、纤维蛋白及其降解产物对SMCs行为，特别是迁移的影响。纤维蛋白原/纤维蛋白刺激SMCs的黏附和迁移，其作用由纤维蛋白原/纤维蛋白α链的含RGD区域和细胞表面的整合素αvβ3介导。即使没有其他趋化刺激，SMCs也会迁移到纤维蛋白凝胶中。与非交联凝胶相比，SMCs向交联纤维蛋白凝胶中的迁移增加了两倍，这表明因子XIIIa对纤维蛋白进行交联形成的三维结构对SMCs的迁移很重要。用仅切割纤维蛋白肽A的巴曲酶、仅切割纤维蛋白肽B的ACTE以及不切割但形成类似纤维蛋白凝胶的硫酸鱼精蛋白制备的纤维蛋白凝胶，以类似于用凝血酶制备的凝胶的方式诱导SMCs迁移，这表明纤维蛋白肽的切割与SMCs的迁移无关。抗纤维蛋白原片段D和E抗体均抑制SMCs向纤维蛋白凝胶中的迁移，这表明纤维蛋白的D区和E区均参与SMCs向纤维蛋白凝胶中的迁移。SMCs向纤维蛋白凝胶中的迁移还取决于含RGD区域和整合素αvβ3。纤维蛋白原片段D和E均抑制SMCs向纤维蛋白凝胶中的迁移，这表明这些片段可能作为纤溶作用的结果参与调节SMCs向纤维蛋白凝胶中的迁移。尽管传代培养的SMCs通常表现出合成表型，但收缩型SMCs的行为可能对细胞随后的迁移至关重要。我们采用体外测定系统来评估纤维蛋白凝胶对从兔主动脉取出的外植体中SMCs迁移的影响。αvβ3整合素和含RGD区域参与SMCs向纤维蛋白凝胶中的迁移。从外植体迁移出的SMCs用抗SMCs肌球蛋白重链异构体、SMemb、SM1和SM2的单克隆抗体染色呈阳性，这表明它们处于从收缩状态转变为合成状态的中间状态。这些发现表明，纤维蛋白（原）本身在没有其他趋化或化学动力学物质的情况下诱导SMCs的黏附和迁移，这表明纤维蛋白（原）在诸如动脉粥样硬化、血栓形成和球囊血管成形术后再狭窄等血管疾病的发生和发展中起关键作用。
