ROLE OF AGE IN VASCULAR SMOOTH MUSCLE CELL MIGRATION AND INVASION

血管平滑肌细胞（VSMCs）的迁移是血管平滑肌细胞增殖的关键事件。 许多血管疾病的发病机制。的发病率和患病率 血管疾病随着年龄的增长而增加，影响大约50%的男性（通过 65岁）和妇女（75岁）。 我们调查了候鸟， 增殖和分化行为的VSMC来自年轻（年龄 3-6月龄）和老年（24月龄）大鼠。VSMC的两个群体（新生内膜和 中位）。 新生内膜和中膜VSMC在细胞形态和模式上不同 的基因表达。 我们在这里展示了它们的体外迁移反应， 与PDGF的梯度也不同。 具体而言，早期传代（P2-P5）老年 与P2-P5相比，中膜VSMC迁移行为增加75% 年轻内侧VSMC。 在后期（P>10），年轻内侧和老年内侧 VSMC具有类似的迁移特性。 此外，年轻的 新生内膜（P2-P5）细胞的迁移率比年轻内膜（P2-P5）细胞高75%。 P5）细胞。两组显示出相似的增殖率和细胞大小， 同时上调了即刻早期基因c-fos和JE的表达 （MCP-1）的表达。 中膜细胞呈钝 细胞内钙离子对离子霉素的反应和50%的减少， 与新生内膜细胞相比，CamKinaseII活化。 有趣的是，用钙调蛋白正义DNA转染新生内膜细胞（a 中膜细胞的遗传标记）使它们的迁移性降低，而反义细胞则使它们的迁移性降低 钙调蛋白没有表现出任何作用。当来自所有组的VSMC生长停滞时， 它们的迁移行为不到年龄/表型匹配的20 增殖细胞。除PDGF外，年轻增殖细胞的迁移 细胞需要自分泌生长因子，碱性FGF。Ol 相比之下，细胞似乎不需要这种额外的因素， 迁移发生。我们观察到72 kD IV型明胶酶和 受体酪氨酸激酶（RTK）激活对PDGF的反应依赖于 如报告278-04和815-02中详述的细胞表型状态。 未来的研究表征这些差异，并进一步采用 对每一组细胞特异的遗传标记应该提供重要的 了解这些与年龄相关的行为差异， VSMC 迁移

The migration of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of many vascular disease. The incidence and prevalence of vascular disease increase with age, affecting approximately 50% of men (by age 65) and women (by age 75). We investigated the migratory, proliferative, and differentiative behavior of VSMC derived from young (age 3-6 mo) and old (age 24 mo) rats. Two populations of VSMC (neointimal and medial) were obtained following balloon catheter injury for each age group. Neointimal and medial VSMCs differ in their cellular morphology and pattern of gene expression. We show here that their in vitro migration in response to PDGF gradient differs, as well. Specifically, early passage (P2-P5) old medial VSMC exhibit 75% more migratory behavior as compared with (P2-P5) young medial VSMC. At later passages (P>10) young medial and old medial VSMC exhibit similar migratory characteristics. In addition, young neointimal (P2-P5) cells show 75% greater migration than young medial (P2- P5) cells. Both groups showed similar proliferation rates and cell sizes, and both upregulated expression of the immediate-early genes,c-fos and JE (MCP-1) in response to PDGF. The medial cells exhibited a blunted intracellular calcium in response to Ionomycin and a 50% reducti on in CamKinaseII activation as compared to neointimal cells. Interestingly, transfection of neointimal cells with Calponin sense DNA (a genetic marker of medial cells) rendered them less migratory while antisens Calponin showed no effect. When VSMC from all groups were growth-arrested, their migratory behavior was less than 20% that of age/phenotype matched proliferating cells. In addition to PDGF, migration of young proliferating cells requires the autocrine production of the growth factor, basic FGF. Ol cells,in contrast, do not appear to require this additional factor for migration to occur. We have observed that 72 kD Type IV gelatinase and receptor tyrosine kinase (RTK) activation in response to PDGF is dependent on phenotypic state of the cell as detailed in reports 278-04 and 815-02. Future studies characterizing these differences and further employing genetic markers specific to each group of cells should provide important information in understanding these age-associated behavioral differences in VSMC migration.