ROLE OF AGE IN VASCULAR SMOOTH MUSCLE CELL MIGRATION AND INVASION

许多血管疾病的发展和进展取决于 血管平滑肌细胞（VSMC）的迁移和增殖， 它们与细胞外基质（ECM）的相互作用。 发生率和 血管疾病的患病率随着年龄的增长而增加， 大约50%的男性（65岁）和女性（75岁）。 我们有 以前发现增殖的VSMC积极地降解， 侵入重建的基底膜屏障（模拟 包围单个VSMC并将它们分开的基底膜 从内弹性膜形式的内皮细胞， 体内）对PDGF的反应，而血清- 饥饿/分化的VSMC低于20%（p <0.001）， 增殖的细胞。 我们证明了VSMC迁移通过 这种ECM屏障需要72 kD的IV型明胶酶。 在这个项目中 我们研究了迁移/侵袭，增殖， 年轻人（3-6月龄）VSMC的分化行为， 老年（24个月）大鼠。 两个VSMC群（新生内膜和中膜） 在每个年龄组的球囊导管损伤后获得。 早期传代（P2-P5）的新生内膜VSMC迁移率高75 与（P2-P5）年轻中膜VSMC相比，具有侵袭行为。 在 后期传代（P6-P16）年轻的中膜和年轻的新生内膜VSMC表现出 类似的迁移和入侵特征。 相比之下，老 内侧（P2-P5）表现为侵略性迁移和侵入行为， 陈旧性新生内膜（P2-P5）。 当四组VSMC均生长 被捕后，他们的迁移和入侵行为不到20%， 年龄/表型匹配的增殖细胞。 我们观察到 活性72 kD IV型明胶酶和受体酪氨酸的差异 在增殖期和增殖期之间， 分化的VSMC未来的研究采用的基因标记物 分化和增殖的VSMC，如钙调蛋白，CHIP 28和 骨桥蛋白以及72 kD IV型明胶酶表达， 激活应该提供重要的信息，了解这些 迁移/入侵行为的年龄相关行为差异 的VSMC。

The development and progression of many vascular diseases depend on the migration and proliferation of vascular smooth muscle cells (VSMC) and their interaction with extracellular matrix (ECM). The incidence and prevalence of vascular disease increase with age, affecting approximately 50% of men (by age 65) and women (by age 75). We have found previously that proliferating VSMC aggressively degrade and invade a reconstituted basement membrane barrier (modeled to mimic the basement membrane which surrounds individual VSMC and separates them from endothelial cells in the form of the internal elastic lamina in vivo) in response to PDGF, while the migration and invasion of serum- starved/differentiated VSMC was less than 20% (p less than 0.001) that of proliferating cells. We demonstrated that VSMC migration through this ECM barrier requires 72 kD Type IV gelatinase. In this project we investigated the migratory/invasive, 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. Early passage (P2-P5) young neointimal VSMC exhibit 75% more migratory and invasive behavior as compared with (P2-P5) young medial VSMC. At later passages (P6-P16) young medial and young neointimal VSMC exhibit similar migratory and invasive characteristics. In contrast, old medial (P2-P5) show as aggressive migratory and invasive behavior as old neointimal (P2-P5). When VSMC from all four groups were growth arrested, their migratory and invasive behavior was less than 20% that of age/phenotype matched proliferating cells. We have observed differences in active 72 kD Type IV gelatinase and in receptor tyrosine kinase (RTK) activation in response to PDGF between proliferating and differentiated VSMC Future studies employing gene markers of differentiated and proliferating VSMC such as calponin, CHIP 28 and Osteopontin as well as 72 kD Type IV gelatinase expression and activation should provide important information in understanding these age-associated behavioral differences in migratory/invasive behavior of VSMC.