ROLE OF AGE IN VASCULAR SMOOTH MUSCLE CELL MIGRATION AND INVASION

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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.