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.
