Expression Profiling Identifies 147 Genes Contributing to a Unique Primate Neointimal Smooth Muscle Cell Phenotype

Abstract

Objective— This study represents the first in an effort to systematically characterize different intimas by using expression array analysis. Methods and Results— We compared smooth muscle cells (SMCs) of the neointima formed 4 weeks after aortic grafting with those from normal aorta and vena cava from cynomolgus monkeys. Hybridization to cDNA arrays identified subsets of 147 and 45 genes differentially expressed in the neointima versus the aorta and vena cava, respectively. The expression pattern differentiating neointima from aortic SMCs was characterized largely by suppression. Only 13 genes were induced in the neointima: 7 encoded matrix proteins (6 collagens and 1 versican) and 2 encoded inducers of matrix synthesis (osteoblast-specific factor-2/Cbfa1 and connective tissue growth factor). The genes suppressed most in the neointima included the regulator of G-protein signaling-5, SPARClike-1/hevin, and nonmuscle myosin heavy chain-B. A smaller gene set differentiated the neointima from the vena cava. Most were induced (39 of 45 genes), and overlap with the neointima-aorta set was significant (10 of 13 genes). Array results were validated with Northern analysis, in situ hybridization, or immunohistochemistry. Conclusions— These data underscore the importance of matrix synthesis in neointimal maturation, and novel genes, newly associated with neointimal SMCs (regulator of G-protein signaling-5 and osteoblast-specific factor-2/Cbfa1), have raised new hypotheses regarding the pathogenesis of intimal hyperplasia.