Characterization of differential gene expression in monkey arterial neointima following balloon catheter injury.

Vaso-occlusive sequelae following percutaneous transluminal coronary angioplasty (PTCA), including smooth muscle cell migration, proliferation, and attendant extracellular matrix production, often results in restenosis of the treated artery. To further understand the molecular mechanisms governing progressive intimal hyperplasia, we performed a molecular screen using differential display PCR on total RNA prepared from injured and normal carotid arterial segments to identify a subset of differentially expressed genes at t=7 days post-balloon catheter injury in a non-human primate. DNA sequence analysis of selected differentially expressed RNA by this procedure using 240 combinations of random primer pairs yielded 41 distinct cDNA sequences: 22 of which have significant sequence homology to previously identified meta-zoan genes, 15 GEMS (genes expressed in monkey neointima), and 4 GSMS (genes suppressed in monkey neointima) that have little homology to reported sequences. Among the up-regulated homologues include i) secreted growth regulatory factors, ii) membrane receptors, iii) transcription factors, iv) cell adhesion molecules, and v) extracellular matrix proteins; some of which have not been previously linked to vascular restenosis. In particular, Cyr61, a known angiogenesis inducer, was found to be highly expressed in the neointima lesion of the balloon-injured monkey artery. This finding provides the first links of Cyr61 to the pathogenesis of vascular restenosis, and identifies a novel locus for potential therapeutic intervention. These studies identified a number of known and unknown genes, whose up- or down-regulated expression during the proliferative phase of vascular restenosis makes them potential targets for therapeutic intervention.