HUMAN CONNECTIVE-TISSUE GROWTH-FACTOR IS EXPRESSED IN ADVANCED ATHEROSCLEROTIC LESIONS

Background Atherosclerosis affects certain but not all vascular beds o f the human circulation. Its molecular mechanisms are only partially u nderstood. Human connective tissue growth factor (hCTGF) is a novel cy steine-rich, secreted polypeptide. hCTGF is implicated in connective t issue formation, which may play an important role in atherosclerosis. Methods and Results By using a differential cloning technique, we isol ated a cDNA clone from a human aorta cDNA library, which is identical to hCTGF. Northern analysis shows that hCTGF mRNA was expressed at 50- to 100-fold higher levels in atherosclerotic blood vessels compared w ith normal arteries. In vascular smooth muscle cells, high-level expre ssion of hCTGF mRNA was induced by transforming growth factor-beta 1. Using in situ hybridization and immunohistochemistry, we found that al l advanced atherosclerotic lesions of human carotid arteries (eight pa tients; mean age, 69; age range, 57 to 85 years) and femoral arteries (two patients; mean age, 71.5 years) that we tested expressed high lev els of both hCTGF mRNA and protein. hCTGF expression was localized mai nly to smooth muscle cells in the plaque lesions that are negative for proliferating cell nuclear antigen staining. In addition, some CD-31- positive endothelial cells of plaque vessels expressed high levels of hCTGF mRNA and protein. hCTGF-positive cells were found predominantly in areas with extracellular matrix accumulation and fibrosis. In contr ast, in normal arteries, we were unable to detect either hCTGF mRNA or immunoreactive hCTGF protein. Conclusions In the present study, we ha ve shown for the first time that both hCTGF mRNA and protein are expre ssed in human arteries in vivo and that hCTGF may represent a novel fa ctor expressed at high levels specifically in advanced lesions and may play a role in the development and progression of atherosclerosis.