Advancing age is the most significant factor in the development of atherosclerosis. More than 40% of the 300,000 elderly patients treated by angioplasty for coronary atherosclerosis develop a fibroproliferative lesion that reoccludes the artery within 6 months. The mechanism of this restenosis is unknown, and thus, it has been resistant to therapy. We have identified and age-related defect in the proliferative capacity of vascular smooth muscle cells (SMC) related to the specific loss of Type II receptors for transforming growth factor-beta1 (TGF-beta1). This receptor defect makes SMC from old animals resistant to growth inhibition by TGF-beta1, but the cells retain their fibrotic responses to TGF-beta1. We now report that this same receptor defect occurs in SMC derived from human coronary atherosclerotic plaques. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we have observed a loss of the mRNA for the Type II TGF- beta1 receptor in atherosclerotic SMC. These cells show no growth inhibitory response to TGF-beta1, but produce collagen, plasminogen activator inhibitor-1, and switch actin phenotypes in response to TGF- beta1. Transfection of Type II receptor cDNA corrects the aberrant behavior of the lesion-derived cells. Preliminary evidence indicates that the loss of the Type II receptor in cells growth from vascular lesions is due to frame-shift mutations in replication error-prone regions of the Type II receptor gene, a defect originally identified in colon carcinoma. Because TGF-beta1 is overexpressed in fibroproliferative vascular lesions, such as restenosis after balloon angioplasty, this selective loss of growth inhibitory function allows the SMC to grow in a slow, uncontrolled fashion, and strongly favors extracellular matrix accumulation. The proposed studies will define the cause of this receptor dysfunction, establish methods to diagnose it, and develop the means to correct it. Transfection and genetically engineered receptors into SMC will be tested as a means of controlling restenosis. th results will identify the causes and consequences of a non-neoplastic TGF-beta1 receptor defect that leads to dysregulated fibrotic and proliferative behavior in human coronary artery SMC. This TGF-beta1 receptor dysfunction has direct implications for atherosclerosis, restenosis, and related fibroproliferative diseases that are prevalent in the elderly population.
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