Atherosclerosis appears to reflect a vascular response to chronic vascular injuries such as hypertension, smoking, and hyperlipidemia. Likewise, restenosis is an excessive vascular response to acute injury induced by balloon agnioplasty or atherectomy. In most cases however, both atherosclerotic and restenotic lesions are reversible. But can convert to chronic, stenosing, fibroproliferative disease. Thus, a vital question is: What factors distinguish normal vascular repair from fibroproliferative vascular disease? Our studies have focused on transforming growth factor-beta (TGF-beta1) because it is produced by vascular cells and it can modulate the key steps in atherogenesis and restenosis: cell migration, proliferation, extracellular matrix synthesis, calcification, and apoptosis. In both humans and animal models, we have determined that smooth-muscle cells (SMC) derived from vascular lesions are resistant to the antiproliferative effect of TGF-beta1, which potently inhibits normal SMC. However, the ability of TGF-beta1 to induce matrix accumulation remains intact. This aberrant response to TGF-beta1 is related to a selective decrease in the expression of the Type II receptor for TGF-beta1 and lower steady-state levels of its mRNA. Transfection of a normal Type II receptor cDNA into lesion-derived SMC restores the antiproliferative response to TGF-beta1. The Type II receptor possesses 2 microsatellite repeats, making it prone to replication errors which inactivate the gene or cause the expression of a dysfunctional receptor. Our Preliminary Data indicates that mutations in these regions occur in cells populating human atherosclerotic tissues and in cells grown from them. The proposed studies would diagnose these mutations in animal models of restenosis and atherosclerosis, and in human coronary artery biopsies. The presence of mutations of gene rearrangements in the Type II receptor will then be correlated with the progression of disease in humans and experimental animals. The causal relationship of these mutations to vascular disease will be tested by using a gene therapy approach to introduce mutant receptors, and conversely, mutation-resistant receptors, into animal and vascular cells, and into animal models of vascular injury. The effect of the genetic manipulations on the response TGF-beta1 in vitro, and on the progress of vascular lesion in vivo, will be quantitated. The results will investigate an entirely new role for acquired TGF-beta1 receptor mutations in non-neoplastic vascular disease on both a correlational and mechanistic level.
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