The expression of TGF-beta receptors in human atherosclerosis: Evidence for acquired resistance to apoptosis due to receptor imbalance

The degree of cellularity in vascular lesions is determined by the balance between the migration and proliferation of cells relative to their rate of egress and apoptosis. Transforming growth factor-beta(1) can act as a poten t antiproliferative and apoptotic factor fur proliferating vascular cells. Our laboratory has previously identified cells cultured from human vascular lesions that are resistant to the antiproliferative effect of TGF-beta(1) due to an acquired mutation in the Type II receptor for TGF-beta(1). In the present studies, the expression of the Type I and II receptors in coronary and carotid atherosclerotic lesions was analysed by immunostaining, RT-PCR , and ill situ RT-PCR. Levels of the Type I and Type II receptors varied wi dely within lesions, with the highest levels in the fibrous cap and at disc rete foci within the lesion. Regions of smooth muscle-like cells (SMC) were commonly found that were Type I positive but Type II receptor negative. In 43 cell lines cultured from 126 human lesions, 84% of the lesion-derived c ell (LDC) cultures exhibited functional resistance to the antiproliferative effect of TGF-beta(1) This resistance was conferred against TGF-beta(1), T GF-beta(2), and TGF-beta(3), but not interferon-gamma or mimosine. While no rmal SMC exhibited a four-fold increase in the rate of apoptosis after TGF- beta(1) treatment, most LDC were resistant to apoptosis in response to TGF- beta(1). Resistant cells exhibited selective loss of Spe II receptor expres sion, and retroviral transfection of Type II receptor cDNA partially correc ted the functional deficit. Thus, resistance to apoptosis may lead to the s low proliferation of resistant cell subsets, thereby contributing to the pr ogression of atherosclerotic and restenotic lesions. (C) 1999 Academic Pres s.