(Circulation. 1999;99:2019-2026.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Vascular Cell Apoptosis
Cell Type–Specific Modulation by Transforming Growth Factor-ß1 in Endothelial Cells Versus Smooth Muscle Cells
From the Cardiovascular Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (M.J.P., G.H.G.); and the Department of Pediatrics, Stanford University Medical Center, Stanford, Calif (L.N.).
Correspondence to Gary H. Gibbons, MD, Brigham and Women's Hospital, Thorn Cardiovascular Research Laboratories-1326, 75 Francis St, Boston, MA 02115. E-mail ggibbons{at}bustoff.bwh.harvard.edu
Background—It is postulated that vascular lesion formation and remodeling involves a balance between vascular cell death and cell proliferation. Transforming growth factor-ß1 (TGF-ß1) is a pleiotropic factor expressed within vascular cells that regulates cell growth in a tissue-specific manner. This study tested the hypothesis that the control of vascular cell apoptosis involves cell type–specific regulation by TGF-ß1.
Methods and Results—In response to serum withdrawal, cultured endothelial cells and vascular smooth muscle cells exhibited apoptosis as evidenced by DNA laddering and quantitated by analysis of nuclear chromatin morphology. Addition of TGF-ß1 to endothelial cells in serum-free media further potentiated the induction of apoptosis in a dose-dependent fashion. Moreover, TGF-ß1 promoted endothelial cell death despite the presence of 10% serum. However, endothelial cells plated on collagen I were resistant to TGF-ß1–induced apoptosis. This antiapoptotic influence of the matrix was mimicked by integrin activation with anti-ß1 antibodies and associated with increased expression of the antiapoptotic factor bcl-2. In accord with the hypothesis that the modulation of antiapoptotic gene expression may mediate the effects of TGF-ß1 and ß1 integrins on cell fate, we observed that endothelial cells with constitutive upregulation of bcl-2 remained viable despite exposure to TGF-ß1 in serum-free conditions. In contrast to the proapoptotic effect of TGF-ß1 in endothelial cells, addition of TGF-ß1 to vascular smooth muscle cells in serum-free media inhibited apoptosis.
Conclusions—These findings suggest that the effect of cytokines such as TGF-ß1 on cell fate is contextual and is modulated by cell-matrix interactions in a cell type–specific manner.
Key Words: vasculature • apoptosis • cells
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