Overexpression of transforming growth factor β1 in arterial endothelium causes hyperplasia, apoptosis, and cartilaginous metaplasia

Overexpression of transforming growth factor β1 in arterial endothelium causes hyperplasia, apoptosis, and cartilaginous metaplasia

^*Molecular Hematology Laboratory, National Heart, Lung, and Blood Institute, Bethesda, MD 20892; ^†Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20307; ^§Laboratory of Chemoprevention, National Cancer Institute, Bethesda, MD 20892; and ^‡Gladstone Institute of Cardiovascular Disease and ^¶Department of Medicine, University of California at San Francisco, San Francisco, CA 94141-9100

Edited by M. Judah Folkman, Harvard Medical School, Boston, MA, and approved March 31, 1998 (received for review July 25, 1997)

Abstract

Uninjured rat arteries transduced with an adenoviral vector expressing an active form of transforming growth factor β1 (TGF-β1) developed a cellular and matrix-rich neointima, with cartilaginous metaplasia of the vascular media. Explant cultures of transduced arteries showed that secretion of active TGF-β1 ceased by 4 weeks, the time of maximal intimal thickening. Between 4 and 8 weeks, the cartilaginous metaplasia resolved and the intimal lesions regressed almost completely, in large part because of massive apoptosis. Thus, locally expressed TGF-β1 promotes intimal growth and appears to cause transdifferentiation of vascular smooth muscle cells into chondrocytes. Moreover, TGF-β1 withdrawal is associated with regression of vascular lesions. These data suggest an unexpected plasticity of the adult vascular smooth muscle cell phenotype and provide an etiology for cartilaginous metaplasia of the arterial wall. Our observations may help to reconcile divergent views of the role of TGF-β1 in vascular disease.

Footnotes

↵ ‖ To whom reprint requests should be addressed at: Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, San Francisco, CA 94141-9100. e-mail: david_dichek{at}quickmail.ucsf.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: β-gal, β-galactosidase; TUNEL, transferase-mediated dUTP-biotin nick end labeling; TGF-β1, transforming growth factor β1.