Published online before print January 22, 2004, doi: 10.1161/01.RES.0000117772.86853.34
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Submitted on June 6, 2003
Revised on December 8, 2003
Accepted on January 9, 2004
Increased Intimal Hyperplasia and Smooth Muscle Cell Proliferation in Transgenic Mice With Heparan Sulfate-Deficient Perlecan
Phan-Kiet Tran *;
From the Department of Surgical Sciences (P.-K.T., K.T.-L., U.H.), Karolinska Hospital, and Departments of Medical Biochemistry and Biophysics (R.S., K.T.) and Cell and Molecular Biology (J.T.), Karolinska Institutet, Stockholm, Sweden.
* To whom correspondence should be addressed. E-mail: kiet.tran{at}kirurgi.ki.se.
Smooth muscle cell (SMC) proliferation is a critical process in vascular disease. Heparan sulfate (HS) proteoglycans inhibit SMC growth, but the role of endogenous counterparts in the vessel wall in control of SMC function is not known in detail. Perlecan is the major HS proteoglycans in SMC basement membranes and in vessel wall extracellular matrix (ECM). In this study, transgenic mice with HS-deficient perlecan were analyzed with respect to vascular phenotype and intimal lesion formation. Furthermore, SMC cultures were established and characterized with respect to morphology, immunocytochemical features, proteoglycan synthesis, proliferative capacity, and ECM binding of basic fibroblast growth factor (FGF-2). In vitro, mutant SMCs formed basement membranes with perlecan core protein, but with decreased levels of HS, they showed diminished secretion of HS-containing perlecan into the medium and a defective ECM-binding capacity of FGF-2. In vitro, mutant SMCs showed increased proliferation compared with wild-type cells, and in vivo, enhanced SMC proliferation and intimal hyperplasia were observed after flow cessation of the carotid artery in mutant mice. The results indicate that the endogenous HS side-chains of perlecan contribute to SMC growth control both in vitro and during intimal hyperplasia, possibly by sequestering heparin-binding mitogens such as FGF-2.
Key words: smooth muscle cells • perlecan • heparan sulfate proteoglycans • intimal hyperplasia • cell proliferation
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