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Increased Intimal Hyperplasia and Smooth Muscle Cell Proliferation in Transgenic Mice with Heparan Sulfate-Deficient Perlecan

Tran, Phan Kiet LU ; Tran-Lundmark, Karin LU ; Soininen, Raija ; Tryggvason, Karl ; Thyberg, Johan and Hedin, Ulf (2004) In Circulation Research 94(4). p.550-558
Abstract

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... (More)

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.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell proliferation, Heparan sulfate proteoglycans, Intimal hyperplasia, Perlecan, Smooth muscle cells
in
Circulation Research
volume
94
issue
4
pages
9 pages
publisher
American Heart Association
external identifiers
  • pmid:14739157
  • scopus:1542283679
ISSN
0009-7330
DOI
10.1161/01.RES.0000117772.86853.34
language
English
LU publication?
no
id
1ef93181-3ca2-4cc8-b4f5-d23e43c9db36
date added to LUP
2019-07-01 22:18:25
date last changed
2024-07-24 01:33:30
@article{1ef93181-3ca2-4cc8-b4f5-d23e43c9db36,
  abstract     = {{<p>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.</p>}},
  author       = {{Tran, Phan Kiet and Tran-Lundmark, Karin and Soininen, Raija and Tryggvason, Karl and Thyberg, Johan and Hedin, Ulf}},
  issn         = {{0009-7330}},
  keywords     = {{Cell proliferation; Heparan sulfate proteoglycans; Intimal hyperplasia; Perlecan; Smooth muscle cells}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{550--558}},
  publisher    = {{American Heart Association}},
  series       = {{Circulation Research}},
  title        = {{Increased Intimal Hyperplasia and Smooth Muscle Cell Proliferation in Transgenic Mice with Heparan Sulfate-Deficient Perlecan}},
  url          = {{http://dx.doi.org/10.1161/01.RES.0000117772.86853.34}},
  doi          = {{10.1161/01.RES.0000117772.86853.34}},
  volume       = {{94}},
  year         = {{2004}},
}