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Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury

Gotha, Lara; Lim, Sang Yup; Osherov, Azriel B.; Wolff, Rafael; Qiang, Beiping; Erlich, Ilana; Nili, Nafiseh; Pillarisetti, Sivaram; Chang, Ya-Ting and Tran, Phan-Kiet LU , et al. (2014) In American Journal of Physiology: Heart and Circulatory Physiology 307(3). p.337-345
Abstract
Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2(Delta 3/Delta 3) (M Delta 3/Delta 3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from M Delta 3/Delta 3 and wild-type mice. Proliferation of M Delta 3/Delta 3 SMC was 1.5x greater than in wild type (P < 0.001),... (More)
Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2(Delta 3/Delta 3) (M Delta 3/Delta 3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from M Delta 3/Delta 3 and wild-type mice. Proliferation of M Delta 3/Delta 3 SMC was 1.5x greater than in wild type (P < 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB (P < 0.001). In M Delta 3/Delta 3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with M Delta 3/Delta 3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the M Delta 3/Delta 3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall. (Less)
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publication status
published
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keywords
heparan sulfate proteoglycans, perlecan, arterial injury, smooth muscle, cells
in
American Journal of Physiology: Heart and Circulatory Physiology
volume
307
issue
3
pages
337 - 345
publisher
American Physiological Society
external identifiers
  • wos:000341080300008
  • scopus:84905223350
ISSN
1522-1539
DOI
10.1152/ajpheart.00654.2013
language
English
LU publication?
yes
id
94c2eec7-b505-427f-a2e0-0e969e953a9c (old id 4725930)
date added to LUP
2014-11-03 07:18:00
date last changed
2017-01-01 03:46:25
@article{94c2eec7-b505-427f-a2e0-0e969e953a9c,
  abstract     = {Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2(Delta 3/Delta 3) (M Delta 3/Delta 3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from M Delta 3/Delta 3 and wild-type mice. Proliferation of M Delta 3/Delta 3 SMC was 1.5x greater than in wild type (P &lt; 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB (P &lt; 0.001). In M Delta 3/Delta 3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with M Delta 3/Delta 3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the M Delta 3/Delta 3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall.},
  author       = {Gotha, Lara and Lim, Sang Yup and Osherov, Azriel B. and Wolff, Rafael and Qiang, Beiping and Erlich, Ilana and Nili, Nafiseh and Pillarisetti, Sivaram and Chang, Ya-Ting and Tran, Phan-Kiet and Tryggvason, Karl and Hedin, Ulf and Tran-Lundmark, Karin and Advani, Suzanne L. and Gilbert, Richard E. and Strauss, Bradley H.},
  issn         = {1522-1539},
  keyword      = {heparan sulfate proteoglycans,perlecan,arterial injury,smooth muscle,cells},
  language     = {eng},
  number       = {3},
  pages        = {337--345},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology: Heart and Circulatory Physiology},
  title        = {Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury},
  url          = {http://dx.doi.org/10.1152/ajpheart.00654.2013},
  volume       = {307},
  year         = {2014},
}