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Challenging the mystique Connection. Deciphering cell-matrix interactions role in atherosclerosis and restenosis.

Murugesan, Vignesh LU (2017)
Abstract
Atherosclerosis is the underlying cause for myocardal infarction, stroke and peripheral arterial disease, collectively
referred to as cardiovascular diseases. These represent the major cause of death globally. Phenotypic modulation
of vascular smooth muscle cells form a contractile to a synthetic state and subsequent migration into the intima, is
one of the prime events that marks the genesis of atherosclerosis. To effectuate, cells are required to weaken the
connection with their own basment membrane, a network of extracellular matrix molecules. This thesis explores
the importance of Cell-ECM connections in atherosclerotic and restenostic settings using mice as a model. In
detail, this thesis discusses the role of... (More)
Atherosclerosis is the underlying cause for myocardal infarction, stroke and peripheral arterial disease, collectively
referred to as cardiovascular diseases. These represent the major cause of death globally. Phenotypic modulation
of vascular smooth muscle cells form a contractile to a synthetic state and subsequent migration into the intima, is
one of the prime events that marks the genesis of atherosclerosis. To effectuate, cells are required to weaken the
connection with their own basment membrane, a network of extracellular matrix molecules. This thesis explores
the importance of Cell-ECM connections in atherosclerotic and restenostic settings using mice as a model. In
detail, this thesis discusses the role of dystrophin and beta-sarcoglycan, two important components of the
Dystrophin-glycoprotein complex — one important way cells use to communicate with basement membranes.
In paper I & II, we investigated whether beta-sarcoglycan has a role in the development of atherosclerotic plaques
and vascular injury induced neointima formation. Much to our surprise, we found that the absence of betasarcoglycan
reduced advanced atherosclerotic plaque development, and in contrast, stimulated neo-intimal
hyperplasia under conditions involving the presence or absence of an ApoE-deficient background, respectively.
Under an atherosclerotic setting, the relative area of differentiated smooth muscle cells in the plaques was
increased in beta-sarcoglycan deficient mice. Further, deficiency of beta-sarcoglycan decreased the weight of
visceral adipose tissue and reduced the size of both brown and white adipocytes.
In paper III, we utilized mdx mice to determine if there is also a role for dystrophin in the process of atherosclerotic
plaque development. We obtained similar results as in the study with sarcoglycan deficient mice; the mdx mice
exhibited a significant attenuation of advanced atherosclerotic plaque growth with an increase in the relative area
of differentiated smooth muscle cells in their plaques. A reduction in T-cell content in these plaques and an overall
reduction in systemic inflammation was also observed.
In paper IV, we observed that actin dynamics influence genes important for regulation of VSMC phenotypes and
found dystrophin to be significantly increased and decreased by actin polymerization and depolymerization,
respectively. A significant downregulation of dystrophin was observed under the influence of vascular injury.
To summarize, this thesis uncovers the important influence of a functional CELL-ECM linkage mediated by
dystrophin and beta-sarcoglycan on vascular lesion development. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • assistant professor Bot, Ilze, Leiden University, Netherlands
organization
publishing date
type
Thesis
publication status
published
keywords
Dystrophin glycoprotein complex, beta-sarcoglycan, dystrophin, Plaque, vascular smooth muscle cells, atherosclerosis, restenosis
pages
97 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC, Sölvegatan 17, Lund
defense date
2017-09-01 13:00
ISBN
978-91-7619-500-0
language
English
LU publication?
yes
id
e0975189-b9f3-4aa7-8b56-2b7a08b15e91
date added to LUP
2017-08-11 16:47:18
date last changed
2017-08-15 12:25:21
@phdthesis{e0975189-b9f3-4aa7-8b56-2b7a08b15e91,
  abstract     = {Atherosclerosis is the underlying cause for myocardal infarction, stroke and peripheral arterial disease, collectively<br>
referred to as cardiovascular diseases. These represent the major cause of death globally. Phenotypic modulation<br>
of vascular smooth muscle cells form a contractile to a synthetic state and subsequent migration into the intima, is<br>
one of the prime events that marks the genesis of atherosclerosis. To effectuate, cells are required to weaken the<br>
connection with their own basment membrane, a network of extracellular matrix molecules. This thesis explores<br>
the importance of Cell-ECM connections in atherosclerotic and restenostic settings using mice as a model. In<br>
detail, this thesis discusses the role of dystrophin and beta-sarcoglycan, two important components of the<br>
Dystrophin-glycoprotein complex — one important way cells use to communicate with basement membranes.<br>
In paper I &amp; II, we investigated whether beta-sarcoglycan has a role in the development of atherosclerotic plaques<br>
and vascular injury induced neointima formation. Much to our surprise, we found that the absence of betasarcoglycan<br>
reduced advanced atherosclerotic plaque development, and in contrast, stimulated neo-intimal<br>
hyperplasia under conditions involving the presence or absence of an ApoE-deficient background, respectively.<br>
Under an atherosclerotic setting, the relative area of differentiated smooth muscle cells in the plaques was<br>
increased in beta-sarcoglycan deficient mice. Further, deficiency of beta-sarcoglycan decreased the weight of<br>
visceral adipose tissue and reduced the size of both brown and white adipocytes.<br>
In paper III, we utilized mdx mice to determine if there is also a role for dystrophin in the process of atherosclerotic<br>
plaque development. We obtained similar results as in the study with sarcoglycan deficient mice; the mdx mice<br>
exhibited a significant attenuation of advanced atherosclerotic plaque growth with an increase in the relative area<br>
of differentiated smooth muscle cells in their plaques. A reduction in T-cell content in these plaques and an overall<br>
reduction in systemic inflammation was also observed.<br>
In paper IV, we observed that actin dynamics influence genes important for regulation of VSMC phenotypes and<br>
found dystrophin to be significantly increased and decreased by actin polymerization and depolymerization,<br>
respectively. A significant downregulation of dystrophin was observed under the influence of vascular injury.<br>
To summarize, this thesis uncovers the important influence of a functional CELL-ECM linkage mediated by<br>
dystrophin and beta-sarcoglycan on vascular lesion development.},
  author       = {Murugesan, Vignesh},
  isbn         = {978-91-7619-500-0},
  keyword      = {Dystrophin glycoprotein complex, beta-sarcoglycan, dystrophin, Plaque, vascular smooth muscle cells, atherosclerosis, restenosis},
  language     = {eng},
  pages        = {97},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Challenging the mystique Connection. Deciphering cell-matrix interactions role in atherosclerosis and restenosis.},
  year         = {2017},
}