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Transcriptional and post-transcriptional regulation of vascular smooth muscle cell phenotype - Implications for vascular disease states

Alajbegovic, Azra LU (2019) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2019(90).
Abstract
As the world population is pushing toward 8 billion, cardiovascular diseases (CVD) remain the leading cause of death worldwide, representing 30% of all global deaths. A large body of work has recognized that smooth muscle cells (SMCs) surrounding the blood vessels play a prominent role in the development and progression of cardiovascular diseases.

SMCs are highly specialized cells with the main function to maintain vascular tension and thereby regulate blood pressure and blood flow. SMCs retain remarkable plasticity. In response to changes in external cues, SMCs can modulate their phenotype from a highly mature contractile phenotype to a synthetic, proliferative phenotype. Although beneficial during key physiological processes... (More)
As the world population is pushing toward 8 billion, cardiovascular diseases (CVD) remain the leading cause of death worldwide, representing 30% of all global deaths. A large body of work has recognized that smooth muscle cells (SMCs) surrounding the blood vessels play a prominent role in the development and progression of cardiovascular diseases.

SMCs are highly specialized cells with the main function to maintain vascular tension and thereby regulate blood pressure and blood flow. SMCs retain remarkable plasticity. In response to changes in external cues, SMCs can modulate their phenotype from a highly mature contractile phenotype to a synthetic, proliferative phenotype. Although beneficial during key physiological processes such as wound healing, phenotypic modulation can contribute to the development and progression of several vascular disease states. Despite extensive studies on the transcriptional programs that define smooth muscle phenotype, the endogenous regulators that control smooth muscle specificity are still far from understood. The aim of this thesis was to gain further insight into the transcriptional and post-transcriptional regulation of gene expression that occurs during disease development and how these changes affect the function of the vascular wall.

The work in the following papers has identified previously unknown mechanisms by which small non-coding RNAs (miRNAs), actin polymerization and transcriptional regulators MRTFA and GATA6 can contribute to the changes in vascular smooth muscle observed in vascular disease states. In summary, we show that actin polymerization and MRTFA regulate a profile of miRNAs that are downregulated in patients with mildly dilated aorta. Moreover, we demonstrate a novel role for MRTFA in lipid accumulation and foam cell formation. We further demonstrate the importance of miRNA-143 and miRNA-145 for vascular function and for adaptation to hypertension. Lastly, we show that GATA6 regulates migration of SMCs. A deeper understanding into the underlying molecular mechanisms is crucial in order to develop new efficient therapeutic approaches against cardiovascular disease states.
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Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Martin, Kathleen, Yale University, New Haven, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Vascular smooth muscle cells (VSMC), cell phenotype, microRNA, Aneurysm, hypertension, Actin polymerization, GATA6, MRTFA, Vascular disease
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2019
issue
90
pages
57 pages
publisher
Lund University: Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2019-10-28 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-819-3
language
English
LU publication?
yes
id
c2560278-7d82-4418-81e5-6a43a3abf803
date added to LUP
2019-09-23 13:45:13
date last changed
2019-11-19 13:49:51
@phdthesis{c2560278-7d82-4418-81e5-6a43a3abf803,
  abstract     = {{As the world population is pushing toward 8 billion, cardiovascular diseases (CVD) remain the leading cause of death worldwide, representing 30% of all global deaths. A large body of work has recognized that smooth muscle cells (SMCs) surrounding the blood vessels play a prominent role in the development and progression of cardiovascular diseases. <br/><br/>SMCs are highly specialized cells with the main function to maintain vascular tension and thereby regulate blood pressure and blood flow. SMCs retain remarkable plasticity. In response to changes in external cues, SMCs can modulate their phenotype from a highly mature contractile phenotype to a synthetic, proliferative phenotype. Although beneficial during key physiological processes such as wound healing, phenotypic modulation can contribute to the development and progression of several vascular disease states. Despite extensive studies on the transcriptional programs that define smooth muscle phenotype, the endogenous regulators that control smooth muscle specificity are still far from understood. The aim of this thesis was to gain further insight into the transcriptional and post-transcriptional regulation of gene expression that occurs during disease development and how these changes affect the function of the vascular wall.<br/><br/>The work in the following papers has identified previously unknown mechanisms by which small non-coding RNAs (miRNAs), actin polymerization and transcriptional regulators MRTFA and GATA6 can contribute to the changes in vascular smooth muscle observed in vascular disease states. In summary, we show that actin polymerization and MRTFA regulate a profile of miRNAs that are downregulated in patients with mildly dilated aorta. Moreover, we demonstrate a novel role for MRTFA in lipid accumulation and foam cell formation. We further demonstrate the importance of miRNA-143 and miRNA-145 for vascular function and for adaptation to hypertension. Lastly, we show that GATA6 regulates migration of SMCs. A deeper understanding into the underlying molecular mechanisms is crucial in order to develop new efficient therapeutic approaches against cardiovascular disease states.<br/>}},
  author       = {{Alajbegovic, Azra}},
  isbn         = {{978-91-7619-819-3}},
  issn         = {{1652-8220}},
  keywords     = {{Vascular smooth muscle cells (VSMC); cell phenotype; microRNA; Aneurysm; hypertension; Actin polymerization; GATA6; MRTFA; Vascular disease}},
  language     = {{eng}},
  number       = {{90}},
  publisher    = {{Lund University: Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Transcriptional and post-transcriptional regulation of vascular smooth muscle cell phenotype - Implications for vascular disease states}},
  url          = {{https://lup.lub.lu.se/search/files/69816700/Azra_Alajbegovic_WEBB.pdf}},
  volume       = {{2019}},
  year         = {{2019}},
}