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Transcriptional control in the vascular wall. Actin-responsive coactivators and smooth muscle transcripts.

Krawczyk, Katarzyna LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Cardiovascular disease (CVD) is the leading cause of death globally. In the European Union (EU) alone, CVD accounts for 1.8 million deaths each year. CVD is a group of disorders involving the heart and the blood vessels. The main risk factors of CVD include unhealthy lifestyles, tobacco smoking, and obesity. It has been demonstrated that chronic high blood pressure (medically termed hypertension) leads to serious clinical complications like myocardial infarction and stroke. Medical costs related to health care of CVD patients are estimated to €111 billion in the EU. It is well established that vascular smooth muscle cells (VSMCs) surrounding the blood vessels contribute to the development and progression of cardiovascular disease states.... (More)
Cardiovascular disease (CVD) is the leading cause of death globally. In the European Union (EU) alone, CVD accounts for 1.8 million deaths each year. CVD is a group of disorders involving the heart and the blood vessels. The main risk factors of CVD include unhealthy lifestyles, tobacco smoking, and obesity. It has been demonstrated that chronic high blood pressure (medically termed hypertension) leads to serious clinical complications like myocardial infarction and stroke. Medical costs related to health care of CVD patients are estimated to €111 billion in the EU. It is well established that vascular smooth muscle cells (VSMCs) surrounding the blood vessels contribute to the development and progression of cardiovascular disease states. VSMCs are responsible for maintaining the vascular tone and for the regulation of blood flow and blood pressure. VSMCs are characterized by a high plasticity, which enables them to modulate their phenotype in response to intracellular and extracellular stimuli, like shear stress, high blood pressure, and hormones. VSMCs can adopt a de-differentiated, synthetic phenotype, which is associated with altered expression of many smooth muscle proteins involved in the contraction-relaxation process. The ability of VSMCs to modulate their phenotype is also termed phenotypic switching. The
synthetic, proliferative VSMCs are essential during the development of vessels and in wound healing processes, whereas in adult blood vessels, most VSMCs exhibit a differentiated, quiescent phenotype. Many studies have demonstrated the contribution of dedifferentiated SMCs to maladaptive arterial remodelling. Hence, understanding the molecular mechanisms involved in phenotypic modulation of VSMCs is crucial to improve global health. The main aim of this thesis was to unravel new molecular mechanisms underlying phenotypic modulation of VSMCs. Here, I demonstrate what is likely to be a major regulatory mechanism for biogenesis of caveolae, which are small membrane organelles typical of contractile and quiescent VSMCs. I find that the expression of caveolin and cavin genes is regulated by two members of the myocardin-related transcription factors: MYOCD and MRTF-A. In the second study, we show that Notch signalling impairment decreases the expression of soluble guanylyl cyclase in VSMCs in hypertension. In my third study, I show that the expression of endothelin type B receptors is controlled by MRTF-B, ELK1, and actin cytoskeletal dynamics. In my last study, finally, synemin is identified as a new target of myocardin-related transcription factors in VSMCs. Taken together, the findings in this thesis expand the knowledge of transcriptional control mechanisms and physiology of vascular smooth muscle. Such understanding is likely to be essential for the development of new effective strategies for the prevention and treatment of cardiovascular disease. (Less)
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author
supervisor
opponent
  • professor De Mey, Jo, Cardiovascular Research Institute in Maastricht, Netherlands
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:28
pages
78 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2020-03-13 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-888-9
language
English
LU publication?
yes
id
9bdd7b11-87a8-4a6b-b520-db48b92074c0
date added to LUP
2020-02-04 15:20:57
date last changed
2020-03-10 10:42:04
@phdthesis{9bdd7b11-87a8-4a6b-b520-db48b92074c0,
  abstract     = {Cardiovascular disease (CVD) is the leading cause of death globally. In the European Union (EU) alone, CVD accounts for 1.8 million deaths each year. CVD is a group of disorders involving the heart and the blood vessels. The main risk factors of CVD include unhealthy lifestyles, tobacco smoking, and obesity. It has been demonstrated that chronic high blood pressure (medically termed hypertension) leads to serious clinical complications like myocardial infarction and stroke. Medical costs related to health care of CVD patients are estimated to €111 billion in the EU. It is well established that vascular smooth muscle cells (VSMCs) surrounding the blood vessels contribute to the development and progression of cardiovascular disease states. VSMCs are responsible for maintaining the vascular tone and for the regulation of blood flow and blood pressure. VSMCs are characterized by a high plasticity, which enables them to modulate their phenotype in response to intracellular and extracellular stimuli, like shear stress, high blood pressure, and hormones. VSMCs can adopt a de-differentiated, synthetic phenotype, which is associated with altered expression of many smooth muscle proteins involved in the contraction-relaxation process. The ability of VSMCs to modulate their phenotype is also termed phenotypic switching. The <br/> synthetic, proliferative VSMCs are essential during the development of vessels and in wound healing processes, whereas in adult blood vessels, most VSMCs exhibit a differentiated, quiescent phenotype. Many studies have demonstrated the contribution of dedifferentiated SMCs to maladaptive arterial remodelling. Hence, understanding the molecular mechanisms involved in phenotypic modulation of VSMCs is crucial to improve global health. The main aim of this thesis was to unravel new molecular mechanisms underlying phenotypic modulation of VSMCs. Here, I demonstrate what is likely to be a major regulatory mechanism for biogenesis of caveolae, which are small membrane organelles typical of contractile and quiescent VSMCs. I find that the expression of caveolin and cavin genes is regulated by two members of the myocardin-related transcription factors: MYOCD and MRTF-A. In the second study, we show that Notch signalling impairment decreases the expression of soluble guanylyl cyclase in VSMCs in hypertension. In my third study, I show that the expression of endothelin type B receptors is controlled by MRTF-B, ELK1, and actin cytoskeletal dynamics. In my last study, finally, synemin is identified as a new target of myocardin-related transcription factors in VSMCs. Taken together, the findings in this thesis expand the knowledge of transcriptional control mechanisms and physiology of vascular smooth muscle. Such understanding is likely to be essential for the development of new effective strategies for the prevention and treatment of cardiovascular disease.},
  author       = {Krawczyk, Katarzyna},
  isbn         = {978-91-7619-888-9},
  issn         = {1652-8220},
  language     = {eng},
  month        = {02},
  number       = {2020:28},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Transcriptional control in the vascular wall. Actin-responsive coactivators and smooth muscle transcripts.},
  year         = {2020},
}