Mechanosensing in the vascular wall - the role of cellular microdomains in vascular remodeling

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

The vascular wall has a remarkable capacity to adapt to mechanical forces exerted by the intraluminal blood pressure and flow. This includes rapid change in contractile tone as well as chronic alteration of vessel structure if the stimulus persists. Stretch of the intact blood vessel wall promotes growth and contractile differentiation. The molecular mechanisms involved are not well defined, but contractile differentiation has been suggested to be mediated by polymerization of the cytoskeletal protein actin. Part of the machinery that signals growth may be assembled in membrane invaginations termed caveolae, and a role for caveolae in mechanosensing has accordingly been proposed. The studies summarized in this thesis aimed to determine the role of these two cellular domains in mechanosensitive signaling in the intact vascular wall using rat or mouse portal veins as well as carotid and small mesenteric arteries.

In the portal vein, we found that stretch promotes contractile differentiation via Rho activation and actin polymerization. An intact actin cytoskeleton is required for stretch-induced synthesis of smooth muscle specific marker proteins and for global protein synthesis. We also found that stabilizing actin filaments produced the same effects as stretch on protein synthesis. Stretch dependency of growth and differentiation was maintained in mice lacking caveolin-1 and vascular caveolae. In arteries from these mice, a reduced myogenic tone was observed, which was mainly caused by excessive nitric oxide (NO) production. Blood pressure was however maintained in vivo despite increased NO production. Maintenance of blood pressure in the setting of increased NO production could be due to increased alpha1-adrenergic contraction, hypertrophic remodeling and increased plasma volume.

In summary, the data suggest that stretch stimulates polymerization of actin, which is necessary for expression of smooth muscle differentiation markers and growth of the intact vascular wall. On the other hand, stretch-induced growth and differentiation is not dependent on caveolin-1 or caveolae, which may however play a role for contractile responses to mechanical stimuli.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Hellstrand, Per, Supervisor
Award date2007 Apr 20
Publisher
ISBN (Print)978-91-85559-35-0
Publication statusPublished - 2007

Bibliographical note

Defence details

Date: 2007-04-20
Time: 09:15
Place: Segerfalksalen Biomedicinskt Centrum Sölvegatan 19 Lund

External reviewer(s)

Name: Nixon, Graeme
Title: Professor
Affiliation: Institute of Medical Sciences, University of Aberdeen

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<div class="article_info">Azad Zeidan, Ina Nordström, Sebastian Albinsson, Ulf Malmqvist, Karl Swärd and Per Hellstrand. <span class="article_issue_date">2003</span>. <span class="article_title">Stretch-induced contractile differentiation of vascular smooth muscle: sensitivity to actin polymerization inhibitors.</span> <span class="journal_series_title">American Journal of Physiology - Cell Physiology</span>, <span class="journal_volume">vol 284</span> <span class="journal_pages">pp C1387-C1396</span>. <span class="journal_distributor">The American Physiological Society</span></div>
<div class="article_info">Sebastian Albinsson, Ina Nordström and Per Hellstrand. <span class="article_issue_date">2004</span>. <span class="article_title">Stretch of the vascular wall induces smooth muscle differentiation by promoting actin polymerization.</span> <span class="journal_series_title">The Journal of Biological Chemistry</span>, <span class="journal_volume">vol 279</span> <span class="journal_pages">pp 34849-34855</span>. <span class="journal_distributor">The American Society for Biochemistry and Molecular Biology</span></div>
<div class="article_info">Sebastian Albinsson and Per Hellstrand. <span class="article_issue_date"></span>. <span class="article_title">Integration of signal pathways for stretch-dependent growth and differentiation in vascular smooth muscle.</span> (submitted)</div>
<div class="article_info">Sebastian Albinsson, Yulia Shakirova, Anna Rippe, Maria Baumgarten, Bert-Inge Rosengren, Catarina Rippe, Rupert Hallman, Per Hellstrand, Bengt Rippe and Karl Swärd. <span class="article_issue_date"></span>. <span class="article_title">Arterial remodeling in caveolin-1 deficient mice</span> (submitted)</div>
<div class="article_info">Sebastian Albinsson, Ina Nordström, Karl Swärd and Per Hellstrand. <span class="article_issue_date"></span>. <span class="article_title">Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall</span> (submitted)</div>

Subject classification (UKÄ)

  • Basic Medicine

Keywords

  • Physiology
  • tissue culture
  • Histologi
  • cytokemi
  • histokemi
  • vävnadskultur
  • cytochemistry
  • histochemistry
  • wall stress
  • shear stress
  • hypertension
  • Histology
  • differentiation
  • growth
  • caveolin
  • smooth muscle
  • actin
  • Fysiologi
  • Cardiovascular system
  • Kardiovaskulära systemet

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