Injury-Induced Signalling in Arterial Smooth Muscle Cells

Sara Moses

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The vascular wall is an active, elastic and integrated organ made up of cellular and extracellular matrix (ECM) components. It is not a static organ; the components dynamically change and reorganize in response to physiological and pathological stimuli. Vascular injury induces a complex healing process, analogous to generalised wound healing. Subsequent to the inflammatory response, proliferation and migration of smooth muscle cells (SMCs) is initiated as well as reorganisation of the ECM. The primary function of SMCs in the normal media is contraction, and to be able to migrate and proliferate they must first change their phenotype.

This thesis focuses on the underlying molecular mechanism involved in the SMC response to injury. The understanding of these mechanisms enables us to understand the overall SMC function in the vessel. It is based on signalling and extracellular matrix events following injury to cultured arterial smooth muscle cells. In the first paper, the cytotoxic effects of 7beta-hydroxycholestrol are characterized. We show that this natural compound induces Ca2+ oscillations, ERK1/2 activation followed by apoptosis in SMCs. In the next two studies, we analysed the involvement of ERK1/2 in SMC responses to mechanical injury. In paper II, intracellular Ca2+ release and tyrosine kinase activation was investigated. Immediately after injury, Ca2+ is released from thapsigargine sensitive Ca2+-pools and subsequent ERK1/2 phosphorylation is initiated. Our data indicate that injury-induced DNA synthesis is dependent on immediate phosphorylation of ERK1/2, and probably other tyrosine kinases, whilst the injury-induced migration is dependent on later phosphorylation events. Paper III suggests that osteopontin, a glycoprotein in the ECM, is a downstream target of ERK1/2 signalling.

We found in paper IV that one part of the immediate SMC response-to-injury to be a generation of a novel dermatan sulphate-containing complex. Our data indicates that this mitogenic complex is formed/released from the ECM/cells as a response to injury. Due to the dermatan sulphate involvement in such a complex, this thesis last part describes biosynthetic differences between SMC phenotypes with regard to their proteoglycan profile.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • [unknown], [unknown], Supervisor, External person
Award date2002 Apr 18
Publisher
ISBN (Print)91-628-5141-1
Publication statusPublished - 2002

Bibliographical note

Defence details

Date: 2002-04-18
Time: 10:15
Place: GK-salen, BMC, Lund. 13.00

External reviewer(s)

Name: Hedin, Ulf
Title: MD PhD
Affiliation: Department of Surgical Sciences, Karolinska Hospital, Stockholm, Sweden

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Article: I. 7beta-hydroxycholesterol induces Ca2+ oscillations, MAP kinase activation and apoptosis in human aortic smooth muscle cells.Ares, M. P., Porn-Ares, M. I., Moses, S., Thyberg, J., Juntti-Berggren, L., Berggren, P., Hultgårdh-Nilsson, A., Kallin, B. and Nilsson, J. (2000). Atherosclerosis. 153(1): 23-35.

Article: II. Smooth muscle cell response to mechanical injury involves intracellular Calcium release and ERK1/ERK2 phosphorylation.Moses, S., Dereja, K., Lindkvist, A., Lövdahl, C., Hellstrand, P. and Hultgårdh-Nilsson, A. (2001). Experimental Cell Research. 269: 88-96.

Article: III. Injury-induced osteopontin gene expression in rat arterial smooth muscle cells is dependent on Mitogen-activated protein kinases ERK1/ERK2.Moses, S., Franzén, A., Lövdahl, C. and Hultgårdh-Nilsson, A. (2001). Arch Biochem Biophys. 396(1): 133-7.

Article: IV. Injury to arterial smooth muscle cells releases a complex with mitogenic activity. Proposed glycosaminoglycan participation.Moses, S., Moses J, and Hultgårdh-Nilsson A. (2002). Manuscript

Article: V. Biglycan is increased during phenotypic modulation of rat aortic smooth muscle cells.Todorova, L., Moses, S., Eklund, E., Hultgårdh-Nilsson, A. and Malmström, A. (2002). Manuscript

Subject classification (UKÄ)

  • Basic Medicine

Keywords

  • GAG
  • Clinical biology
  • Klinisk biologi
  • proteoglycan
  • osteopontin
  • ERK
  • MAPK
  • signalling
  • smooth muscle cell
  • injury

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