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ECM stiffness modulates aVb3 integrin-directed gene expression of ECM-proteins
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-217026OAI: oai:DiVA.org:uu-217026DiVA: diva2:691631
Available from: 2014-01-28 Created: 2014-01-28 Last updated: 2014-04-29
In thesis
1. Extracellular Matrix and Actin Cytoskeleton - the Control Unit of Interstitial Fluid Volume
Open this publication in new window or tab >>Extracellular Matrix and Actin Cytoskeleton - the Control Unit of Interstitial Fluid Volume
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The regulation of fluid (water) volume in the body is crucial for tissue homeostasis. The interstitial fluid, which comprises almost 20% of the body fluid, is stored in the loose connective tissue and its volume is actively regulated by components of this tissue. The loose connective tissue provides a path for fluid flow from capillaries to the tissue and lymphatics. This fluid is partially stored in the interstitium and the remainder is directed to the lymphatics. The fibroblasts in the loose connective tissue actively compact the fibrous extracellular matrix (ECM) through mechanotransduction via integrins. This in turn, maintains the interstitial fluid pressure and keeps the ground substance underhydrated. The interstitial fluid pressure is part of the forces that regulate the efflux of fluid from capillaries and keep the ground substance underhydrated. The underhydrated ground substance has a potential to take up fluid 3-fold the plasma volume. Therefore, the active contraction of the ECM via fibroblasts is crucial to prevent the risk of evacuation of fluid from capillaries. During pathologies, such as inflammation and carcinogenesis, the interstitial fluid pressure and hence the interstitial fluid volume is altered.

The results presented in this thesis show that the signaling events downstream of αVβ3 integrin, collagen-binding β1 integrins, and platelet-derived growth factor receptor β, that induce cell-mediated matrix contraction, included paired function of PI3K and PLCγ, cofilin activation, actin turnover, and generation of actomyosin forces. Furthermore, the results highlight new potential roles for fibrin and αVβ3 integrins, for instance during clearance of edema. Notably, fibrin extravasation at inflammatory sites induced αVβ3 integrin-dependent matrix contraction, leading to normalization of the altered interstitial fluid volume. It also reprograms the expression of ECM-related genes and hence induces ECM turnover. Taken together, these results provide further insight into the regulatory mechanism through which the loose connective tissue actively regulates the interstitial fluid volume.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 971
Keyword
Collagen, fibrin, integrins, PDGF-BB, gel contraction, fluid homeostasis, interstitial fluid pressure
National Category
Medical and Health Sciences
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-217027 (URN)978-91-554-8865-9 (ISBN)
Public defence
2014-03-14, A1:111a, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-02-20 Created: 2014-01-28 Last updated: 2014-04-29

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