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Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on beta3 but not beta1 integrins
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2006 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 98, no 5, 635-641 p.Article in journal (Refereed) Published
Abstract [en]

Interstitial fluid pressure (PIF) is one of the determinants of transcapillary fluid flux and thereby interstitial fluid volume. Cell-mediated control of PIF regulates fluid content in the loose interstitial connective tissues that surround the capillary bed. To maintain a normal PIF in dermis, β1 integrins mediate the tensile strength applied by connective tissue cells on the extracellular matrix. Platelet-derived growth factor (PDGF)-BB normalizes anaphylaxis-induced reduction of PIF. Anti–β3 integrin IgG and a cyclic RGD peptide that inhibits the αVβ3 integrin blocked the ability of PDGF-BB to normalize the lowered PIF resulting from mast cell degranulation. PDGF-BB was unable to normalize PIF lowered as a result of mast cell degranulation in β3-negative mice. Monoclonal anti–β3 integrin IgG had no effect on PIF in normal mouse dermis. In contrast, administration of anti–β1 integrin IgM lowered PIF in normal dermis but had no effect on PDGF-BB–induced normalization of PIF after anaphylaxis. Furthermore, collagen gel contraction mediated by wild-type mouse embryonal fibroblasts were only marginally affected by function-blocking anti–β1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by αV-negative mouse embryonic fibroblasts was completely blocked by anti–β1 integrin antibodies, even after stimulation with PDGF-BB. These results show a previously unrecognized in vivo function for the αVβ3 integrin, as a participant in the control of PIF during inflammatory reactions. Furthermore, our data demonstrate that PDGF-BB induces connective tissue cells to generate tensile forces via αVβ3 during such reactions.

Place, publisher, year, edition, pages
2006. Vol. 98, no 5, 635-641 p.
Keyword [en]
Animals, Antigens; CD29/*physiology, Capillary Permeability/*drug effects, Cell Degranulation, Collagen/physiology, Edema/etiology, Extracellular Fluid/*metabolism, Female, Integrin beta3/*physiology, Mast Cells/*physiology, Mice, Mice; Inbred BALB C, Mice; Inbred C57BL, Platelet-Derived Growth Factor/*pharmacology, Pressure, Skin/*metabolism
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94098DOI: 10.1161/​01.RES.0000207393.67851.d4PubMedID: 16456102OAI: oai:DiVA.org:uu-94098DiVA: diva2:167837
Available from: 2006-03-16 Created: 2006-03-16 Last updated: 2013-03-21Bibliographically approved
In thesis
1. Integrin αVβ3-Directed Contraction by Connective Tissue Cells: Role in Control of Interstitial Fluid Pressure and Modulation by Bacterial Proteins
Open this publication in new window or tab >>Integrin αVβ3-Directed Contraction by Connective Tissue Cells: Role in Control of Interstitial Fluid Pressure and Modulation by Bacterial Proteins
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis aimed at studying mechanisms involved in control of tissue fluid homeostasis during inflammation.

The interstitial fluid pressure (PIF) is of importance for control of tissue fluid balance. A lowering of PIF in vivo will result in a transport of fluid from the circulation into the tissue, leading to edema. Loose connective tissues that surround blood vessels have an intrinsic ability to take up fluid and swell. The connective tissue cells exert a tension on the fibrous network of the tissues, thereby preventing the tissues from swelling. Under normal homeostasis, the interactions between the cells and the fibrous network are mediated by β1 integrins. Connective tissue cells are in this way actively controlling PIF.

Here we show a previously unrecognized function for the integrin αVβ3, namely in the control of PIF. During inflammation the β1 integrin function is disturbed and the connective tissue cells release their tension on the fibrous network resulting in a lowering of PIF. Such a lowering can be restored by platelet-derived growth factor (PDGF) -BB. We demonstrated that PDGF-BB restored PIF through a mechanism that was dependent on integrin αVβ3. This was shown by the inability of PDGF-BB to restore a lowered PIF in the presence of anti-integrin β3 IgG or a peptide inhibitor of integrin αVβ3. PDGF-BB was in addition unable to normalize a lowered PIF in β3 null mice. Furthermore, we demonstrated that extracellular proteins from Streptococcus equi modulated αVβ3-mediated collagen gel contraction. Because of the established concordance between collagen gel contraction in vitro and control of PIF in vivo, a potential role for these proteins in control of tissue fluid homeostasis during inflammation could be assumed. Sepsis and septic shock are severe, and sometimes lethal, conditions. Knowledge of how bacterial components influence PIF and the mechanisms for tissue fluid control during inflammatory reactions is likely to be of clinical importance in treating sepsis and septic shock.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 47 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 118
Biochemistry, interstitial fluid pressure, collagen gel contraction, integrin αVβ3, septic shock, fibronectin, Biokemi
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:uu:diva-6601 (URN)91-554-6485-8 (ISBN)
Public defence
2006-04-07, B22, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-03-16 Created: 2006-03-16Bibliographically approved

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