title: Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on beta3 but not beta1 integrins.
abstract: 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, beta1 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-beta3 integrin IgG and a cyclic RGD peptide that inhibits the alphaVbeta3 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 beta3-negative mice. Monoclonal anti-beta3 integrin IgG had no effect on PIF in normal mouse dermis. In contrast, administration of anti-beta1 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-beta1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by alphaV-negative mouse embryonic fibroblasts was completely blocked by anti-beta1 integrin antibodies, even after stimulation with PDGF-BB. These results show a previously unrecognized in vivo function for the alphaVbeta3 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 alphaVbeta3 during such reactions.
authors.affiliation: Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden.
authors.forename: Asa
authors.initials: A
authors.lastname: Lidén
authors.forename: Ansgar
authors.initials: A
authors.lastname: Berg
authors.forename: Torbjørn
authors.initials: T
authors.lastname: Nedrebø
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Reed
authors.forename: Kristofer
authors.initials: K
authors.lastname: Rubin
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002199:Capillary Permeability / Q000187:drug effects*; D015550:Cell Degranulation; D003094:Collagen / Q000502:physiology; D004487:Edema / Q000209:etiology; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D019012:Integrin beta1 / Q000502:physiology*; D039661:Integrin beta3 / Q000502:physiology*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011312:Pressure; D020574:Proto-Oncogene Proteins c-sis; D012867:Skin / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D039661:Integrin beta3; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D003094:Collagen