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.