Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on β3 but Not β1 Integrins

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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, 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.