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(Circulation Research. 2006;98:635.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on ß3 but Not ß1 Integrins

Åsa Lidén, Ansgar Berg, Torbjørn Nedrebø, Rolf K. Reed, Kristofer Rubin

From the Department of Medical Biochemistry and Microbiology (A.L., K.R.), University of Uppsala, Sweden; and the Department of Biomedicine (A.B., T.N., R.K.R.), Division of Physiology, University of Bergen, Norway.

Correspondence to Prof Kristofer Rubin, Department of Medical Biochemistry and Microbiology, University of Uppsala, BMC Box 582, SE-751 23 Uppsala, Sweden. E-mail Kristofer.Rubin{at}imbim.uu.se

Interstitial fluid pressure (P_IF) is one of the determinants of transcapillary fluid flux and thereby interstitial fluid volume. Cell-mediated control of P_IF regulates fluid content in the loose interstitial connective tissues that surround the capillary bed. To maintain a normal P_IF in dermis, ß1 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 P_IF. Anti–ß3 integrin IgG and a cyclic RGD peptide that inhibits the Vß3 integrin blocked the ability of PDGF-BB to normalize the lowered P_IF resulting from mast cell degranulation. PDGF-BB was unable to normalize P_IF lowered as a result of mast cell degranulation in ß3-negative mice. Monoclonal anti–ß3 integrin IgG had no effect on P_IF in normal mouse dermis. In contrast, administration of anti–ß1 integrin IgM lowered P_IF in normal dermis but had no effect on PDGF-BB–induced normalization of P_IF after anaphylaxis. Furthermore, collagen gel contraction mediated by wild-type mouse embryonal fibroblasts were only marginally affected by function-blocking anti–ß1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by V-negative mouse embryonic fibroblasts was completely blocked by anti–ß1 integrin antibodies, even after stimulation with PDGF-BB. These results show a previously unrecognized in vivo function for the Vß3 integrin, as a participant in the control of P_IF during inflammatory reactions. Furthermore, our data demonstrate that PDGF-BB induces connective tissue cells to generate tensile forces via Vß3 during such reactions.

Key Words: anaphylaxis • V integrins • collagen gel contraction • edema • fluid homeostasis

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