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  • Title: Integrin αV β3 can substitute for collagen-binding β1 -integrins in vivo to maintain a homeostatic interstitial fluid pressure.
    Author: Lidén Å, Karlsen TV, Guss B, Reed RK, Rubin K.
    Journal: Exp Physiol; 2018 May 01; 103(5):629-634. PubMed ID: 29524327.
    Abstract:
    NEW FINDINGS: What is the central question of this study? Collagen-binding β1 -integrins function physiologically in cellular control of dermal interstitial fluid pressure (PIF ) in vivo and thereby participate in control of extravascular fluid volume. During anaphylaxis, simulated by injection of compound 48/80, integrin αV β3 takes over this physiological function. Here we addressed the question whether integrin αV β3 can replace collagen-binding β1 -integrin to maintain a long-term homeostatic PIF . What is the main finding and its importance? Mice lacking the collagen-binding integrin α11 β1 show a complex dermal phenotype with regard to the interstitial physiology apparent in the control of PIF . Notably dermal PIF is not lowered with compound 48/80 in these animals. Our present data imply that integrin αV β3 is the likely candidate that has taken over the role of collagen-binding β1 -integrins for maintaining a steady-state homeostatic PIF . A better understanding of molecular processes involved in control of PIF is instrumental for establishing novel treatment regimens for control of oedema formation in anaphylaxis and septic shock. ABSTRACT: Accumulated data indicate that cell-mediated contraction of reconstituted collagenous gels in vitro can serve as a model for cell-mediated control of interstitial fluid pressure (PIF ) in vivo. A central role for collagen-binding β1 -integrins in both processes has been established. Furthermore, integrin αV β3 takes over the role of collagen-binding β1 -integrins in mediating contraction after perturbations of collagen-binding β1 -integrins in vitro. Integrin αV β3 is also instrumental for normalization of dermal PIF that has been lowered due to mast cell degranulation with compound 48/80 (C48/80) in vivo. Here we demonstrate a role of integrin αV β3 in maintaining a long term homeostatic dermal PIF in mice lacking the collagen-binding integrin  α11 β1 (α11-/- mice). Measurements of PIF were performed after circulatory arrest. Furthermore, cell-mediated integrin αV β3 -directed contraction of collagenous gels in vitro depends on free access to a collagen site known to bind several extracellular matrix (ECM) proteins that form substrates for αV β3 -directed cell attachment, such as fibronectin and fibrin. A streptococcal collagen-binding protein, CNE, specifically binds to and blocks this site on the collagen triple helix. Here we show that whereas CNE perturbed αV β3 -directed and platelet-derived growth factor BB-induced normalization of dermal PIF after C48/80, it did not affect αV β3 -dependent maintenance of a homeostatic dermal PIF . These data imply that dynamic modification of the ECM structure is needed during acute patho-physiological modulations of PIF but not for long-term maintenance of a homeostatic PIF . Our data thus show that collagen-binding β1 -integrins, integrin αV β3 and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis.
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