Integrin α(V)β(3) can substitute for collagen‐binding β(1)‐integrins in vivo to maintain a homeostatic interstitial fluid pressure

NEW FINDINGS: What is the central question of this study? Collagen‐binding β(1)‐integrins function physiologically in cellular control of dermal interstitial fluid pressure (P (IF)) in vivo and thereby participate in control of extravascular fluid volume. During anaphylaxis, simulated by injection of compound 48/80, integrin α(V)β(3) takes over this physiological function. Here we addressed the question whether integrin α(V)β(3) can replace collagen‐binding β(1)‐integrin to maintain a long‐term homeostatic P (IF). What is the main finding and its importance? Mice lacking the collagen‐binding integrin α(11)β(1) show a complex dermal phenotype with regard to the interstitial physiology apparent in the control of P (IF). Notably dermal P (IF) is not lowered with compound 48/80 in these animals. Our present data imply that integrin α(V)β(3) is the likely candidate that has taken over the role of collagen‐binding β(1)‐integrins for maintaining a steady‐state homeostatic P (IF). A better understanding of molecular processes involved in control of P (IF) 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 (P (IF)) in vivo. A central role for collagen‐binding β(1)‐integrins in both processes has been established. Furthermore, integrin α(V)β(3) takes over the role of collagen‐binding β(1)‐integrins in mediating contraction after perturbations of collagen‐binding β(1)‐integrins in vitro. Integrin α(V)β(3) is also instrumental for normalization of dermal P (IF) that has been lowered due to mast cell degranulation with compound 48/80 (C48/80) in vivo. Here we demonstrate a role of integrin α(V)β(3) in maintaining a long term homeostatic dermal P (IF) in mice lacking the collagen‐binding integrin α(11)β(1) (α11(−/−) mice). Measurements of P (IF) were performed after circulatory arrest. Furthermore, cell‐mediated integrin α(V)β(3)‐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 α(V)β(3)‐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 α(V)β(3)‐directed and platelet‐derived growth factor BB‐induced normalization of dermal P (IF) after C48/80, it did not affect α(V)β(3)‐dependent maintenance of a homeostatic dermal P (IF). These data imply that dynamic modification of the ECM structure is needed during acute patho‐physiological modulations of P (IF) but not for long‐term maintenance of a homeostatic P (IF). Our data thus show that collagen‐binding β(1)‐integrins, integrin α(V)β(3) and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis.