Integrin α_V β₃ can substitute for collagen-binding β₁ -integrins in vivo to maintain a homeostatic interstitial fluid...

What is the central question of this study? Collagen-binding β₁ -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 β₃ takes over this physiological function. Here we addressed the question whether integrin α_V β₃ can replace collagen-binding β₁ -integrin to maintain a long-term homeostatic P_IF . 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 P_IF . Notably dermal P_IF is not lowered with compound 48/80 in these animals. Our present data imply that integrin α_V β₃ is the likely candidate that has taken over the role of collagen-binding β₁ -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.

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 β₁ -integrins in both processes has been established. Furthermore, integrin α_V β₃ takes over the role of collagen-binding β₁ -integrins in mediating contraction after perturbations of collagen-binding β₁ -integrins in vitro. Integrin α_V β₃ 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 β₃ in maintaining a long term homeostatic dermal P_IF in mice lacking the collagen-binding integrin  α₁₁ β₁ (α11^-/- mice). Measurements of P_IF were performed after circulatory arrest. Furthermore, cell-mediated integrin α_V 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 α_V 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 α_V β₃ -directed and platelet-derived growth factor BB-induced normalization of dermal P_IF after C48/80, it did not affect α_V β₃ -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 β₁ -integrins, integrin α_V β₃ and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis.