Integrin αVβ3 can substitute for collagen‐binding β1‐integrins in vivo to maintain a homeostatic interstitial fluid pressure
Authors: Lidén Åsa , Karlsen Tine Veronika , Guss Bengt , Reed Rolf K. , Rubin Kristofer 
Published: March 2018

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 αVβ3 takes over this physiological function. Here we addressed the question whether integrin αVβ3 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 α11β1 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 αVβ3 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.

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 αVβ3 takes over the role of collagen‐binding β1‐integrins in mediating contraction after perturbations of collagen‐binding β1‐integrins in vitro. Integrin αVβ3 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 αVβ3 in maintaining a long term homeostatic dermal PIF in mice lacking the collagen‐binding integrin  α11β1 (α11−/− mice). Measurements of PIF were performed after circulatory arrest. Furthermore, cell‐mediated integrin αVβ3‐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 αVβ3‐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 αVβ3‐directed and platelet‐derived growth factor BB‐induced normalization of dermal PIF after C48/80, it did not affect αVβ3‐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 αVβ3 and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis.