Integrin αVβ3 can substitute for collagen-binding β1-integrins in vivo to maintain a homeostatic interstitial fluid pressure

New Findings

• 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_Vβ₃ takes over this physiological function. Here we addressed the question whether integrin α_Vβ₃ 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 α₁₁β₁ 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 infer the integrin α_Vβ₃ to be 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 edema 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 β₁-integrins in both processes has been established. Furthermore, integrin α_Vβ₃ takes over the role of collagen-binding β₁-integrins in mediating contraction after perturbations of collagen-binding β₁-integrins in vitro. Integrin α_Vβ₃ 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_Vβ₃ in maintaining a long term homeostatic dermal P_IF in mice lacking the collagen-binding integrin  α₁₁β₁ (α11^−/- mice). Measurements of P_IF were performed after circulatory arrest. Furthermore, cell-mediated integrin α_Vβ₃-directed contraction of collagenous gels in vitro depends on free access of a collagen-site known to bind several ECM proteins that form substrates for α_Vβ₃-directed cell attachment, such as fibronectin and fibrin. A streptococcal collagen-binding protein, CNE, specifically binds to and block this site on the collagen triple helix. Here we show that whereas CNE perturbed α_Vβ₃-directed and PDGF-BB induced normalization of dermal P_IF after C48/80 it did not affect α_Vβ₃-dependent maintenance of a homeostatic dermal P_IF. These data imply that dynamic modifications of the ECM structure is needed during acute patho-physiologic 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_Vβ₃ and ECM-structure are potential targets for novel therapy aimed to modulate edema formation and hypovolemic shock during anaphylaxis.

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