title: Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1.
abstract: Activated neutrophils interacting with the vessel wall can alter vascular permeability to macromolecules such as albumin via release of various secretion products that induce changes in the endothelial monolayer. In the current work we used cremaster microvessels of anesthetized mice to show that, in addition to this paracrine mechanism, leukocyte ligation of endothelial ICAM-1 directly activates endothelial cell (EC) signaling, altering EC permeability to albumin [i.e., solute permeability (P(s))]. We show that antibody cross-linking of surface ICAM-1 in intact microvessels is sufficient to increase P(s) even in the absence of interacting leukocytes. Unstimulated arterioles do not support leukocyte-EC interactions, but despite this, antibody ligation of ICAM-1 in these vessels induced a twofold increase in P(s). Similarly, in venules that were depleted of interacting neutrophils, P(s) was decreased to below resting levels and was restored by ligation of ICAM-1. Use of function-blocking antibodies to separately block leukocyte rolling or adhesion under unstimulated or TNF-α-activated conditions established that both rolling and adhered leukocytes contribute to P(s) regulation in situ. Both rolling and adhesion activated EC-dependent signaling mechanisms that increased P(s). ICAM-1 ligation with primary antibody alone or primary followed by secondary antibodies showed that regulation of P(s) is directly dependent on the degree of ICAM-1 clustering. Under physiological versus inflamed conditions, respectively, this ICAM-1 clustering-dependent regulation of P(s) switches from PKC dependent and Src independent to Src dependent and PKC independent. This study thus identifies a new mechanism by which antiadhesion treatment may constitute a potential therapy for tissue edema.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, New York 14642, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Sumagin
authors.forename: Julia M
authors.initials: JM
authors.lastname: Kuebel
authors.forename: Ingrid H
authors.initials: IH
authors.lastname: Sarelius
mesh_terms: D000418:Albumins / Q000502:physiology*; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D002448:Cell Adhesion; D005786:Gene Expression Regulation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D036904:Leukocyte Rolling / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000418:Albumins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1