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Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signaling

Departments of ¹Biomedical Engineering and ²Pharmacology and Physiology, University of Rochester, Rochester, New York

Submitted 16 April 2008 ; accepted in final form 8 July 2008

Two key characteristics of the inflammatory response are the recruitment of leukocytes to inflamed tissue as well as changes in vessel permeability. We explored the relationship between these two processes using intravital confocal microscopy in cremasters of anesthetized (65 mg/kg Nembutal ip) mice. We provide direct evidence that intercellular adhesion molecule-1 (ICAM-1) links leukocyte-endothelial cell interactions and changes in solute permeability (P_s). Importantly, we show that arterioles, not just venules, respond to proinflammatory stimuli, thus contributing to microvascular exchange. We identified two independent, ICAM-1-mediated pathways regulating P_s. Under control conditions in wild-type (WT) mice, there is a constitutive PKC-dependent pathway (P_s = 1.0 ± 0.10 and 2.2 ± 0.46 x 10^–6 cm/s in arterioles and venules, respectively), which was significantly reduced in ICAM-1 knockout (KO) mice (P_s = 0.54 ± 0.07 and 0.77 ± 0.11 x 10^–6 cm/s). The PKC inhibitor bisindolylmaleimid l (1 µmol/l in 0.01% DMSO) decreased P_s in WT mice to levels similar to those in ICAM-1 KO mice. Likewise, a PKC activator (phorbol-12-myristate-acetate; 1 µmol/l in 0.01% DMSO) successfully restored P_s in ICAM-1 KO vessels to be not different from that of the WT controls. On the other hand, during TNF--induced inflammation, P_s in WT mice was significantly increased (2-fold in venules and 2.5-fold in arterioles) in a Src-dependent and PKC-independent manner. The blockade of Src (PP2; 2 µmol/l in 0.01% DMSO) but not PKC significantly reduced the TNF--dependent increase in P_s. We conclude that ICAM-1 plays an essential role in the regulation of P_s in microvessels and that there are two separate (constitutive and inducible) signaling pathways that regulate permeability under normal and inflamed conditions.

adhesion molecules; microvascular exchange

This article has been cited by other articles:

				P. G. Frank and M. P. Lisanti ICAM-1: role in inflammation and in the regulation of vascular permeability Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H926 - H927. [Full Text] [PDF]