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

Ronen Sumagin, Elena Lomakina, Ingrid H. Sarelius

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

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 (Ps). 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 Ps. Under control conditions in wild-type (WT) mice, there is a constitutive PKC-dependent pathway (Ps = 1.0 ± 0.10 and 2.2 ± 0.46 × 10-6 cm/s in arterioles and venules, respectively), which was significantly reduced in ICAM-1 knockout (KO) mice (Ps = 0.54 ± 0.07 and 0.77 ± 0.11 × 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 Ps in ICAM-1 KO vessels to be not different from that of the WT controls. On the other hand, during TNF-α-induced inflammation, Ps 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-α-dependent increase in Ps. We conclude that ICAM-1 plays an essential role in the regulation of Ps in microvessels and that there are two separate (constitutive and inducible) signaling pathways that regulate permeability under normal and inflamed conditions.

Original languageEnglish (US)
Pages (from-to)H969-H977
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number3
DOIs
StatePublished - Sep 2008

Keywords

  • Adhesion molecules
  • Microvascular exchange

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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