Increased ICAM-1 Expression Causes Endothelial Cell Leakiness, Cytoskeletal Reorganization and Junctional Alterations

Abstract

Tumor necrosis factor (TNF)-induced ICAM-1 in endothelial cells (EC) promotes leukocyte adhesion. Here we report that ICAM-1 also effects EC barrier function. Control- or E-selectin-transduced human dermal microvascular EC (HDMEC) form a barrier to flux of proteins and to passage of current (measured as transendothelial electrical resistance or TEER). HDMEC transduced with ICAM-1 at levels comparable to that induced by TNF show reduced TEER, but do so without overtly changing their cell junctions, cell shape, or cytoskeleton organization. Higher levels of ICAM-1 further reduce TEER, increase F/G-actin ratios, rearrange the actin cytoskeleton to cause cell elongation, and alter junctional zona occludens 1 and vascular endothelial-cadherin staining. Transducing with ICAM-1 lacking an intracellular region also reduces TEER. TNF-induced changes in TEER and shape follow a similar time course as ICAM-1 induction; however, the fall in TEER occurs at lower TNF concentrations. Inhibiting NF-kappaB activation blocks ICAM-1 induction; TEER reduction, and shape change. Specific small-interfering RNA knockdown of ICAM-1 partially inhibits TNF-induced shape change. We conclude that moderately elevated ICAM-1 expression reduces EC barrier function and that expressing higher levels of ICAM-1 affects cell junctions and the cytoskeleton. Induction of ICAM-1 may contribute to but does not fully account for TNF-induced vascular leak and EC shape change.

ICAM-1/LFA-1 interaction contributes to the induction of endothelial cell-cell separation: implication for enhanced leukocyte diapedesis

“…In addition, this cellular event is coupled with the increased adhesion of circulating leukocytes to the EC luminal surface (Clark et al, 2007). In the current study, the finding that cells which express high levels of ICAM-1 (IC1 hi-C ) reveal an increased EC contraction and junctional alteration (Figure 2A and B) also corroborates the pervious reports by others (Muller, 2001(Muller, , 2003.…”

“…Several studies have demonstrated junctional alteration of ECs and inter-endothelial gap formation during diapedesis (McDonald et al, 1999;Johnson-Leger et al, 2000;Clark et al, 2007;Ley et al, 2007). However, we were particularly interested in whether contracted endothelium can be relaxed to recover its barrier function, because no report, to our knowledge, has directly addressed this question yet.…”

“…It has been known that increased ICAM-1 expression causes EC leakiness, cytoskeletal reorganization and junctional alterations (Clark et al, 2007). In addition, this cellular event is coupled with the increased adhesion of circulating leukocytes to the EC luminal surface (Clark et al, 2007).…”

Intercellular adhesion molecule-1 is a regulator of blood–testis barrier function

“…sICAM-1, which is derived from the proteolytic cleavage of membranebound ICAM-1, has been suggested in some biological contexts to have a role that is opposite to that of ICAM-1 (Clark et al, 2007). Interestingly, Sertoli cell barrier/BTB function was found to be compromised in vitro and in vivo following sICAM-1 overexpression, illustrating that sICAM-1 can negatively regulate Fig.…”

Cisplatin up‐regulates ICAM‐1 expression in endothelial cell via a NF‐κB dependent pathway

“…(46) Secondly, an increased incidence of thrombosi, (15) following cisplatin-based combination chemotherapy, including combinatorial therapies with antiangiogenic agents, (16) may at least in part be mediated by enhanced leukocyte/ endothelium interactions, since endothelial cells can be injured by the activation and the adhesion of neutrophil, the injury of the endothelial cells causes the exposure of subendothelial tissues, and then induces the platelet adhesion on these surfaces for the initial event of platelet aggregates. Thirdly, increased ICAM-1 expression can cause endothelial cell leakiness (47) which is also presented in our hamster's cheek pouch carcinoma tumor model. This may facilitate the high interstitial fluid pressure inside tumors and thus impede chemotherapeutic drug delivery.…”