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* Division of Human Immunology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Adelaide,
South Australia, 5000 Australia; Tumor necrosis factor- Vascular Biology Laboratory, Baker Medical Research Institute, Prahran Victoria 3181; and § Director of Lung Research, Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania
Medical Center, Philadelphia, Pennsylvania 19104-4283
, interleukin-1, and
endotoxin stimulate the expression of vascular endothelial cell (EC) adhesion molecules. Here we describe
a novel pathway of adhesion molecule induction that is
independent of exogenous factors, but which is dependent on integrin signaling and cell-cell interactions. Cells plated onto gelatin, fibronectin, collagen or fibrinogen, or anti-integrin antibodies, expressed increased
amounts of E-selectin, vascular cell adhesion molecule-1,
and intercellular adhesion molecule-1. In contrast, ECs
failed to express E-selectin when plated on poly-L-lysine
or when plated on fibrinogen in the presence of attachment-inhibiting, cyclic Arg-Gly-Asp peptides. The duration and magnitude of adhesion molecule expression
was dependent on EC density. Induction of E-selectin
on ECs plated at confluent density was transient and returned to basal levels by 15 h after plating when only 7 ± 2% (n = 5) of cells were positive. In contrast, cells
plated at low density displayed a 17-fold greater expression of E-selectin than did high density ECs with 57 ± 4%
(n = 5) positive for E-selectin expression 15 h after
plating, and significant expression still evident 72 h after plating. The confluency-dependent inhibition of expression of E-selectin was at least partly mediated through the cell junctional protein, platelet/endothelial
cell adhesion molecule-1 (PECAM-1). Antibodies
against PECAM-1, but not against VE-cadherin, increased E-selectin expression on confluent ECs. Co-
culture of subconfluent ECs with PECAM-1- coated
beads or with L cells transfected with full-length PECAM-1 or with a cytoplasmic truncation PECAM-1
mutant, inhibited E-selectin expression. In contrast, untransfected L cells or L cells transfected with an adhesion-defective domain 2 deletion PECAM-1 mutant
failed to regulate E-selectin expression. In an in vitro
model of wounding the wound front displayed an increase in the number of E-selectin-expressing cells, and
also an increase in the intensity of expression of E-selectin positive cells compared to the nonwounded monolayer. Thus we propose that the EC junction, and in
particular, the junctional molecule PECAM-1, is a powerful regulator of endothelial adhesiveness.
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