PECAM-1 (CD31) regulates a hydrogen peroxide–activated nonselective cation channel in endothelial cells

Hydrogen peroxide (H(2)O(2)) released by neutrophils is an important mediator of endothelial cell (EC) injury and vascular inflammation via its effect on EC-free Ca(2+), [Ca(2+)](i). Although the underlying mechanisms are not well understood, platelet endothelial cell adhesion molecule (PECAM)-1/CD-31 is a critical modulator of neutrophil–EC transmigration. PECAM-1 is also known to regulate EC calcium signals and to undergo selective tyrosine phosphorylation. Here, we report that PECAM-1 molecules transduce EC responses to hydrogen peroxide. In human umbilical vein EC and REN cells (a PECAM-1–negative EC-like cell line) stably transfected with PECAM-1 (RHP), noncytolytic H(2)O(2) exposure (100–200 μM H(2)O(2)) activated a calcium-permeant, nonselective cation current, and a transient rise in [Ca(2+)](i) of similar time course. Neither response was observed in untransfected REN cells, and H(2)O(2)-evoked cation current was ablated in REN cells transfected with PECAM-1 constructs mutated in the cytoplasmic tyrosine–containing domain. The PECAM-dependent H(2)O(2) current was inhibited by dialysis of anti–PECAM-1 cytoplasmic domain antibodies, required Src family tyrosine kinase activity, was independent of inositol trisphosphate receptor activation, and required only an intact PECAM-1 cytoplasmic domain. PECAM-1–dependent H(2)O(2) currents and associated [Ca(2+)](i) transients may play a significant role in regulating neutrophil–endothelial interaction, as well as in oxidant-mediated endothelial response and injury.