P‐Rex1 is critical for vascular hyper‐permeability and edema in the lungs

Abstract

The primary objective of this study was to investigate a role for P‐Rex1 (PIP3 dependent Rac exchanger 1) a guanine nucleotide exchange factor for Rac, previously known for G protein‐coupled receptor signaling, in mediating TNF‐α‐induced vascular hyper‐permeability. Using gene deletion and knockdown approaches, we investigated the potential role of P‐Rex1 in TNF‐α‐induced lung vascular injury. P‐Rex1, previously found in neutrophils and neurons, is also expressed in endothelial cells. In cultured human lung microvascular endothelial cells (HLMVECs), small interference (si) RNA‐mediated knockdown of P‐Rex1 prevented TNF‐α‐induced intercellular gap formation, Rac activation and reactive oxygen species (ROS) production. TNF‐α stimulated P‐Rex1 membrane translocation and the resulting Rac activation in a PI3K dependent manner. P‐Rex1 knockout mice were also refractory to TNF‐α‐induced lung vascular hyper‐permeability and edema. Both, in vivo and in vitro, absence of P‐Rex1 resulted in significantly less ICAM‐1 induction and neutrophil transendothelial migration. These results demonstrate for the first time that P‐Rex1 is activated downstream of TNF‐α, which is not a GPCR. We conclude that P‐Rex1 is a novel mediator of endothelial barrier disruption and therefore could be a potential therapeutic target in the control of vascular permeability and neutrophil infiltration to inflammatory tissues.