CAMP agonists stabilize the microvascular barrier in ischemiareperfusion

Abstract

Compartment syndrome, caused by excessive leakage of fluid and protein from the vascular compartment into skeletal muscle, is a severe complication in ischemia‐reperfusion (I‐R) injury. While the causes of vascular hyperpermeability are well understood, the mechanisms of hyperpermeability deactivation are largely unknown. Because cAMP is linked to restoration of endothelial barrier properties, we tested the hypothesis that glucagon‐like peptide 1 (GLP‐1, a cAMP agonist) stabilizes the microvascular barrier. We used cross‐clamping of the hamster cremaster artery as an in vivo I‐R model, and determined permeability to FITC‐dextran‐150 measuring integrated optical intensity. We used confluent monolayers of human microvascular endothelial cells (HMVEC) to assess molecular changes associated with hypoxia‐reoxygenation (in vitro I‐R model). Topical application of GLP‐1 reduced the I‐R induced hyperpermeability in the hamster cremaster relative to control. Reoxygenation of HMVEC increased the levels of Rap‐1‐GTP and Rac‐1‐GTP. Interestingly, changes in Rac‐1‐GTP preceded changes in Rap‐1‐GTP indicating that cAMP may activate several molecular pathways to restore endothelial barrier properties following I‐R. We propose that cAMP increasing agonists, such as GLP‐1, will assist vascular surgeons in preventing compartment syndrome. (Supported by NIH grants 5RO1 HL070634 & 5RO1 HL088479).