Epac1/Rap1 and Rnd3 signaling pathways inhibit hemorrhagic shock‐induced venular hyperpermeability

Abstract

Hemorrhagic shock (HS) causes significant microvascular leakage in the gut, which complicates resuscitation in shock patients. Our goal is to target signaling pathways that will improve microvascular barrier integrity following HS. We tested the hypothesis that activation of the Epac1/Rap1 pathway, or introducing excess Rnd3 protein to inhibit Rho/ROCK signaling, can reduce HS‐induced hyperpermeability in mesenteric venules. We utilized a model of fixed‐pressure HS in conscious, unrestrained rats. Rats were then anesthetized and the intestinal mesentery was excised to isolate venules for study. The permeability coefficient for FITC‐albumin (Ps) was determined in isolated, perfused, mesenteric venules (70–120 μm) from HS and control rats. The selective Epac1 activator 8‐pCPT‐2′‐O‐Me‐cAMP (8CPT), cell‐permeable (CP)‐Rnd3 protein, or no treatment was then applied to the venules from HS rats. The results show that venules from the HS rats had 5‐fold higher Ps than control. 8‐CPT and CP‐Rnd3 both caused a gradual decrease in Ps in HS venules, that was significantly different from untreated HS venules by the 30 min. time point. Our data suggest that Epac1 and Rnd3 both promote microvascular barrier integrity. In addition, 8CPT and CP‐Rnd3 can be used to reduce HS‐induced venular hyperpermeability. Supported by NIH P20RR018766 and a grant from the American Heart Association.