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Activation of the Epac1/Rap1 pathway attenuates fMLP‐induced microvascular hyperpermeability in vivo
Author(s) -
Kurtz Kristine M,
Belaidi Marisa B,
Breslin Jerome W
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1022.9
Subject(s) - intravital microscopy , rap1 , microcirculation , small gtpase , vascular permeability , chemistry , inflammation , medicine , endocrinology , signal transduction , biochemistry
Elevation of intracellular cAMP levels has been shown to enhance microvascular barrier integrity. Recent studies have shown a novel mechanism of cAMP‐mediated endothelial barrier regulation via the cAMP‐dependent nucleotide exchange factor Epac1 and its downstream effector Rap1 GTPase. We tested the hypothesis that the Epac/Rap1 activator 8‐pCPT‐2′‐O‐Me‐cAMP (8CPT) will inhibit inflammation‐induced hyperpermeability, using 10 μM fMLP as an inflammatory stimulus. Male Sprague Dawley rats (275–325 g) rats were anesthetized, catheterized (artery and vein), and a midline laparotomy was performed. The mesentery was exteriorized for intravital fluorescence microscopic viewing of the mesenteric microcirculation. Rats received an i.v. bolus (100 mg/kg) followed by continuous infusion (0.15 mg/kg/min) of FITC‐albumin. The integrated optical intensity (IOI) of multiple extravascular regions in the mesentery, and arteriolar diameter were measured every 5 min. for a 20‐min. baseline and 1 h with fMLP. Our results show that fMLP caused a marked increase in IOI, that was significantly attenuated by pretreatment with 200 μM 8CPT. Treatment with fMLP also caused constriction of arterioles that was not changed by 8CPT pretreatment. Our results suggest that Epac1/Rap1 activation can attenuate acute inflammation‐induced microvascular leakage. Supported by the American Heart Association and NIH P20RR018766.