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Lipopolysaccharide reduces electrical coupling between microvascular endothelial cells of wild type but not connexin40 null mice in tyrosine‐, PKA‐ and ERK1/2‐dependent manner
Author(s) -
Bolon Michael Louis,
Kidder Gerald M,
Tyml Karel
Publication year - 2006
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.20.4.a275-b
Subject(s) - lipopolysaccharide , wild type , chemistry , endothelium , intracellular , coupling (piping) , endocrinology , microbiology and biotechnology , medicine , biology , biophysics , mutant , biochemistry , materials science , metallurgy , gene
Electrical coupling along the endothelium is central in the arteriolar conducted response and in control of vascular resistance. It has been shown that exposure of endothelium to lipopolysaccharide (LPS, an initiating factor in sepsis) reduces intercellular communication in vitro and in vivo . The molecular basis for this reduction is not known. We examined the effect of LPS on electrical coupling in monolayers of cultured microvascular endothelial cells (MMEC) derived from the mouse hindlimb skeletal muscle. To assess coupling, we measured the spread of electrical current injected into the monolayer and computed the intercellular resistance (inverse measure of coupling). LPS (10 μg/ml, 1 h) reduced coupling (i.e., increased resistance) in MMEC isolated from wild type, Cx37 null mutant and Cx43 G60S nonfunctional mutant mice, but not in MMEC derived from Cx40 null mutant mice. LPS also activated JNK1/2 and ERK1/2 MAP kinases. Pretreatment of WT monolayers with ERK1/2 inhibitor U0126 (20 μM, 1 h) prevented the LPS‐induced decrease in coupling, while inhibition of JNK1/2 with SP600125 (20 μM, 1 h) had no effect. Furthermore, inhibition of tyrosine kinases with PP‐2 (10 nM, 1 h), and activation of PKA by 8‐bromo‐cAMP (1 mM, 5 min) also prevented the reduction in coupling. We propose that LPS reduces inter‐endothelial electrical coupling via tyrosine‐, PKA‐ and ERK1/2‐dependent signaling that targets Cx40. We suggest this mechanism contributes to compromised arteriolar function following LPS exposure. (Supported by CIHR and HSFO).