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Lipopolysaccharide modulation of phenylephrine-dependent vasoconstriction is dependent on intercellular communication


The role of gap junctional intercellular communication between endothelial cells and vascular smooth muscle cells during the inflammatory process is not well understood. In particular, the role of vascular connexins (gap junction proteins) in regulating blood flow in response to inflammatory agents such as lipopolysaccharide (LPS) has not been fully investigated. We have previously demonstrated that the endothelium modulates the LPS response in microvessels via an unknown mechanism. Our hypothesis is that LPS modulation of agonist-mediated vasoconstriction is dependent on the presence of connexin 40 (Cx40) within the microvessel wall.


Wildtype (WT) and Cx40 knockout (Cx40-/-) animals were treated with LPS (15 mg/kg intraperitoneally) or saline for 18 hours. Small mesenteric resistance arteries (190–220 μm) were isolated, mounted on glass cannulae, pressurized at 60 mmHg with no lumen flow and placed on the stage of an inverted microscope. The external arteriolar diameter was measured and concentration–response curves to phenylephrine (PE, 10-9 to 10-4 M) and to extracellular Ca2+ (0–2 mM) under depolarizing conditions (120 mM K+) were conducted. The half-maximal effect (EC50) was determined for each dose–response curve.


LPS treatment resulted in hyporesponsiveness to PE in WT mice (EC50 2.07 ± 0.45 mM vs 0.56 ± 0.15 mM in shams) but resulted in hyperresponsiveness in Cx40-/- mice (EC50 0.27 ± 0.03 mM vs 3.15 ± 1.50 mM in shams). However, LPS treatment resulted in hyporesponsiveness to Ca2+ in both WT mice (EC50 0.39 ± 0.03 mM vs 0.23 ± 0.01 mM in shams) and Cx40-/- mice (EC50 0.75 ± 0.24 mM vs 0.23 ± 0.03 mM in shams).


We conclude that agonist-mediated but not Ca2+-mediated vasoconstriction is modulated by the presence of Cx40. This suggests an important role for intercellular communication during LPS-mediated inflammation.

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Ouellette, Y. Lipopolysaccharide modulation of phenylephrine-dependent vasoconstriction is dependent on intercellular communication. Crit Care 12 (Suppl 2), P393 (2008).

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