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Endothelial dependence of matrix metalloproteinase-mediated vascular hyporeactivity caused by lipopolysaccharide

Jonathan Cena1, Manoj M Lalu, Cory Rosenfelt

  • 1Department of Pharmacology, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada.

European Journal of Pharmacology
|February 5, 2008
PubMed

Insights

Matrix metalloproteinases (MMP) contribute to septic shock-induced vascular hyporeactivity. The vascular endothelium plays a key role in this MMP-mediated dysfunction, which can be blocked by MMP inhibitors.

Area of Science:

  • Vascular Biology
  • Sepsis Pathophysiology
  • Matrix Metalloproteinases

Background:

  • Septic shock is a major cause of intensive care unit mortality.
  • Matrix metalloproteinases (MMPs) are implicated in sepsis pathogenesis, contributing to vascular hyporeactivity.
  • The precise mechanism of MMP-mediated vascular hyporeactivity remains unclear.

Purpose of the Study:

  • To investigate the role of the vascular endothelium in MMP-mediated responses to lipopolysaccharide (LPS).
  • To determine the involvement of nitric oxide (NO) synthase in LPS-induced vascular hyporeactivity.
  • To assess the efficacy of MMP inhibitors in preventing LPS-induced vascular dysfunction.

Main Methods:

  • Isolated rat aortic rings (endothelium-intact and -denuded) were exposed to LPS.
  • Vascular tone was measured in response to phenylephrine.
  • Experiments involved nitric oxide synthase inhibition (l-NAME) and MMP inhibition (doxycycline, GM6001).
  • MMP activity (specifically MMP-2) was quantified.

Main Results:

  • LPS reduced phenylephrine-induced tone in both endothelium-intact and -denuded rings, with a greater effect in intact rings.
  • l-NAME abolished LPS-induced hyporeactivity in both groups.
  • MMP inhibitors prevented LPS-induced tone loss in endothelium-intact rings but not in denuded rings.
  • LPS increased MMP-2 activity in endothelium-intact aortae, an effect attenuated by doxycycline; no change was observed in denuded aortae.

Conclusions:

  • The vascular endothelium contributes significantly to MMP-mediated vascular dysfunction induced by LPS.
  • The protective effect of MMP inhibition against LPS-induced hyporeactivity is endothelium-dependent.
  • This study reveals a novel mechanism involving the endothelium in MMP-mediated vascular dysfunction during sepsis.

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