Role of connexins in microvascular dysfunction during inflammation

Can J Physiol Pharmacol. 2011 Jan;89(1):1-12. doi: 10.1139/y10-099.

Abstract

In arterioles, a locally initiated diameter change can propagate rapidly along the vessel length (arteriolar conducted response), thus contributing to arteriolar hemodynamic resistance. The response is underpinned by electrical coupling along the arteriolar endothelial layer. Connexins (Cx; constituents of gap junctions) are required for this coupling. This review addresses the effect of acute systemic inflammation (sepsis) on arteriolar conduction and interendothelial electrical coupling. Lipopolysaccharide (LPS; an initiating factor in sepsis) and polymicrobial sepsis (24 h model) attenuate conducted vasoconstriction in mice. In cultured microvascular endothelial cells harvested from rat and mouse skeletal muscle, LPS reduces both conducted hyperpolarization-depolarization along capillary-like structures and electrical coupling along confluent cell monolayers. LPS also tyrosine-phosphorylates Cx43 and serine-dephosphorylates Cx40. Since LPS-reduced coupling is Cx40- but not Cx43-dependent, only Cx40 dephosphorylation may be consequential. Nitric oxide (NO) overproduction is critical in advanced sepsis, since the removal of this overproduction prevents the attenuated conduction. Consistently, (i) exogenous NO in cultured cells reduces coupling in a Cx37-dependent manner, and (ii) the septic microvasculature in vivo shows no Cx40 phenotype. A complex role emerges for endothelial connexins in sepsis. Initially, LPS may reduce interendothelial coupling and arteriolar conduction by targeting Cx40, whereas NO overproduction in advanced sepsis reduces coupling and conduction by targeting Cx37 instead.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arterioles / chemistry
  • Arterioles / pathology
  • Arterioles / physiopathology
  • Arteritis / metabolism
  • Arteritis / pathology*
  • Arteritis / physiopathology*
  • Connexins / physiology*
  • Endothelium, Vascular / chemistry
  • Endothelium, Vascular / pathology*
  • Endothelium, Vascular / physiopathology*
  • Humans
  • Microvessels / chemistry
  • Microvessels / pathology*
  • Microvessels / physiopathology*
  • Sepsis / metabolism
  • Sepsis / pathology
  • Sepsis / physiopathology
  • Vasoconstriction / physiology

Substances

  • Connexins