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Microparticles generated during chronic cerebral ischemia increase the permeability of microvascular endothelial

Hamidreza Edrissi1, Sarah C Schock2, Antoine M Hakim2

  • 1University of Ottawa, Neuroscience Graduate Program, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.

Brain Research
|January 3, 2016
PubMed

Insights

Microparticles (MPs) from chronic cerebral ischemia increase blood-brain barrier permeability by activating tumor necrosis factor-alpha (TNF-α) and caspase 3 pathways, leading to apoptosis. Inhibitors block this effect, revealing MP signaling mechanisms.

Area of Science:

  • Neuroscience
  • Cardiovascular Research
  • Cell Biology

Background:

  • Circulating microparticles (MPs) are elevated in cardiovascular disorders and implicated in inflammatory intercellular signaling.
  • Their specific role in blood-brain barrier (BBB) dysfunction requires further elucidation.

Purpose of the Study:

  • To investigate the signaling properties of MPs from rats with chronic cerebral ischemia using an in vitro blood-brain barrier model.
  • To determine the molecular mechanisms by which these MPs affect endothelial barrier integrity.

Main Methods:

  • Isolation of MPs from rat plasma following chronic cerebral ischemia or sham operation.
  • Assessment of endothelial barrier function using transendothelial electrical resistance (TEER) assays.
  • Inhibition studies using specific inhibitors for caspase 3, TNF-α, TACE (ADAM 17), and Rho kinase (ROCK).
  • Detection of ROCK and RhoA within MPs via Western blot.

Main Results:

  • MPs from ischemic rats significantly reduced TEER in vitro, unlike MPs from control rats.
  • Inhibitors of caspase 3, TNF-α, TACE, and ROCK attenuated the MP-induced reduction in TEER.
  • MPs contained pro-TNF-α, active TACE, and active ROCK, with ROCK and RhoA detected by Western blot.
  • VEGF stimulated transcellular transport, whereas MPs did not.

Conclusions:

  • MPs generated during cerebral ischemia increase endothelial barrier permeability.
  • This increase is primarily mediated by MP-induced apoptosis via activation of the TNF-α pathway, caspase 3, and Rho kinases.
  • MPs deliver active signaling molecules, including TACE and ROCK, to endothelial cells, contributing to BBB dysfunction.
Keywords:
ApoptosisCerebral ischemiaEndothelial barrier permeabilityMicroparticlesRho kinaseTNF-α

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