Hypoxic preconditioning induces an AT2-R/VEGFR-2(Flk-1) interaction in the neonatal brain microvasculature for neuroprotection

Neuroscience. 2012 Aug 2;216:1-9. doi: 10.1016/j.neuroscience.2012.04.070. Epub 2012 May 6.


The angiotensin II receptor subtype 2 (AT2-R) has been proposed to mediate protective vascular actions after brain injury. In this study we investigated the participation of this peptide in the tolerance to cellular damage induced by preconditioning in a rat model of neonatal hypoxia-ischemia (HI). We found that injured animals present a decreased number of microvessels in the ipsilateral (IPLT) side of the brain while in the contralateral (CNLT) side the microvessel number is increased. On the contrary, in the preconditioned animals the microvessels maintained the same number as in control animals. However these vessels show a remarkable increase of the fluorescent signal when they are labeled with antiFlk-1 (VEGFR2), while the Flt-1 (VEGFR1) signal faded in both the injured and the preconditioned animals. The pharmacological blockade of the AT2-R by the drug PD123319 (1.69 mM in the lateral ventricle) diminished the resilience of the microvasculature to HI injury provided by preconditioning and also the Flk-1 increase that occurred in these animals. In conclusion these results suggest an interaction of the AT2-R with VEGFR2 in the neonatal brain microvasculature that produces protective effects which are associated with injury tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 2 Receptor Blockers / pharmacology
  • Animals
  • Animals, Newborn
  • Brain / blood supply
  • Brain / drug effects
  • Brain / growth & development
  • Brain / pathology
  • Fetal Hypoxia / metabolism
  • Fetal Hypoxia / physiopathology
  • Hypoxia-Ischemia, Brain / metabolism*
  • Hypoxia-Ischemia, Brain / physiopathology
  • Hypoxia-Ischemia, Brain / prevention & control
  • Imidazoles / pharmacology
  • Ischemic Preconditioning
  • Microvessels / drug effects
  • Microvessels / physiopathology*
  • Neuroprotective Agents / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Angiotensin, Type 2 / metabolism*
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Angiotensin II Type 2 Receptor Blockers
  • Imidazoles
  • Neuroprotective Agents
  • Pyridines
  • Receptor, Angiotensin, Type 2
  • PD 123319
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2