Endothelial nitric oxide synthase mediates arteriolar vasodilatation after traumatic brain injury in mice

J Neurotrauma. 2015 May 15;32(10):731-8. doi: 10.1089/neu.2014.3650. Epub 2015 Feb 25.


Brain edema and increased cerebral blood volume (CBV) contribute to intracranial hypertension and hence to unfavorable outcome after traumatic brain injury (TBI). The increased post-traumatic CBV may be caused in part by arterial vasodilatation. The aim of the current study was to uncover the largely unknown mechanisms of post-traumatic arteriolar vasodilatation. The diameter of pial arterioles and venules was monitored by intravital fluorescence microscopy before (baseline) and for 30 min after controlled cortical impact in C57BL/6 and endothelial nitric oxide synthase (eNOS)-/- mice (n=5-6/group) and in C57BL/6 mice (n=6/group) receiving vehicle (phosphate-buffered saline [PBS]) or 4-amino-tetrahydro-L-biopterine (VAS203), a NOS inhibitor previously shown to reduce post-traumatic intracranial hypertension. Temperature, end-tidal partial pressure of carbon dioxide (pCO₂), and mean arterial blood pressure were kept within the physiological range throughout the experiments. Arteriolar diameters were stable during baseline monitoring but increased significantly in C57BL/6 mice after controlled cortical impact (136±7% of baseline; p<0.001 vs. baseline). This response was reduced by 78% in eNOS-/- mice (108±3% of baseline; p<0.005 vs. wild-type). Application of VAS203, a NOS inhibitor, or PBS did not affect vessels diameter before TBI. After trauma, however, administration of VAS203 reduced arteriolar diameter to 92±2% of baseline (p<0.05). The diameter of pial veins was not affected. Our results suggest that arteriolar vasodilatation after TBI is largely mediated by excess production of endothelial nitric oxide. Accordingly, our data may explain the beneficial effects of the NOS inhibitor VAS203 in the early phase after TBI and suggest that inhibition of excess endothelial nitric oxide production may represent a novel therapeutic strategy following TBI.

Keywords: brain trauma; eNOS; intracranial hypertension; mice; vessel diameter.

MeSH terms

  • Animals
  • Arterioles / drug effects
  • Arterioles / physiopathology*
  • Biopterins / analogs & derivatives
  • Biopterins / pharmacology
  • Brain Injuries / drug therapy
  • Brain Injuries / metabolism*
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism*
  • Pia Mater / blood supply
  • Vasodilation / drug effects
  • Vasodilation / physiology*


  • 4-amino-tetrahydrobiopterin
  • Biopterins
  • Nitric Oxide Synthase