Insulin-Like Growth Factor (IGF)-I Modulates Endothelial Blood-Brain Barrier Function in Ischemic Middle-Aged Female Rats

Endocrinology. 2016 Jan;157(1):61-9. doi: 10.1210/en.2015-1840. Epub 2015 Nov 10.

Abstract

In comparison with young females, middle-aged female rats sustain greater cerebral infarction and worse functional recovery after stroke. These poorer stroke outcomes in middle-aged females are associated with an age-related reduction in IGF-I levels. Poststroke IGF-I treatment decreases infarct volume in older females and lowers the expression of cytokines in the ischemic hemisphere. IGF-I also reduces transfer of Evans blue dye to the brain, suggesting that this peptide may also promote blood-brain barrier function. To test the hypothesis that IGF-I may act at the blood-brain barrier in ischemic stroke, 2 approaches were used. In the first approach, middle-aged female rats were subjected to middle cerebral artery occlusion and treated with IGF-I after reperfusion. Mononuclear cells from the ischemic hemisphere were stained for CD4 or triple-labeled for CD4/CD25/FoxP3 and subjected to flow analyses. Both cohorts of cells were significantly reduced in IGF-I-treated animals compared with those in vehicle controls. Reduced trafficking of immune cells to the ischemic site suggests that blood-brain barrier integrity is better maintained in IGF-I-treated animals. The second approach directly tested the effect of IGF-I on barrier function of aging endothelial cells. Accordingly, brain microvascular endothelial cells from middle-aged female rats were cultured ex vivo and subjected to ischemic conditions (oxygen-glucose deprivation). IGF-I treatment significantly reduced the transfer of fluorescently labeled BSA across the endothelial monolayer as well as cellular internalization of fluorescein isothiocyanate-BSA compared with those in vehicle-treated cultures, Collectively, these data support the hypothesis that IGF-I improves blood-brain barrier function in middle-aged females.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / immunology
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / immunology
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Capillary Permeability / drug effects
  • Cell Hypoxia / drug effects
  • Cells, Cultured
  • Cerebrum / drug effects
  • Cerebrum / immunology
  • Cerebrum / metabolism
  • Cerebrum / pathology
  • Drug Implants
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Female
  • Humans
  • Hypoglycemia / etiology
  • Insulin-Like Growth Factor I / administration & dosage
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / therapeutic use*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Microvessels / drug effects
  • Microvessels / immunology
  • Microvessels / metabolism
  • Microvessels / pathology
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism
  • Rats, Sprague-Dawley
  • Receptor, IGF Type 1 / agonists*
  • Receptor, IGF Type 1 / metabolism
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Signal Transduction / drug effects*
  • Stroke / drug therapy
  • Stroke / immunology
  • Stroke / metabolism
  • Stroke / pathology

Substances

  • Drug Implants
  • IGF1 protein, human
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1