Insulin-like Growth Factor (IGF)-1 treatment stabilizes the microvascular cytoskeleton under ischemic conditions

Abstract

Our previous studies showed that Insulin-like Growth Factor (IGF)-1 reduced blood brain barrier pemeability and decreased infarct volume caused by middle cerebral artery occlusion (MCAo) in middle aged female rats. Similarly, cultures of primary brain microvessel endothelial cells from middle-aged female rats and exposed to stroke-like conditions (oxygen glucose deprivation; OGD) confirmed that IGF-1 reduced dye transfer across this cell monolayer. Surprisingly, IGF-1 did not attenuate endothelial cell death caused by OGD. To reconcile these findings, the present study tested the hypothesis that, at the earliest phase of ischemia, IGF-1 promotes barrier function by increasing anchorage and stabilizing cell geometry of surviving endothelial cells. Cultures of human brain microvessel endothelial cells were subject to oxygen-glucose deprivation (OGD) in the presence of IGF-1, IGF-1+JB-1 (IGFR inhibitor) or vehicle. OGD disrupted the cell monolayer and reduced cell-cell interactions, which was preserved in IGF-1-treated cultures and reversed by concurrent treatment with JB-1. IGF-1-mediated preservation of the endothelial monolayer was reversed with LY294002 treatment, but not by Rapamycin, indicating that IGF-1s actions on cell-cell contacts are likely mediated via the PI3K pathway. In vivo, microvessel morphology was evaluated in middle-aged female rats that were subjected to ischemia by MCAo, and treated ICV with IGF-I, IGF-1 + JB-1, or artificial CSF (aCSF; vehicle) after reperfusion. Compared to vehicle controls, IGF-1 treated animals displayed larger microvessel diameters in the peri-infarct area and increased staining density for vinculin, an anchorage protein. Both these measures were reversed by concurrent IGF-1+JB-1 treatment. Moreover these effects were restricted to 24h after ischemia-reperfusion and no treatment effects were seen at 5d post stroke. Collectively, these data suggest that in the earliest hours during ischemia, IGF-I promotes receptor-mediated anchorage of endothelial cells, and its actions may be accurately characterized as vasculoprotective.

Sexually dimorphic microglia and ischemic stroke

“…It is also apparent that IGF‐1/IGF‐binding protein 3 declines faster in males than females, which may also contribute to the differences seen in microglial‐mediated IGF‐1 signaling between aged males and females. This notion is also supported by a study, in which IGF‐1 improves stroke recovery aged female rats …”

“…Furthermore, certain experimental anti‐inflammatory treatments, such as minocycline, which inhibits the PARP‐1 pathway, are more effective in males in both preclinical and clinical studies . Lastly, IGF‐1, which can be microglial‐regulated, has shown promise as treatment in estrogen‐deficient middle‐aged females by reducing stroke‐induced damage and motor impairment in the aging brain . It is possible that the sexual dimorphism in microglial function may contribute to the differences that are seen in treatment effectiveness between the two sexes.…”

“…This notion is also supported by a study, in which IGF-1 improves stroke recovery aged female rats. 34 Aside from neurogenesis, microglia support cell genesis and regulate stem cell pools. For example, microglia can promote astrogliogenesis from stem cells in culture through the release of the anti-inflammatory cytokine IL-6.…”

“…109,110 Lastly, IGF-1, which can be microglial-regulated, has shown promise as treatment in estrogen-deficient middle-aged females by reducing stroke-induced damage and motor impairment in the aging brain. 34 It is possible that the sexual dimorphism in microglial function may contribute to the differences that are seen in treatment effectiveness between the two sexes. Further research targeting microglial-regulated inflammatory and sex hormone responses are necessary to further the development of pharmacological treatment poststroke.…”

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…While endothelial tight junctions are formed by proteins such as claudin, occludin and zonula occluden (ZO), the basal lamina forms the basement membrane of ECM and includes laminin, collagen, and fibronectin [177,178]. Astrocyte-derived factors including angiopoietin-1 (ANG-1) [179][180][181], sonic hedgehog (SHH) [182][183][184][185], glial-derived neurotrophic factor (GDNF) [186][187][188], retinoic acid (RA) [189][190][191], and IGF-1 [192,193] have been demonstrated to promote recovery of the BBB by protecting endothelial cells and/or enhancing tight junction reassembly, via signaling mediated by their receptors, tie-2, patched-1, GDNF receptor alpha-1 and alpha-2, nuclear RA receptor, and IGF-1 receptor, respectively [78,79] (Table. 1).…”