Astrocyte responses to injury: VEGF simultaneously modulates cell death and proliferation

Abstract

Hypoxia is linked to changes in blood-brain barrier (BBB) permeability, and loss of BBB integrity is characteristic of many pathological brain diseases including stroke. In particular, astrocytes play a central role in brain homeostasis and BBB function. We investigated how hypoxia affects astrocyte survival and assessed whether VEGF release through hypoxia-inducible factor-1alpha (HIF-1alpha) induction plays a role in tolerance of these cells to insult. Thus primary astrocytes were subjected to normoxic (21% O(2)), hypoxic (1% O(2)), or near-anoxic (<0.1% O(2)) conditions in the presence or absence of glucose. Cell death was significantly initiated after combined oxygen glucose deprivation, and, surprisingly, astrocyte proliferation increased concomitantly. Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity, whereas oxygen and glucose deprivation accelerated HIF-1alpha accumulation. Unexpectedly, Hif-1alpha knockdown studies showed that elevated VEGF levels following increased insult was only partially due to HIF-1alpha induction, suggesting alternative mechanisms of VEGF regulation. Notably, endogenous VEGF signaling during insult was essential for cell fate since VEGF inhibition appreciably augmented cell death and reduced proliferation. These data suggest Hif-1 only partially contributes to VEGF-mediated astrocyte responses during chronic injury (as occurs in clinical hypoxic/ischemic insults) that may ultimately be responsible for disrupting BBB integrity.

Hypoxic postconditioning reduces microglial activation, astrocyte and caspase activity, and inflammatory markers after hypoxia–ischemia in the neonatal rat brain

“…In addition, pharmacological inhibition of VEGF caused a reduction in proliferation and survival in astrocyte cultures after hypoxia and glucose deprivation. Hence, our observation of increased intensity of GFAP staining might be due to hypoxia-induced VEGF expression (40). Postconditioning with ischemia was also seen to offer beneficial effects after a middle cerebral artery occlusion in rats by increasing tight junction proteins and improving blood-brain barrier integrity (41).…”

The roles of blood-derived macrophages and resident microglia in the neuroinflammatory response to implanted Intracortical microelectrodes

“…Upon insertion of a microelectrode into the cortical tissue, astrocytes become activated and form a glial scar encapsulating the electrode [51–53]. Therefore, we used glial fibril acidic protein (GFAP) as a marker to label immature/mature resting and activated astrocytes [54].…”

Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen‐glucose deprivation

“…We also investigated the effect of treating OGD-exposed primary neuronal cultures with medium from astrocytes previously conditioned with OGD and sEH inhibitors. We focused on astrocyte release of vascular endothelial growth factor (VEGF) because astrocytes release VEGF under hypoxic conditions (Sinor et al 1998, Schmid-Brunclik et al 2008), sEH inhibitors can promote VEGF release in other tissue (Panigrahy et al 2013) and VEGF can exert pro-survival effects in neurons and may promote reparative mechanisms through its angiogenic effects (Sanchez et al 2010, Shibuya 2009, Li et al 2012). Two main hypotheses were tested.…”