Spatial distribution of insulin-like growth factor binding protein-2 following hypoxic-ischemic injury

Abstract

BackgroundInsulin-like growth factor binding protein-2 (IGFBP-2) regulates the bioavailability, transportation, and localization of insulin-like growth factor-I (IGF-I), an effective neuroprotectant in animal stroke models especially when administered intranasally. Therefore, determining IGFBP-2′s endogenous distribution in the normal and ischemic brain is essential in maximizing the neuroprotective potential of the intranasal IGF-I treatment approach. However, current data on IGFBP-2 is limited to mRNA and in situ hybridization studies. The purpose of this study was to determine if there are any changes in IGFBP-2 protein levels and distribution in ischemic brain and also to determine if IGFBPs play a role in the transportation of intranasally administered IGF-I into the brain.ResultsUsing an in vitro approach, we show that ischemia causes changes in the distribution of IGFBP-2 in primary cortical neurons and astrocytes. In addition, we show using the transient middle cerebral artery occlusion (MCAO) model in mice that there is a significant increase in IGFBP-2 levels in the stroke penumbra and core after 72 h. This correlated with an overall increase in IGF-I after stroke, with the highest levels of IGF-I in the stroke core after 72 h. Brain sections from stroke mice indicate that neurons and astrocytes located in the penumbra both have increased expression of IGFBP-2, however, IGFBP-2 was not detected in microglia. We used binding competition studies to show that intranasally administered exogenous IGF-I uptake into the brain is not receptor mediated and is likely facilitated by IGFBPs.ConclusionsThe change in protein levels indicates that IGFBP-2 plays an IGF-I-dependent and -independent role in the brain’s acute (neuroprotection) and chronic (tissue remodeling) response to hypoxic-ischemic injury. Competition studies indicate that IGFBPs may have a role in rapid transportation of exogenous IGF-I from the nasal tissue to the site of injury.

IGFBP2 Plays an Essential Role in Cognitive Development during Early Life

“…[17] The distribution of IGFBP2-positive cells in the hippocampus suggests that IGFBP2 acts there by an autocrine and/or paracrine mechanism to influence synaptic activity and learning and memory. [17] The distribution of IGFBP2-positive cells in the hippocampus suggests that IGFBP2 acts there by an autocrine and/or paracrine mechanism to influence synaptic activity and learning and memory.…”

Up‐regulated basigin‐2 in microglia induced by hypoxia promotes retinal angiogenesis

“…IGF‐1 has high binding affinity for IGFBP‐2, and this interaction is thought to play a significant role in modulating IGF‐1 localization to its receptor, protecting it from degradation, facilitating its transportation to the injury site. Although, cellular origins of IGFBP‐2 and mechanistically an IGF‐1‐dependent or independent pathway were still in doubt, previous reports have shown IGFBP‐2 increased after hypoxic‐ischaemic injury to the brain 33, and co‐localized with endogenous IGF‐1 at the injury site 32, 52.…”

Insulin-Like Growth Factor Binding Protein-2 Promotes Adhesion of Endothelial Progenitor Cells to Endothelial Cells via Integrin α5β1

“…In addition, it is reported that IGFBP-2 level was significantly up-regulated by oxygen-glucose deprivation in brain microvascular endothelial cells (Wang et al 2013). An increase in IGFBP-2 expression was also found in the stroke penumbra and core, or hippocampus in animal models (Jin et al 2001;Fletcher et al 2013). Thus, we hypothesize that IGFBP-2 may contribute to the interaction and adhesion of EPCs to ECs, namely EPC-endothelial adhesion.…”