Up-regulation of Wnt/β-catenin expression is accompanied with vascular repair after traumatic brain injury

Abstract

Recent data suggest that repairing the cerebral vasculature after traumatic brain injury (TBI) may help to improve functional recovery. The Wnt/β-catenin signaling pathway promotes blood vessel formation during vascular development, but its role in vascular repair after TBI remains elusive. In this study, we examined how the cerebral vasculature responds to TBI and the role of Wnt/β-catenin signaling in vascular repair. We induced a moderate controlled cortical impact in adult mice and performed vessel painting to visualize the vascular alterations in the brain. Brain tissue around the injury site was assessed for β-catenin and vascular markers. A Wnt transgenic mouse line was utilized to evaluate Wnt gene expression. We report that TBI results in vascular loss followed by increases in vascular structure at seven days post injury (dpi). Immature, non-perfusing vessels were evident in the tissue around the injury site. β-catenin protein expression was significantly reduced in the injury site at 7 dpi. However, there was an increase in β-catenin expression in perilesional vessels at 1 and 7 dpi. Similarly, we found increased number of Wnt-GFP-positive vessels after TBI. Our findings suggest that Wnt/β-catenin expression contributes to the vascular repair process after TBI.

Acute Treatment With Gleevec Does Not Promote Early Vascular Recovery Following Intracerebral Hemorrhage in Adult Male Rats

“…Tan and colleagues reported increased angiogenesis around the hematoma at 7-14 days after ICH likely via a vascular endothelial growth factor (VEGF) mechanisms (Tang et al, 2007) and confirmed in subsequent reports (Zhou et al, 2012). This vascular repair timeline is very similar to what we have reported in traumatic brain injury, albeit via a Wnt/β-catenin mechanism (Salehi et al, 2018a). In stroke, Gleevec protected the BBB, as well as "normalized" vessels within the brain early (1 h) post-injury (Su et al, 2008).…”

“…However, adverse vascular events have been reported in patients treated with Gleevec or other related tyrosine kinase inhibitors (Pasvolsky et al, 2015). It is intriguing to speculate that the early lack of effect on vascular morphology seen in our study could be related to downstream effects of Gleevec on BCR-ABL on Wnt/β-catenin cascades (Cilloni and Saglio, 2012) which we have previously reported is involved in late vascular remodeling following traumatic brain injury (Salehi et al, 2018a).…”

Wnt Pathway: An Emerging Player in Vascular and Traumatic Mediated Brain Injuries

“…Most of these studies emphasized on the role of β-catenin, the main effector of the canonical Wnt pathway. Indeed, it has been shown that β-catenin expression was increased in the peri-lesional microvasculature of mice at 1 and 7 days post-TBI, whereas it was reduced in injury site 7 days post-TBI (Salehi et al, 2018). A similar expression pattern was reported in a transgenic mouse line reporter for the canonical Wnt pathway activity, TCF:LEF1:H2B-GFP mice (Salehi et al, 2018).…”

“…Indeed, it has been shown that β-catenin expression was increased in the peri-lesional microvasculature of mice at 1 and 7 days post-TBI, whereas it was reduced in injury site 7 days post-TBI (Salehi et al, 2018). A similar expression pattern was reported in a transgenic mouse line reporter for the canonical Wnt pathway activity, TCF:LEF1:H2B-GFP mice (Salehi et al, 2018). Indeed, β-catenin expression increased 24 h after TBI, and was associated to an enhanced angiogenesis within the peri-lesional zone (Salehi et al, 2018).…”

Exploring Pharmacological Mechanisms of Xuefu Zhuyu Decoction in the Treatment of Traumatic Brain Injury via a Network Pharmacology Approach

“…Neuronal differentiation is induced by overexpression of β -catenin or the pharmacological inhibition of GSK3 β (the phosphorylating enzyme of β -catenin) [ 89 , 90 ]. This pathway also promotes blood vessel formation during vascular development, as well as the vascular repair process after TBI [ 91 ]. In addition, wogonin (Mol 160) from Achyranthis Bidentatae Radix (the Chen herb) specifically targeted fibronectin (FN1), Bcl-2-binding component 3 (BBC3), and Protein Kinase C delta type (PRKCD).…”