A Window of Vascular Plasticity Coupled to Behavioral Recovery after Stroke

Abstract

Stroke causes remodeling of vasculature surrounding the infarct, but whether and how vascular remodeling contributes to recovery are unclear. We established an approach to monitor and compare changes in vascular structure and blood flow with high spatiotemporal precision after photothrombotic infarcts in motor cortex using longitudinal 2-photon and multiexposure speckle imaging in mice of both sexes. A spatially graded pattern of vascular structural remodeling in peri-infarct cortex unfolded over the first 2 weeks after stroke, characterized by vessel loss and formation, and selective stabilization of a subset of new vessels. This vascular structural plasticity was coincident with transient activation of transcriptional programs relevant for vascular remodeling, reestablishment of peri-infarct blood flow, and large improvements in motor performance. Local vascular plasticity was strongly predictive of restoration of blood flow, which was in turn predictive of behavioral recovery. These findings reveal the spatiotemporal evolution of vascular remodeling after stroke and demonstrate that a window of heightened vascular plasticity is coupled to the reestablishment of blood flow and behavioral recovery. Our findings support that neovascularization contributes to behavioral recovery after stroke by restoring blood flow to peri-infarct regions. These findings may inform strategies for enhancing recovery from stroke and other types of brain injury.

Donor-derived vasculature is required to support neocortical cell grafts after stroke

“…Notably, grafts at stroke sites were larger (with a higher percentage of donor-derived vessels) than grafts at nonstroke sites. This suggests that the environment in which cells are transplanted also plays an important role in graft vascularization, survival, and growth, consistent with observed dynamic post-stroke revascularization (Williamson et al, 2020). Several possible factors could account for the better vascularization and engraftment at stroke sites.…”

Reactive astrocytes facilitate vascular repair and remodeling after stroke

“…We analyzed a reactive astrocyte transcriptome resource (GEO: GSE35338) ( Zamanian et al, 2012 ) to elucidate functional changes in reactive astrocytes during the first week after experimental stroke, which is a time of significant vascular plasticity and repair ( Williamson et al, 2020 ). Samples were collected from 30-to 35-day-old Aldh1l1-EGFP mice on a Swiss Webster background subjected to 60-min middle cerebral artery occlusion or sham procedures ( Zamanian et al, 2012 ).…”

“…Mice were euthanized 2 weeks post-stroke ( Figure 3D ). We chose this survival time because most neovascularization occurs during the first 2 weeks post-stroke in this model ( Williamson et al, 2020 ). Lesion volume and location were not different between groups ( Figures 3E – 3G ).…”

“…Multi-exposure speckle imaging of blood flow MESI was done as previously described (Clark et al, 2019a;Williamson et al, 2020). MESI provides a label-free, quantitative measure of micro-and macrovascular perfusion.…”

“…These reparative processes include plasticity of vascular structure and repair of the neurovascular unit ( Freitas-Andrade et al, 2020 ). Vascular remodeling in peri-infarct cortex occurs largely during the first 2 weeks post-stroke in rodent models, and it is characterized by concurrent formation and pruning of capillary segments to help restore blood flow to residual tissue ( Williamson et al, 2020 ). This process contributes to behavioral recovery and is thought to be crucial for resolving metabolic failure in surviving tissue and re-establishing a microenvironment that can support other aspects of neural repair ( Mostany et al, 2010 ; Rust et al, 2019a ; Williamson et al, 2020 ).…”