Purpose of review Angiogenesis or vascular reorganization plays a role in recovery after stroke and traumatic brain injury (TBI). In this review, we have focused on two major events that occur during stroke and TBI from a vascular perspective – what is the process and time course of blood–brain barrier (BBB) breakdown? and how does the surrounding vasculature recover and facilitate repair? Recent findings Despite differences in the primary injury, the BBB changes overlap between stroke and TBI. Disruption of BBB involves a series of events: formation of caveolae, trans and paracellular disruption, tight junction breakdown and vascular disruption. Confounding factors that need careful assessment and standardization are the severity, duration and extent of the stroke and TBI that influences BBB disruption. Vascular repair proceeds through long-term neovascularization processes: angiogenesis, arteriogenesis and vasculogenesis. Enhancing each of these processes may impart beneficial effects in endogenous recovery. Summary Our understanding of BBB breakdown acutely after the cerebrovascular injury has come a long way; however, we lack a clear understanding of the course of BBB disruption and BBB recovery and the evolution of individual cellular events associated with BBB change. Neovascularization responses have been widely studied in stroke for their role in functional recovery but the role of vascular reorganization after TBI in recovery is much less defined.

Background and purpose Pre-existing diabetes worsens brain functionality in ischemic stroke. We have previously shown that type-2-diabetic rats exhibit enhanced dysfunctional cerebral neovascularization and when these rats are subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation (HT) and greater neurological deficits. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that vascular repair is impaired in the post-stroke period in diabetes, and this is associated with poor sensorimotor and cognitive function. We further hypothesized that glycemic control prevents impaired vascularization and improves functional outcome in diabetes. Methods Vascularization was assessed in the ipsilateral and contralateral hemispheres in control, diabetes and diabetes plus metformin groups 14 days after ischemic reperfusion injury as well as in respective sham controls. 3-dimensional reconstruction of the FITC stained vasculature was achieved by confocal microscopy and stereological parameters including vascular volume and surface area were measured. Astrogliosis was determined by GFAP staining. The relative rates of sensorimotor recovery, cognitive decline and spontaneous activity were assessed. Results Vascular density in the peri-infarct area was significantly reduced in diabetes whereas there was reparative neovascularization in control rats. Astroglial swelling and reactivity was more pronounced in diabetic stroke compared to control stroke. Diabetes blunted sensorimotor recovery and also exacerbated anxiety-like symptoms and cognitive deficits. Glycemic control started after stroke partially prevented these changes. Conclusion Diabetes impairs post-stroke reparative neovascularization and impedes the recovery. Glycemic control after stroke can improve neurovascular repair and improve functional outcome.

We previously reported enhanced cerebrovascular remodeling and arteriogenesis in experimental type 2 diabetes. This study tested the hypotheses that 1) cerebral but not peripheral angiogenesis is increased in a spatial manner and 2) peroxynitrite orchestrates vascular endothelial growth factor (VEGF)-mediated brain angiogenesis in diabetes. Stereology of brain, eye, and skeletal muscle microvasculature was evaluated in control and diabetic rats using three-dimensional images. Migration and tube formation properties of brain microvascular endothelial cells (BMECs) were analyzed as markers of angiogenesis. Vascular density, volume, and surface area were progressively increased from rostral to caudal sections in both the cerebral cortex and striatum in diabetic rats. Unperfused new vessels were more prominent and the pericyte–to–endothelial cell ratio was decreased in diabetes. Vascularization was greater in the retina but lower in the peripheral circulation. VEGF and nitrotyrosine levels were higher in cerebral microvessels of diabetic animals. Migratory and tube formation properties were enhanced in BMECs from diabetic rats, which also expressed high levels of basal VEGF, nitrotyrosine, and membrane-type (MT1) matrix metalloprotease (MMP). VEGF-neutralizing antibody and inhibitors of peroxynitrite, src kinase, or MMP blocked the migration. Diabetes increases and spatially regulates cerebral neovascularization. Increased VEGF-dependent angiogenic function in BMECs is mediated by peroxynitrite and involves c-src and MT1-MMP activation.