Pathophysiologic responses in brain after stroke are highly complex. Thus far, a singular focus on saving neurons alone has not revealed any clinically effective neuroprotectants. To address this limitation, the concept of a neurovascular unit was developed. Within this conceptual framework, brain function and dysfunction are manifested at the level of cell–cell signaling between neuronal, glial and vascular elements. For stroke, coordinated responses at the neurovascular interface will mediate acute as well as chronic events in ischemic and hemorrhagic brain tissue. In this minireview, we briefly survey two representative examples of neurovascular responses in stroke. During the early acute phase of neurovascular injury, blood–brain barrier perturbations should predominate with key roles for various matrix proteases. During the delayed phase, brain angiogenesis may provide the critical neurovascular substrates for neuronal remodeling. In this minireview, we propose the hypothesis that the biphasic nature of neurovascular responses represents an endogenous attempt by damaged parenchyma to trigger brain angiogenesis and repair. This phenomenon may allow acute deleterious signals to transition into beneficial effects during stroke recovery. Understanding how neurovascular signals and substrates make the transition from initial injury to angiogenic recovery will be important if we are to find new therapeutic approaches for stroke.

We show that cerebral endothelial cells secrete trophic factors that support the survival and proliferation of rat oligodendrocyte precursor cells (OPCs). This OPC-supportive phenomenon was mediated by Akt and Src signaling pathways. Noncytotoxic levels of oxidative stress downregulate trophic factor production and disrupt the ability of cerebral endothelial cells to support OPCs. These data suggest that a novel oligovascular niche may be important for sustaining oligodendrocyte renewal and homeostasis in mammalian brain.

Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). Forin vitroexperiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl₂for 7 d,in vitroOPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. Forin vivoexperiments, we analyzed a transgenic mouse line (GFAP^cre/BDNF^wt/fl) in which BDNF expression is downregulated specifically in GFAP⁺astrocytes. Both wild-type (GFAP^wt/BDNF^wt/flmice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF.SIGNIFICANCE STATEMENTThe repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However, the underlying mechanisms are still mostly unknown. Here, we use a combination of cell biology and an animal model to report a new pathway in which astrocyte-derived BDNF supports oligodendrogenesis and regeneration after white matter damage. These findings provide new mechanistic insight into white matter physiology and pathophysiology, which would be broadly and clinically applicable to CNS disease.

Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: Pdgfra^Cre/Tgfb1^flox/wt mice or OPC-specific TGF-β1 total KO mice: Pdgfra^Cre/Tgfb1^flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity.

Originally identified as an angiogenic factor, vascular endothelial growth factor (VEGF-A) is now known to play multiple roles in the CNS, including the direct regulation of neuronal and astrocytic functions. Here, we ask whether VEGF-A can also have a novel role in white matter by modulating oligodendrocyte precursor cells (OPCs). OPCs were cultured from rat neonatal cortex. Expression of VEGF-receptor2/KDR/Flk-1 was confirmed with Western blot and immunostaining. VEGF-A did not affect proliferation or differentiation in OPC cultures, but VEGF-A promoted OPC migration in a concentration-dependent manner. Consistent with this migration phenotype, VEGF-A-treated OPCs showed reorganization of actin cytoskeleton in leading-edge processes. VEGF-A-induced migration and actin reorganization were inhibited by an anti-Flk-1 receptor-blocking antibody. Mechanistically, VEGF-A induced binding of focal adhesion kinase (FAK) with paxillin. The FAK inhibitor PF573228 reduced VEGF-A-induced OPC migration. VEGF-A signaling also evoked a transient rise in reactive oxygen species (ROS), and OPC migration was increased when antioxidants were removed from the culture media. Our findings demonstrate that VEGF-A can induce OPC migration via an ROS- and FAK-dependent mechanism, and suggest a novel role for VEGF-A in white-matter maintenance and homeostasis.

Oligodendrocyte precursor cells (OPCs) are thought to maintain homeostasis and contribute to long-term repair in adult white matter; however, their roles in the acute phase after brain injury remain unclear. Mice that were subjected to prolonged cerebral hypoperfusion stress developed white matter demyelination over time. Prior to demyelination, we detected increased MMP9 expression, blood-brain barrier (BBB) leakage, and neutrophil infiltration in damaged white matter. Notably, at this early stage, OPCs made up the majority of MMP9-expressing cells. The standard MMP inhibitor GM6001 reduced the early BBB leakage and neutrophil infiltration, indicating that OPC-derived MMP9 induced early BBB disruption after white matter injury. Cell-culture experiments confirmed that OPCs secreted MMP9 under pathological conditions, and conditioned medium prepared from the stressed OPCs weakened endothelial barrier tightness in vitro. Our study reveals that OPCs can rapidly respond to white matter injury and produce MMP9 that disrupts the BBB, indicating that OPCs may mediate injury in white matter under disease conditions.