Melissa Trotman-Lucas, PhD
@TrolucaM
Despite the collective history of failed neuroprotective therapies aimed at treating ischemic injury, the need to discover alternative stroke therapies is still present. However, despite improvements in the detection and treatment of ischemic strokes, a significant proportion of patients are ineligible for treatment and, therefore, unable to benefit. This impacts patient outcome, leaving many individuals with lifelong disabilities. Currently, the neurovascular unit (NVU) is being considered as a viable therapeutic target. This complex combination of capillaries, endothelial cells, pericytes, astrocytes and neurons closely controls connectivity between the brain and the blood. Events in the NVU contribute to cell death and neurological dysfunction during infarction, but also certain cell types within the unit have been shown to play a role in the preservation of post-stroke brain function. Endothelial cells, for instance, are key to the dynamic process of neovascularization, whereby these cells proliferate, migrate and differentiate following ischemic injury. Neovascularization is thought to be a key process in ischemia recovery, stimulating blood flow, vascular collateralization and neuroplasticity. In addition to the role of endothelial cells post-injury, astrocytes are also understood to be prominent in post-stroke recovery, transforming in the presence of molecules released during ischemic damage such as cytokines. These transformed astrocytes termed reactive astrocytes are known to be important in the formation of a glial scar that surrounds the damaged tissue. Interestingly, for some time it has been thought that the glial scar hindered axonal growth during brain recovery; however, recent evidence suggests the opposite and indeed promotion of axon development.
This recent article by Blochet et al. aimed to characterize the expression of Caveolin-I (Cav-I) and determine its effects post stroke using a KO model, focusing on endothelial cells and astrocytes of the NVU. Cav-I is thought to be one of the key structural proteins of caveolae; these are micro-invaginations of the plasma membrane present in most cell types. Caveolae are known to play a role in modulation of the blood brain barrier, survival signaling, neuroinflammation and angiogenesis. The group led their investigation by assessing post-stroke expression of Cav-I using an experimentally induced model of stroke in wild-type (WT) mice, reporting enhanced Cav-I levels in the injured hemisphere. They also described increased Cav-I expression within both endothelial cells and, for the first time, Cav-I expression within reactive astrocytes — both discoveries within the infarcted area. The groups Cav-I expression data suggests there is modulation of Cav-I expression within the NVU post-stroke, potentially playing a part in the post-damage coping mechanisms of the tissue. Following on from this, the group then utilized Cav-I knockout (KO) mice to investigate the impact post-stroke, to edge closer to determining Cav-I’s role during and following ischemic brain injury. Blochet and colleagues assessed this using a variety of post-stroke measures, including lesion volume analysis, sensorimotor assessment and quantification of both neovascularization and astrogliosis. Reporting worsened post-stroke outcomes in the absence of Cav-I, including increased mortality and tissue damage alongside exacerbated functional deficits. Interestingly, KO mice showed reactive astrocytes with a distinct, potentially impaired, morphology to those seen in WT tissue post-stroke, suggesting impaired astrogliosis. Within the lesion, a reduced number of proliferating endothelial cells were also seen, suggesting a role of Cav-I in the neovascularization process post-injury.
This study shines a light towards a potential novel therapeutic target for ischemic stroke treatment, highlighting the importance of focus on the NVU. The results indicate a protective role for Cav-I and caveolae in the acute phase post-stroke. However, the mechanisms by which Cav-I impacts/promotes astrogliosis and neovascularization remain to be fully elucidated. The exact mechanisms by which caveolae, and Cav-I in particular, function need to be determined to move towards new therapeutic treatments for ischemic stroke.
