Stroke and the neurovascular unit: glial cells, sex differences, and hypertension

A functional neurovascular unit (NVU) is central to meeting the brain's dynamic metabolic needs. Poststroke damage to the NVU within the ipsilateral hemisphere ranges from cell dysfunction to complete cell loss. Thus, understanding poststroke cell-cell communication within the NVU is of critical importance. Loss of coordinated NVU function exacerbates ischemic injury. However, particular cells of the NVU (e.g., astrocytes) and those with ancillary roles (e.g., microglia) also contribute to repair mechanisms. Epidemiological studies support the notion that infarct size and recovery outcomes are heterogeneous and greatly influenced by modifiable and nonmodifiable factors such as sex and the co-morbid condition common to stroke: hypertension. The mechanisms whereby sex and hypertension modulate NVU function are explored, to some extent, in preclinical laboratory studies. We present a review of the NVU in the context of ischemic stroke with a focus on glial contributions to NVU function and dysfunction. We explore the impact of sex and hypertension as modifiable and nonmodifiable risk factors and the underlying cellular mechanisms that may underlie heterogeneous stroke outcomes. Most of the preclinical investigative studies of poststroke NVU dysfunction are carried out primarily in male stroke models lacking underlying co-morbid conditions, which is very different from the human condition. As such, the evolution of translational medicine to target the NVU for improved stroke outcomes remains elusive; however, it is attainable with further research.