The brain is dependent upon multiple cell types for protection that include neurons, inflammatory microglia, astrocytes, endothelial cells and pericytes. Each of these cell types form vital components for areas of the brain that determine cognition as well as emotion. Furthermore, the various cell types of the brain must work in an integrated fashion to not only assist with common function but also protect the brain on a larger scale. For example, pericytes are an important component to the neurovascular unit that consists of neurons, cerebral endothelial cells, and astrocytes. Pericytes assist with the maintenance of the blood-brain barrier, help maintain the survival of endothelial cells during toxic insults, and can promote endothelial cell growth during angiogenesis. Pericytes themselves also can differentiate into mesenchymal stem cells and smooth muscle cells.
If one looks further at the cellular level in this neurovascular unit, multiple pathways can control survival as well as regenerative processes. One interesting pathway involves the Wnt proteins that are secreted cysteine-rich glycosylated proteins that can control proliferation, differentiation, and survival in several cellular populations that include neurons, endothelial cells, and inflammatory cells such as microglia. Wnt proteins also regulate the differentiation of pericytes, endothelial cells, and the progression of angiogenesis. In addition, Wnt proteins oversee inflammatory cell control and the regulation of endovascular injury. The Wnt pathway can ultimately determine the integrity of the neurovascular unit since activated immune cells can lead to the phagocytic removal of both neurons and vascular cells.
It is clear that the different cell types and complex pathways of the brain must form an integrated network to protect and foster the function of the brain. In this issue of Current Neurovascular Research, our papers highlight several novel aspects of this vital network. Arimura and co-authors show that platelet derived growth factor receptor is expressed in pericytes during cerebral ischemic injury and that platelet derived growth factor itself in pericytes prevents apoptotic responses, suggesting that pericytes rely upon platelet derived growth factor signaling to provide protection for the brain. In the paper by Marie-Francoise Ritz et al., the authors tie the effects of hypertension to injury responses in the cortex of the brain. In addition to expected blood flow changes with hypertension, the study demonstrates that hypertension also alters gene expression in the brain that can lead to cerebral vessel disease through the up-regulation of genetic pathways involving energy and lipid metabolism, ischemia, and oxidative stress. In the next paper of this issue, Wang and co-authors elucidate new roles for Wnt signaling in hippoacampal neurons through the Wnt1 inducible signaling pathway protein 1 (WISP1). WISP1 governs a specific set of unique interconnected pathways that are not usually considered part of the Wnt signaling family that involve PI 3-K, Akt1, Bad, GSK-3β, Bim, Bax, and Bcl-xL to control mitochondrial membrane permeability, caspase activation, and neuron apoptotic injury during oxidant stress. In the work by Xi et al., they demonstrate for us the role of flavonoids to block endothelial cell degeneration associated with β-amyloid and to protect components of the neurovascular unit through signaling of the NF-E2- related factor 2 pathway. Lin and Feng take a more clinical perspective in their work in patients hospitalized with intracranial hemorrhage and show a racial disparity among risk factors in younger African Americans for recurrent stoke, myocardial infarction, and death due to vascular complications. This work points to the need for improved treatment and understanding of the cellular pathology in various patient populations that suffer from intracerebral hemorrhage. In the work by Steckert et al., they show that protein kinase C may not only play an important role during bipolar disorder, since inhibition of the protein kinase C pathway can reduce hyperactivity, but also that protein kinase C may ameliorate oxidative damage that may be a component of bipolar disorder. Studies by Bulku et al. focus upon curcumin, a popular coloring and flavor agent that has recently been demonstrated to have protective properties for the brain. The authors current work now shows that curcumin may offer more global protection in the body to indirectly protect the brain through the prevention of drug-induced hepatic injury through anti-apoptotic gene expression. Our final article by Argandona et al. provides a welcome overview of the “neuroglialvascular” unit addressing areas that involve brain development as well as environmental enrichment and physical exercise. The thought provoking studies in this issue of Current Neurovascular Research emphasize some of the complexity and the commonality of the pathways that determine the protection of the brain and the richness of the neurovascular unit. However, given the many unknowns that continue to exist, such as why an individual may experience a different and severe response to a nervous system insult in comparison to another individual that suffers minimal deficits, we must quickly move ahead and “throw caution to the Wnts” in our pursuit to develop new treatment strategies for many nervous system disorders that are without effective therapies.