Schizophrenia is a chronic debilitating mental disorder characterized by perturbations in thinking, perception, and behavior, along with brain connectivity deficiencies, neurotransmitter dysfunctions, and loss of gray brain matter. To date, schizophrenia has no cure and pharmacological treatments are only partially efficacious, with about 30% of patients describing little to no improvement after treatment. As in most neurological disorders, the main descriptions of schizophrenia physiopathology have been focused on neural network deficiencies. However, to sustain proper neural activity in the brain, another, no less important network is operating: the vast, complex and fascinating vascular network. Increasing research has characterized schizophrenia as a systemic disease where vascular involvement is important. Several neuro-angiogenic pathway disturbances have been related to schizophrenia. Alterations, ranging from genetic polymorphisms, mRNA, and protein alterations to microRNA and abnormal metabolite processing, have been evaluated in plasma, post-mortem brain, animal models, and patient-derived induced pluripotent stem cell (hiPSC) models. During embryonic brain development, the coordinated formation of blood vessels parallels neuro/gliogenesis and results in the structuration of the neurovascular niche, which brings together physical and molecular signals from both systems conforming to the Blood-Brain barrier. In this review, we offer an upfront perspective on distinctive angiogenic and neurogenic signaling pathways that might be involved in the biological causality of schizophrenia. We analyze the role of pivotal angiogenic-related pathways such as Vascular Endothelial Growth Factor and HIF signaling related to hypoxia and oxidative stress events; classic developmental pathways such as the NOTCH pathway, metabolic pathways such as the mTOR/AKT cascade; emerging neuroinflammation, and neurodegenerative processes such as UPR, and also discuss non-canonic angiogenic/axonal guidance factor signaling. Considering that all of the mentioned above pathways converge at the Blood-Brain barrier, reported neurovascular alterations could have deleterious repercussions on overall brain functioning in schizophrenia.

Background: Hyperbaric oxygen treatment (HBOT) has been used for more than a decade to treat diverse diseases like diabetic foot ulcers and ischemic injuries. More recently, HBOT has been reported to modulate proliferation of neural and intestinal stem cell populations, but the molecular mechanisms underlying these effects are not completely understood. Objective: In this study we aimed to determine HBOT stem cell modulation by evaluating in particular the role of the mTOR complex 1 (mTORc1), a key regulator of cell metabolism that modifies its activity depending on oxygen levels, as a potential mediator of HBOT in murine intestinal stem cells (ISCs). Methods: Mouse were exposed to 10 or 20 HBOT sessions and the proliferation of the ISCs were analyzed by immunofluorescence or immunohistochemistry using the specific ISCs marker, Olfm4. The regulation of HBOT and mTORc1 pathway was analyzed through S6K1 phosphorylation by western-blot and through the inhibition by rapamycin. Results: We discovered that acute HBOT can increase proliferation of ISCs in a synchronous fashion without affecting the animal’s oxidative metabolism. Noteworthy, the mTORc1 inhibitor rapamycin also increases the proliferation of ISCs. This effect has been attributed to its capacity to mimic a caloric restriction (CR). Interestingly, the combination of HBOT and rapamycin does not have a synergic effect. Nevertheless, HBOT can recover rapamycin induced mTORc1 inhibition, possibly acting through a competitive modulation on mTORC1. Conclusions: Collectively, our results suggest that HBOT proliferative effect on ISCs is modulated by mTORc1 signaling representing a promising new approach to treat intestinal conditions.