Microvascular anomaly conditions in psychiatric disease. Schizophrenia - angiogenesis connection

Abstract

Schizophrenia (SZ) is a severe mental disorder with unknown etiology and elusive neuropathological and neurobiological features have been a focus of many theoretical hypotheses and empirical studies. Current genetic and neurobiology information relevant to SZ implicates neuronal developmental and synaptic plasticity abnormalities, and neurotransmitter, microglial and oligodendrocytes dysfunction. Several recent theories have highlighted the neurovascular unit as a potential contributor to the pathophysiology of SZ. We explored the biological plausibility of a link between SZ and the neurovascular system by examining insights gained from genetic, neuroimaging and postmortem studies, which include gene expression and neuropathology analyses. We also reviewed information from animal models of cerebral angiogenesis in order to understand better the complex interplay between angiogenic and neurotrophic factors in development, vascular endothelium/blood brain barrier remodeling and maintenance, all of which contribute to sustaining adequate regional blood flow and safeguarding normal brain function. Microvascular and hemodynamic alterations in SZ highlight the importance of further research and reveal the neurovascular unit as a potential therapeutic target in SZ.

Keywords: Angiogenesis; Endothelial cells; Gene expression; Neurovascular unit; Schizophrenia.

Figure 1

Plausible mechanisms (including participating genes) that take place in postnatal angiogenesis and their general effects in healthy and schizophrenia brains. Active angiogenic mechanisms aiming development of adequate vascular supply take place during early development (neurogenesis) and after birth, during myelination and synaptic plasticity, the processes that entail extraordinary metabolic demands. Growth factors, signaling angiogenic pathways and tissue remodeling proteins are released from neural cells, leading to the building of well-developed vascular plexus that maintain healthy brain function. In schizophrenia reduced gene expression of angiogenesis signals and remodeling proteins suggests reduced vessel sprouting/microvascular length, leading to an overall reduced blood flow and oxygenation of brain tissue. At the cellular level, the ECs begin to reduce the expression of growth factor receptors affecting the survival capacity of vascular endothelium and formation of endothelial junction in BBB. Many of these factors combine may create conditions for permeable/underdeveloped BBB, which result in spill over systemic plasma proteins into the brain tissue affecting wide-range of neural processes, including myelination, formation perineuronal nets-ECM and ultimately neuronal connectivity.