Association of serum VEGF levels with prefrontal cortex volume in schizophrenia

Abstract

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence

“…In vitro data have shown that pro-inflammatory cytokines (TNF-α, IL-1β, and IFN-γ) cause a dose-dependent increase in BBB permeability by (a) inducing expression of adhesion molecules such as ICAM-1 and VCAM-1 on the luminal surface of BBB endothelial cells in animals (91–93) and humans (94), which facilitates transendothelial lymphocyte and monocyte migration; (b) causing vascular endothelial oxidative injury by impairing vascular endothelial mitochondrial oxidative metabolism (65, 95); and (c) directly damaging endothelial tight junctions (11, 16). More recently, an association was described between elevated serum IL-6 and VEGF levels in schizophrenia (40), supporting the role of inflammation in inducing BBB hyperpermeability in schizophrenia. More studies are needed to fully explore the relevance of these mechanisms to the onset and progression of schizophrenia pathology.…”

“…Therefore, genetically predetermined heparan sulfate abnormalities may increase BBB hyperpermeability and facilitate transendothelial leukocyte migration in some individuals with schizophrenia (34). Recent studies have documented elevated serum levels of vascular endothelial growth factor (VEGF) (40) and significantly reduced expression of VEGF receptor 2 in the prefrontal cortex (41), which likely reflects its accelerated destruction by increased levels and activity of VEGF in individuals with schizophrenia. VEGF regulates angiogenesis and increases BBB permeability (40).…”

“…Recent studies have documented elevated serum levels of vascular endothelial growth factor (VEGF) (40) and significantly reduced expression of VEGF receptor 2 in the prefrontal cortex (41), which likely reflects its accelerated destruction by increased levels and activity of VEGF in individuals with schizophrenia. VEGF regulates angiogenesis and increases BBB permeability (40). VEGF activation in animal models of ischemia promotes BBB disruption through endothelial endocytosis (42).…”

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

“…VEGF is associated with inflammation reaction. Its serum levels are related to prefrontal cortex abnormalities in schizophrenia [71]. Shortened telomere length is found in unremitted schizophrenic patients [72].…”

Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study

“…In SZ, post mortem brain analysis demonstrated that dysregulated VEGF signaling occurs in both the dorsolateral prefrontal cortex (Fulzele and Pillai, 2009) and thalamus (Chu et al , 2009). Recently, Pillai et al demonstrated that serum VEGF levels were associated with prefrontal cortical volume (Pillai et al , 2015). These studies demonstrate that an imbalance of angiogenesis regulation can have detrimental effects.…”