Potential crosstalk between sonic hedgehog‐WNT signaling and neurovascular molecules: Implications for blood–brain barrier integrity in autism spectrum disorder

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disease originating from combined genetic and environmental factors. Post‐mortem human studies and some animal ASD models have shown brain neuroinflammation, oxidative stress, and changes in blood–brain barrier (BBB) integrity. However, the signaling pathways leading to these inflammatory findings and vascular alterations are currently unclear. The BBB plays a critical role in controlling brain homeostasis and immune response. Its dysfunction can result from developmental genetic abnormalities or neuroinflammatory processes. In this review, we explore the role of the Sonic Hedgehog/Wingless‐related integration site (Shh/Wnt) pathways in neurodevelopment, neuroinflammation, and BBB development. The balance between Wnt‐β‐catenin and Shh pathways controls angiogenesis, barriergenesis, neurodevelopment, central nervous system (CNS) morphogenesis, and neuronal guidance. These interactions are critical to maintain BBB function in the mature CNS to prevent the influx of pathogens and inflammatory cells. Genetic mutations of key components of these pathways have been identified in ASD patients and animal models, which correlate with the severity of ASD symptoms. Disruption of the Shh/Wnt crosstalk may therefore compromise BBB development and function. In turn, impaired Shh signaling and glial activation may cause neuroinflammation that could disrupt the BBB. Elucidating how ASD‐related mutations of Shh/Wnt signaling could cause BBB leaks and neuroinflammation will contribute to our understanding of the role of their interactions in ASD pathophysiology. These observations may provide novel targeted therapeutic strategies to prevent or alleviate ASD symptoms while preserving normal developmental processes. Cover Image for this issue: https://doi.org/10.1111/jnc.15081

Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity

“…While a trend of increased CD31 was noticeable in all three brain areas, it did not reach significance. Interestingly, CD31 (Figure 11) and P-selectin antibodies (Figure 9) produce little labeling of cerebral blood vessels in WT animals consistent with previous reports in adult mice [39,40]. The average Fibrinogen staining intensity per unit area in the hippocampus, cortex, and amygdala was significantly higher in the Sema 3F KO mice when compared to the control groups, (*** p ≤ 0.0001; ** p ≤ 0.001; * p ≤ 0.01; n = 3) (Figure 11).…”

“…Indeed, while both CD31 and p-selectin are expressed in endothelial cells and platelets, both are critical to platelet–endothelial interactions and the increased p-selectin expression which occurs at the time of platelet activation, recruiting flowing leukocytes and contributing to inflammation [ 112 ]. P-selectin and CD31/PECAM-1 labeling was mainly observed in cerebral tissue rather than in blood vessels ( Figure 9 and Figure 11 ) [ 39 , 40 ]. Similarly, soluble P-selectin and CD31/PECAM-1 are decreased in the plasma of children with ASD compared to age/sex matched neurotypical controls [ 130 ].…”

Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging

“…Both endogenous and exogenous Shh signaling have the potential to mitigate inflammatory immune cell profiles and restrain the release of proinflammatory cytokines ( 154 , 155 ) with better pathological outcomes ( 154 ). The role of SHH in angiogenesis and maintenance has been reviewed by Chapouly and his colleagues ( 156 ), and SHH and Wnt signaling could interact with each other to regulate the BBB, which was reviewed by Gozal and his colleagues ( 157 ).…”

Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

“…Like AD research studies, post-mortem human studies and some animal ASD models have shown brain neuroinflammation, oxidative stress, and changes in BBB integrity. 55 The balance between Wnt-β-catenin and Shh pathways controls angiogenesis, barrier genesis, neurodevelopment, CNS morphogenesis, and neuronal guidance that are related to both AD 56, 57 and ASD. 55…”

“…55 The balance between Wnt-β-catenin and Shh pathways controls angiogenesis, barrier genesis, neurodevelopment, CNS morphogenesis, and neuronal guidance that are related to both AD 56, 57 and ASD. 55…”