Semaphorin 3A Contributes to Secondary Blood–Brain Barrier Damage After Traumatic Brain Injury

Abstract

Semaphorin 3A (SEMA3A) is a member of the Semaphorins family, a class of membrane-associated protein that participates in the construction of nerve networks. SEMA3A has been reported to affect vascular permeability previously, but its influence in traumatic brain injury (TBI) is still unknown. To investigate the effects of SEMA3A, we used a mouse TBI model with a controlled cortical impact (CCI) device and a blood–brain barrier (BBB) injury model in vitro with oxygen-glucose deprivation (OGD). We tested post-TBI changes in SEMA3A, and its related receptors (Nrp-1 and plexin-A1) expression and distribution through western blotting and double-immunofluorescence staining, respectively. Neurological outcomes were evaluated by modified neurological severity scores (mNSSs) and beam-walking test. We examined BBB damage through Evans Blue dye extravasation, brain water content, and western blotting for VE-cadherin and p-VE-cadherin in vivo , and we examined the endothelial cell barrier through hopping probe ion conductance microscopy (HPICM), transwell leakage, and western blotting for VE-cadherin and p-VE-cadherin in vitro . Changes in miR-30b-5p were assessed by RT-PCR. Finally, the neuroprotective function of miR-30b-5p is measured by brain water content, mNSSs and beam-walking test. SEMA3A expression varied following TBI and peaked on the third day which expressed approximate fourfold increase compared with sham group, with the protein concentrated at the lesion boundary. SEMA3A contributed to neurological function deficits and secondary BBB damage in vivo . Our results demonstrated that SEMA3A level following OGD injury almost doubled than control group, and the negative effects of OGD injury can be improved by blocking SEMA3A expression. Furthermore, the expression of miR-30b-5p decreased approximate 40% at the third day and 60% at the seventh day post-CCI. OGD injury also exhibited an effect to approximately decrease 50% of miR-30b-5p expression. Additionally, the expression of SEMA3A post-TBI is regulated by miR-30b-5p, and miR-30b-5p could improve neurological outcomes post-TBI efficiently. Our results demonstrate that SEMA3A is a significant factor in secondary BBB damage after TBI and can be abolished by miR-30b-5p, which represents a potential therapeutic target.

LncRNA MEG3 targeting miR-424-5p via MAPK signaling pathway mediates neuronal apoptosis in ischemic stroke

“…Bioinformatic analysis of the data set GSE22255 screened out an mRNA highly expressed in IS, Sema3A, as well as a Sema3A-related MAPK signaling pathway, which was aberrantly modulated in IS. As a growth and apoptosis-related gene, the role of Sema3A had been explored in traumatic brain injury [25], autoimmune disease [21] and tumors [26]. According to previous studies, Sema3A functioned as a negative guidance molecule which led to an inhibitory environment where axonal growth was retarded and growth cone collapse [27].…”

Common Dysregulation of Innate Immunity Pathways in Human Primary Astrocytes Infected With Chikungunya, Mayaro, Oropouche, and Zika Viruses

“…We performed RT-qPCR of 16 common genes dysregulated for all viruses in order to validate our RNA-seq data ( Figure 6 ). We selected genes belonging to cytoskeleton and motility (Actin Alpha 2, ACTA2 ) ( Rockey et al., 2019 ), autophagy (Decidual Protein Induced By Progesterone, DEPP1), L-serine synthesis (Phosphoserine Aminotransferase 1, PSAT1 ) ( Jiang et al., 2020 ), inflammatory response (Interleukin 7 Receptor, IL7R , and Major Histocompatibility Complex, Class II, DO Beta, HLA-DOB ) ( Inchley et al., 2013 ; Alsadeq et al., 2018 ), axonal guidance and neuropathology (Semaphorin 3A, SEMA3A ) ( Niclou et al., 2003 ; Yang et al., 2019 ), interferon induction ( DDX58 , Interferon Induced With Helicase C Domain 1, IFIH1 , TRIM25 , and IRF7 ), and interferon responsive/agonist genes with antiviral activity ( IFIT1 , IFIT2 , MX1 , MX2 , ISG15 , and RSAD2 ) ( García-Sastre, 2017 ; Schoggins, 2019 ).…”

PlexinA1-deficient mice exhibit decreased cell density and augmented oxidative stress in parvalbumin-expressing interneurons in the medial prefrontal cortex

“…Thus, another hypothesis for increased oxidative stress in PlxnA1 KO mice is that enhanced vascular permeability may induce the increase of oxidative stress, decrease of PV cells and abnormal behavior. Nrp1 is involved in regulating developmental angiogenesis and, vascular permeability and angiogenesis under various pathological states by functioning as a coreceptor for Sema3A ( Domingues and Fantin, 2021 , Yang et al, 2019 ). Sema3A-induced endothelial cell permeability needs PlxnA1 to cause instability of interendothelial junctions integrity ( Le Guelte et al, 2012 ).…”