Vascular endothelial growth factor aggravates cerebral ischemia and reperfusion-induced blood-brain-barrier disruption through regulating LOC102640519/HOXC13/ZO-1 signaling

Wang

et al. 2018

Front. Cell. Neurosci.

The blood-brain barrier (BBB) is a physical and biochemical barrier that maintains cerebral homeostasis. BBB dysfunction in an ischemic stroke, results in brain injury and subsequent neurological impairment. The aim of this study was to determine the possible protective effects of 1, 25-dihydroxyvitamin D3 [1, 25(OH)2D3, 1, 25-D3, vit D] on BBB dysfunction, at the early stages of an acute ischemic brain injury. We analyzed the effects of 1, 25-D3 on BBB integrity in terms of histopathological changes, the neurological deficit, infarct size and the expression of brain derived neurotrophic factor (BDNF), in a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model. BBB permeability and the expression of permeability-related proteins in the brain were also evaluated by Evans blue (EB) staining and Western blotting respectively. To determine the possible mechanism underlying the role of 1, 25-D3 in BBB maintenance, after MCAO/R, the rats were treated with the specific peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662. Supplementation with 1, 25-D3 markedly improved the neurological scores of the rats, decreased the infarct volume, prevented neuronal deformation and upregulated the expression of the tight junction (TJ) and BDNF proteins in their brains. Furthermore, it activated PPARγ but downregulated neuro-inflammatory cytokines such as nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α), after MCAO/R. Taken together, 1, 25-D3 protects against cerebral ischemia by maintaining BBB permeability, upregulating the level of BDNF and inhibiting PPARγ-mediated neuro-inflammation.

Section: Introductionmentioning

confidence: 99%

RETRACTED: 1, 25-D3 Protects From Cerebral Ischemia by Maintaining BBB Permeability via PPAR-γ Activation

Wang

et al. 2018

Front. Cell. Neurosci.

“…Despite that some astrocyte-derived factors maintain the BBB function, some astrocyte-derived factors damage the BBB by inducing endothelial cell apoptosis or decreasing the expression of endothelial tight junctionrelated proteins, which include vascular endothelial growth factor (VEGF) [204][205][206][207], glutamate [208][209][210], endothelins (ETs) [21,211,212], MMP [208,213,214], and nitric oxide (NO) [215,216] (Table 1). As zincendopeptidases, MMPs can directly degrade endothelial tight junction-related proteins and ECM molecules, which promotes angiogenesis whereas simultaneously increases BBB permeability [78,217,218].…”

Section: The Bbb Integrity-suppressing Effects Of Astrocytesmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocytederived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporalenvironment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies.

“…On the other hands, VEGFs are also well-established to promote BBB permeability. For example, exogenous treatment with VEGF in animals and in cultured brain microvessel endothelial cells caused increased BBB permeability [35,36], while treatment with an anti-VEGF neutralizing antibody reduced BBB leakage (Evans blue staining) in cerebral ischemia/reperfusion [37] and focal TBI by fluid percussion injury (FPI) [12] animal models. Inhibition of VEGF signaling by SU5416, a VEGF receptor-2 inhibitor, and specific VEGF receptor-2 knockdown, also reduced BBB disruption after permanent ischemic damage by thrombosis [38].…”

Section: Regulation Of Bbb Function By Astrocyte-derived Factorsmentioning

confidence: 99%

Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

Michinaga

Kōyama

2019

IJMS

206

143

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.