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Glaucoma is one of the leading causes of vision loss worldwide. More and more studies have suggested that glaucoma is a complicated retinal neurovascular disease. The homeostasis imbalance of retinal neurovascular unit(RNVU)composed of neurons, glial cells and microvascular cells not only induces changes in microvascular structure and glial cells, but also affects the nerve tissue of the retina, resulting in vision loss, which there is no effective treatment to reverse, currently. Exploring the cellular composition and molecular structure of RNVU and investigating the destruction mechanism of normal cellular environment and intercellular connections in glaucoma are of great significance in exploring the pathogenesis and the treatment of glaucoma. The research progress on structural changes and dysfunction of RNVU in glaucoma are reviewed, hoping to provide new ideas for the treatment of glaucoma.
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Based on the neurovascular unit(NVU), neurovascular coupling functions as a barrier to maintain the homeostasis of the microenvironment by regulating the signaling and metabolic activity of nerve cells and capillaries. Widely dispersed across the retina, the NVU is essential to preserving its normal physiological function. A disturbance in retinal neurovascular homeostasis produced by a range of factors can result in a variety of retinal disorders, such as diabetic retinopathy(DR), glaucoma, retinitis pigmentosa(RP)and age-related macular degeneration(ARMD). The retina also has a widespread distribution of brain-derived neurotrophic factor(BDNF), which functions to promote neuron growth and repair damage by binding to its receptor TrkB. In recent years, BDNF was found to play a protective role against damage in the early stage of retinal neurovascular homeostasis imbalance, often known as the neurodegenerative stage. It also helps to reduce the production of pro-angiogenic substances of neurological origin and offers a fresh approach for the early detection and treatment of associated eye disorders.
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The concept of neurovascular unit(NVU), formalized in 2001 at a stroke conference, emphasizes the intimate relationship between the brain and its vessels, i.e., symbiotic relationship between brain cells and cerebral blood vessels in the developmental, structural and functional interdependence. The retina is a piece of brain. Several researchers have introduced the concept of NVU to the retina since 2007. The NVU in the retina includes neurons, glial cells, microvascular endothelial cells and pericytes. Dysfunctional NVU plays a critical role in diabetic retinopathy(DR). The current limited treatments for DR focus on the late-stage complications, i.e., diabetic macular edema and proliferative DR. While the further study on retinal NVU will develop efficacious therapeutic options for the early and all stages of DR.
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A complex pathophysiological mechanism is involved in the brain injury following cerebral infarction. The neurovascular unit (NVU) is a complex multi-cellular structure consisting of endothelial cells , neurons, glia, smooth muscle cells, and pericytes. The dyshomeostasis of NVU directly participates in the inflammatory immune regulation process. The components of NVU promote inflammatory overreaction and also synergize with the overactivation of autonomic nervous system to initiate stroke-induced immunosuppression (SIID). SIID can alleviate the damage caused by inflammation, however, it also makes stroke patients more susceptible to infection, leading to systemic damage and worsening the condition. This article reviews the mechanism of SIID and the roles of NVU components in SIID, to provide a perspective for recanalization, prognosis and immune regulation therapy of cerebral infarction.
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Diabetic retinopathy(DR)is a neurovascular disease caused by the neurovascular unit(NVU)impairment. Immune imbalance and inflammation are key factors that affect the normal function of NVU and lead to the progression of DR. Nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome is indicated as an important component of the inflammatory response, and it can identify endogenous danger signals, leading to the activation of caspase-1 and then activating a series of inflammatory cytokines and pyroptosis. Early activation of inflammasome maintains and promotes innate immunity against bacterial and viral infections, while excessive inflammasome activation results in excessive expression and ongoing action of inflammatory proteins, which in turn triggers off immune disorders and an inflammatory cascade that seriously harms the body. This review summarizes the recent research progress on the mechanism of NLRP3 inflammasome in NVU impairment of DR, including the related drugs targeting NLRP3 pathways.
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Diabetic retinopathy(DR), one of the common complications of diabetes, is a major cause of blindness. Traditionally, DR has been considered primarily a microvascular disease, and as research has progressed, it is now believed that disruption of the neuro-glia-vascular unit(NVU)and imbalance in its coupling mechanisms(coupling)play a key role in the early onset of DR. Understanding the cellular and molecular basis of NVU and how diabetes alters normal cellular communication and disrupts the cellular environment is important for the early prevention and treatment of DR. This paper summarizes the retinal NVU and its involvement in the molecular mechanism of DR pathogenesis, DR treatment based on retinal NVU repair, and discusses the future prospects and problems of DR.
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Neurovascular unit (NVU) refers to a functional complex of neural cells and vasculature, which plays an important role in maintaining retinal homeostasis and matching metabolic demands. In physiological situation, retinal NVU mainly exerts two effects: (1) maintaining blood-retinal barrier for retinal homeostasis maintenance; (2) regulating local blood flow to meet metabolic and functional demands of the retina. The pathological changes in retinal diseases are reflected in each functional part of retinal NVU, including cell-cell connections, signal pathways, metabolic activities and cellular functions. However, the main pattern and manifestation of NVU impairment differs among retinal diseases due to different etiologies. At present, understanding on retinal NVU is still insufficient, and its clinical application is even more limited. Further application in the diagnosis and treatment of retinal diseases is an important direction for future research on NVU.
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ObjectiveTo investigate the protective effect of Liuwei Dihuangwan on neurovascular injury in SAMP8 mice. MethodThe Alzheimer's disease （AD） model with insufficiency of kidney essence was induced in 75 SAMP8 mice aging 6 months. The model mice were divided into model group， positive control group （donepezil hydrochloride， 0.747 mg·kg-1·d-1）， and high-， medium-， and low-dose Liuwei Dihuangwan groups （2.700， 1.350， 0.675 g·kg-1·d-1）， with 15 mice in each group. Fifteen SAMR1 mice were assigned to a normal control group. All mice were administered continuously for 2 months. The spatial memory of mice was tested by the Morris water maze. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the hippocampus and cortex of brain tissues. The immunohistochemical method （IHC） was used to detect the deposition of amyloid β-protein （Aβ） and the expression of von Willebrand factor （vWF） and CD34 in the hippocampus and cortex of brain tissues. Electron microscopy was used to observe the ultrastructural changes in cerebral microvessels. Western blot was used to detect the protein expression levels of the receptor of advanced glycation endproduct （RAGE）， low-density lipoprotein receptor-related protein 1 （LRP1）， vascular endothelial growth factor A （VEGF-A）， and P-selection in the hippocampus and cortex of brain tissues. ResultCompared with the normal control group， the model group showed prolonged escape latency and swimming distance （P<0.01）， increased number of glial cells， decreased number of nerve cells， blurred tight junctions or enlarged gap of the brain microvascular endothelial cells， severely injured membrane structure， swollen mitochondria of endothelial cells， ruptured membrane， massive dissolution in cristae， increased protein expression of Aβ and vWF in the hippocampus and cortex （P<0.01）， reduced protein expression of CD34 （P<0.05）， elevated protein expression of RAGE and P-selection in the cortex （P<0.01）， and decreased protein expression level of LRP1 and VEGF-A （P<0.01）. Compared with the model group， the Liuwei Dihuangwan groups showed shortened escape latency and swimming distance （P<0.05）， reduced number of glial cells in the cortex and hippocampus， increased number of microvessels in the cortex， clear double-layer membrane structure in tight junctions between the microvascular endothelial cells， increased number of mitochondria with intact membrane and recovered mitochondrial cristae， decreased protein expression of Aβ， vWF， RAGE， and P-selection in the hippocampus and cortex （P<0.05）， and increased protein expression of CD34， LRP1， and VEGF-A （P<0.05）. ConclusionLiuwei Dihuangwan can regulate Aβ metabolism through the RAGE/LRP1 receptor system and promote cerebral microvascular angiogenesis by inhibiting vWF expression and increasing VEGF-A and CD34， thereby improving cerebral microvascular injury in SAMP8 mice.
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@#Diabetic retinopathy(DR)is the most common complication of diabetes mellitus and remains the leading cause of blindness in working-age population. DR affects almost all the retinal cells, leading to the disruption and dysfunction of neurovascular unit and the neural-glial network. Erythropoietin(EPO), a glycoprotein hormone, plays a pivotal role in neuroprotection, neurotrophy, anti-inflammation, anti-apoptosis and anti-oxidation <i>etc.</i>, in various central nervous system diseases. This review discussed the protective effect of EPO in DR so as to provide new options for DR treatment.
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OBJECTIVE：To obs erve the protective effect of protoca techuic aldehyde（PAL）on neurovascular unit （NVU） homeostasis damage in rats after cerebral ischemia-reperfusion injury （CIRI）. METHODS ：SD rats were randomly divided into sham operation group ，model group ，PAL high-dose and low-dose groups （10，20 mg/kg），with 11 rats in each group. Administration groups were given relevant medicine intragastrically. Sham operation group and model group were given the same volume of normal saline intragastrically ，10 mL/kg once a day ，for 5 days. After last administration ，CIRI model was induced by suture method ；the ultrastructural changes of NVU were observed by transmission electron microscope. Western blot assay was used to detect the expression of NUV related proteins （MAP-2，GFAP，AQP-4）in cerebral tissue. Immunofluorescence staining was used to observe the positive expression of above proteins in cerebral cortex. RESULTS ：Compared with sham operation group ， blood-brain barrier （BBB）structure of model group was destroyed severely ，the vascular lumen became narrower ，lateral edema of endothelial cells was severe ，and the thickness of basement membrane varied ；the nuclei of neurons were pyknosis and there was a large area of edema in the surrounding tissues ；the structure of glial cells was seriously damaged ，the cell body was shrunk and organelles were lost ；protein expression （or positive expression ）of MAP- 2 in brain tissue （or cerebral cortex ）were significantly decreased （P＜0.05 or P＜0.01），while protein expression （or positive expression ） of GFAP and AQP- 4 were increased significantly（P＜0.01）. After PAL intervention ，the rats had less BBB damage ，and the morphology of vascular lumen and basement membrane were not completely destroyed ；the damage of neurons was alleviated ，the pyknosis of neurons was decreased ， the chromatin was homogeneous and the heterochromatin was decreased；the damage of glial cell structure was alleviated protein expression of GFAP and AQP- 4（except for low-dose group） in cerebral tissue and positive expression of MAP- 2 and GFAP protein in cerebral cortex were reversed @qq.com significantly （P＜0.05 or P＜0.01）. CONCLUSIONS ：PAL can protect the stability of NVU from damage in CIRI model rats； the mechanism may be related to up-regulating the expression of MAP- 2 protein in cerebral cortex and down-regulating the expression of GFAP and AQP- 4 protein in brain tissue.
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Buyang Huanwu Decoction, a representative prescription in traditional Chinese medicine(TCM) for tonifying Qi and activating blood, has been proved to be effective in preventing and treating acute cerebral infarction(ACI). It consists of Astragali Radix, Angelicae Sinensis Radix, Paeoniae Radix Rubra, Pheretima, Chuanxiong Rhizoma, Carthami Flos, and Persicae Semen, possessing multiple active ingredients. The neurovascular unit is a functionally and structurally interdependent multicellular complex composed of neurons-glial cells-blood vessels. It plays an important role in the pathological changes of cerebral ischemia and the permeability variation of the blood-brain barrier. In recent years, Buyang Huanwu Decoction has been found to protect the integrity of neurovascular units and improve the permeability of the blood-brain barrier, thereby alleviating stroke and other diseases caused by cerebral ischemia. This paper collated and summarized the protective effects of Buyang Huanwu Decoction on neurovascular units.
Subject(s)
Humans , Brain Ischemia/drug therapy , Cerebral Infarction , Drugs, Chinese Herbal , Medicine, Chinese TraditionalABSTRACT
RNA methylation is of great significance in the regulation of gene expression, among which the more important methylation modifiers are N6-methyladenosine (m6A) and 5-methylcytosine (m5C). The methylation process is mainly regulated by 3 kinds of proteins: methyltransferase, demethylase, and reader. m6A, m5C, and their related proteins have high abundance in the brain, and they have important roles in the development of the nervous system and the repair and remodeling of the vascular system. The neurovascular unit (NVU) is a unit of brain structure and function composed of neurons, capillaries, astrocytes, supporting cells, and extracellular matrix. The local microenvironment for NVU has an important role in nerve cell function repair, and the remodeling of NVU is of great significance in the prognosis of various neurological diseases.
Subject(s)
5-Methylcytosine , Adenosine/metabolism , Methylation , Methyltransferases/metabolism , RNAABSTRACT
Objective: To investigate the protective effects and mechanism of Zuogui Jiangtang Jieyu Formulation (ZGF) on hippocampal neuron of neurovascular unit (NVU) induced by autophagy in diabetes mellitus with depression (DD). Methods Hippocampal neurons, astrocytes and brain microvascular endothelial cells from SD rats were primitively isolated, purified and cultured, and then immunocytochemistry staining was employed to identify primitive cells. The DD model of NVU was established by applying intervention of high glucose (150 mmol/L) and cortisone (200 μmol/L) after co-culture system was built in vitro. The cultured cells were randomly divided into normal group, blank serum group, model group, and medicated serum of ZGF group. Intracellular calcium levels (Ca2+) on hippocampal neuron of NVU was detected by Furo-3/AM staining. The expression of autophagy marker Beclin-1, LC3-II, and GluR2/Ca2+/mTOR signaling pathway key proteins was detected by high content analysis. The apoptosis of hippocampal neurons was observed by Tunel staining. Results:Compared with the normal group, Ca2+ levels was remarkably increased, expression of autophagy marker Beclin-1 and LC3-II was dramatically up-regulated, proteins expression of GluR2 and mTOR was obviously down-regulated while AMPK up-regulated, and the apoptosis in hippocampal neuron of NVU was significantly increased in model and blank serum group. Compared with the model group, intracellular calcium levels was obviously decreased, expression of autophagy marker Beclin-1 and LC3-II was down-regulated, GluR2/Ca2+/mTOR signaling pathway proteins expression of GluR2, mTOR was up-regulated while AMPK down-regulated, furthermore the apoptosis of hippocampal neurons was significantly decreased in ZGF group. Conclusion: ZGF has significant protective effects on hippocampal neuron of NVU induced by autophagy in DD, and its mechanism is related to the GluR2/Ca2+/mTOR signaling pathway and apoptosis.
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OBJECTIVE: To observe the effect of eye-acupuncture intervention on cerebro-cortical apoptosis of microvascular endothelial cells, neurons and astrocytes (main components of neurovascular unit) and the expression of Bad (an apoptosis promoter) and B-cell lymphoma-extra large(Bcl-xL) proteins in focal cerebral ischemia-reperfusion injury (CIRI) rats, so as to explore its mechanisms underlying improvement of CIRI. METHODS: SD rats were randomly divided into control, sham-operation, model 3 h, model 24 h, model 72 h, eye-acupuncture 3 h, eye-acupuncture 24 h and eye-acupuncture 72 h groups(n＝12 in each group). The CIRI model was established by middle cerebral artery occlusion/reperfusion (MCAO/R). Eye-acupuncture was applied to bilateral "Gan" (Liver) regions, "Shen" (Kidney) regions, "Shangjiao" (Upper-energizer) and "Xiajiao" (Lower-energizer) for 20 min, once 3 h and every 12 h after modeling. The expression levels of Bad and Bcl-xL in the ischemic cerebral cortex tissue were detected by Western blot. The apoptotic neurons, microvascular endothelial cells and astrocytes were assayed by immunofluorescence double labeling (Nestin/TUNEL, CD34/TUNEL and glial fibrillary acidic protein [GFAP]/TUNEL) separately. RESULTS: After modeling, the numbers of apoptotic neurons, microvascular endothelial cells and astrocytes in the ischemic cerebral cortex tissue were significantly increased in the model 72 h group than in the sham-operation group (P<0.01). Following the treatment, the numbers of the 3 types of apoptotic cells were markedly lower in the eye-acupuncture 72 h group than in the model 72 h group(P<0.01). The expression levels of Bad and Bcl-xL proteins were notably up-regulated in the model 3 h, model 24 h and model 72 h groups than in the sham operation group(P<0.01). Following eye-acupuncture intervention, modeling induced increase of the Bad expression were obviously reversed in eye-acupuncture 24 h and eye-acupuncture 72 h groups than those in the 2 model groups(P<0.05). And the increase of Bcl-xL expression levels were further increased in the eye-acupuncture groups in comparison with those in the 3 model groups (P<0.01). CONCLUSION: Eye-acupuncture can down-regulate the expression of Bad protein, and up-regulate the expression of Bcl-xL protein in the ischemic cerebral cortex in CIRI rats, which may contribute to its function in reducing apoptotic neurons, microvascular endothelial cells and astrocytes, suggesting a protective effect of eye-acupuncture intervention on neurovascular unit.
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Ischemic stroke is a type of clinical syndrome caused by brain blood supply disorders due to various cerebrovascular diseases, which lead to local cerebral ischemia, hypoxic necrosis, and corresponding neurological defects. In recent years, the neurovascular unit mechanism of ischemic stroke has been proposed in modern medicine. With the principles of syndrome differentiation-based treatment and holistic view in traditional Chinese medicine, acupuncture has the advantage of multi-target and multi-link effect and good clinical efficacy on this disease, and current studies have shown that acupuncture has a marked effect on each component and the whole of neurovascular unit. This article reviews the effect of acupuncture on the regulation of blood-brain barrier, astrocytes, microglial cells, neurons, and neurovascular units.
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Pericytes, endothelial cells (EC), astrocytes and extracellular space together constitute the blood-brain barrier. Pericytes and EC participate in the various regulations of blood-brain barriers through many mechanisms to maintain the stability of neurovascular units (NVU). The injury and repair of NVU involve a lot of signal transduction at molecular levels, and angiogenesis is primarily about the generation and maturation of EC and the supporting adhesion process of pericytes. This article briefly reviewed EC-related angiogenesis signaling pathways in pericytes after NVU ischemic injury.
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Pericytes, endothelial cells (EC), astrocytes and extracellular space together constitute the blood-brain barrier. Pericytes and EC participate in the various regulations of blood-brain barriers through many mechanisms to maintain the stability of neurovascular units (NVU). The injury and repair of NVU involve a lot of signal transduction at molecular levels, and angiogenesis is primarily about the generation and maturation of EC and the supporting adhesion process of pericytes. This article briefly reviewed EC-related angiogenesis signaling pathways in pericytes after NVU ischemic injury.
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Carbon monoxide (CO) is a gaseous molecule produced from heme by heme oxygenase (HO). Endogenous CO production occurring at low concentrations is thought to have several useful biological roles. In mammals, especially humans, a proper neurovascular unit comprising endothelial cells, pericytes, astrocytes, microglia, and neurons is essential for the homeostasis and survival of the central nervous system (CNS). In addition, the regeneration of neurovascular systems from neural stem cells and endothelial precursor cells after CNS diseases is responsible for functional repair. This review focused on the possible role of CO/HO in the neurovascular unit in terms of neurogenesis, angiogenesis, and synaptic plasticity, ultimately leading to behavioral changes in CNS diseases. CO/HO may also enhance cellular networks among endothelial cells, pericytes, astrocytes, and neural stem cells. This review highlights the therapeutic effects of CO/HO on CNS diseases involved in neurogenesis, synaptic plasticity, and angiogenesis. Moreover, the cellular mechanisms and interactions by which CO/HO are exploited for disease prevention and their therapeutic applications in traumatic brain injury, Alzheimer’s disease, and stroke are also discussed.
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Humans , Astrocytes , Brain Injuries , Carbon Monoxide , Carbon , Central Nervous System , Central Nervous System Diseases , Endothelial Cells , Heme , Heme Oxygenase (Decyclizing) , Homeostasis , Mammals , Microglia , Neural Stem Cells , Neurogenesis , Neuronal Plasticity , Neurons , Pericytes , Regeneration , Stroke , Therapeutic UsesABSTRACT
The concept of neurovascular units studies the interaction between neural cells and blood vessels, regards the blood-brain barrier as the core,and relates with the neurodegenerative diseases.This paper reviewed the relationship be-tween neurovascular units and neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease,multiple sclerosis,etc.
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Chronic cerebral hypoperfusion (CCH) may result in neurovascular unit (NVU) injury,causing cognitive impairment.The NVU consists of neurons,glial cells,vascular cells and extracellular matrix.The damage of NVU can induce the blood-brain barrier dysfunction,abnormal cell signaling,as well as cognitive impairment.However,its molecular mechanism is unclear.Thus,investigating the role of NUV in CCH-induced cognitive impairment may provide a theoretical basis for the novel treatment of cognitive impairment.