Cerebral Angiogenesis Research Articles

Effects of mesencephalic astrocyte-derived neurotrophic factor on cerebral angiogenesis in a rat model of cerebral ischemia

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum stress-related protein that exhibits neuroprotective effects. Recent studies have shown that MANF promotes poststroke functional recovery in rats. However, the underlying mechanisms have not yet been fully understood. Here, we examined the effects of MANF on cerebral angiogenesis in a permanent middle cerebral artery occlusion model in rats. Recombinant human MANF was administered intracerebroventricularly 24 h after stroke. We performed neurobehavioral tests and assessed microvessel density, functional microvessels, and regional cerebral blood flow (rCBF), as well as detected angiogenic factors in the peri-infarct cerebral cortex. Results showed that MANF ameliorated neurobehavioral scores, promoted rCBF, upregulated the expression of CD34, as well as the total vessel surface area and the number of microvessel branch points, and activated the vascular endothelial growth factor (VEGF) pathway. In conclusion, our findings provide insight into the mechanisms of MANF in promoting functional recovery from ischemic stroke. Our results suggest that MANF improves neurobehavioral recovery from cerebral ischemic injury, and that this effect is mediated partly by its proangiogenic effects and augmentation of rCBF, which are possibly associated with VEGF.

Atg7 Silencing Inhibits Laminin-5 Expression to Suppress Tube Formation by Brain Endothelial Cells.

Cerebral angiogenesis is a key event during brain development and recovery from brain injury. We previously demonstrated that Atg7 knockout impaired angiogenesis in the mouse brain. However, the role of Atg7 in angiogenesis is not completely understood. In this study, we used human brain microvascular endothelial cells (HBMECs) to investigate the mechanism of Atg7-regulated cerebral angiogenesis. We found that Atg7 depletion specifically diminished the expression of the β3 and γ2 chains of laminin-5, a major component of the extracellular matrix. In contrast, autophagy inhibitors did not affect laminin-5 expression, suggesting that Atg7-regulated laminin-5 expression is autophagy-independent. We also found that Atg7-regulated laminin-5 expression occurred at the transcriptional level through NF-κB signaling. Exogenous laminin-5 or the NF-κB agonist betulinic acid effectively rescued tube formation by Atg7-deficient HBMECs. Taken together, our study identified a novel mechanism by which Atg7 regulates laminin-5 expression via NF-κB to modulate tube formation by brain endothelial cells during cerebral angiogenesis. Anat Rec, 302:2255-2260, 2019. © 2019 American Association for Anatomy.

Ginsenoside Rg1 promotes cerebral angiogenesis via the PI3K/Akt/mTOR signaling pathway in ischemic mice

Angiogenesis plays an important role in the remodeling process of the ischemic brain and the recovery of neurological function after ischemic stroke. Ginsenoside Rg1 has been reported to exert neuroprotective effects on the central nervous system. However, the effects of ginsenoside Rg1 on cerebral angiogenesis in cerebral ischemia remained unclear. The current study aimed to investigate the potential protective effects of ginsenoside Rg1 on cerebral angiogenesis as well as its underlying mechanisms. Mice were subjected to treatment with vehicle or ginsenoside Rg1 daily for 14 d beginning at 24 h after distal middle cerebral artery occlusion (dMCAO). Compared with the dMCAO group, ginsenoside Rg1 improved the neurobehavioral outcomes and reduced the brain infarct volume. Ginsenoside Rg1 treatment increased the expression of the cluster of differentiation 31 (CD31), bromodeoxyuridine+/CD31+ microvessels and GFAP-positive vessels in the peri-infarct cortex. The expression of VEGF was significantly enhanced in ginsenoside Rg1 group. In vitro, human brain microvascular endothelial (hCMEC/D3) cells was successfully cultured, and oxygen and glucose deprivation (OGD) model was established. Ginsenoside Rg1 significantly increased proliferation, migration and tube formation of endothelial cells after OGD, as well as upregulated the expressions of VEGF, HIF-1α, PI3K, p-Akt, and p-mTOR. Furthermore, administration of PI3K/Akt/mTOR signaling pathway inhibitor LY294002 abolished the beneficial effects of ginsenoside Rg1. In conclusion, ginsenoside Rg1 promoted cerebral angiogenesis through increasing the expression of VEGF via PI3K/Akt/mTOR signaling pathway after ischemic stroke.

Ginsenoside F1 promotes angiogenesis by activating the IGF-1/IGF1R pathway

Ischemic stroke is one of the most lethal and highly disabling diseases that seriously affects the human health and quality of life. A therapeutic angiogenic strategy has been proposed to alleviate ischemia-induced injury by promoting angiogenesis and improving cerebrovascular function in the ischemic regions. The insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF1R) axis is crucial for cerebral angiogenesis and neurogenesis. However, effective drugs that prevent cerebral ischemic injury by inducing cerebral angiogenesis via activation of the IGF1R pathway are lacking. Here, we screened a pro-angiogenic agent ginsenoside F1 (GF1), a ginseng saponin isolated from a traditional Chinese medicine that was widely used in ischemic stroke treatment. It promoted the proliferation, mobility and tube formation of human umbilical vein endothelial cells and human brain microvascular endothelial cells, as well as pericytes recruitment to the endothelial tubes. GF1 stimulated vessel sprouting in the rat arterial ring and facilitated neovascularization in chicken embryo chorioallantoic membrane (CAM). In the in vivo experiments, GF1 rescued the axitinib-induced vascular defect in zebrafish. It also increased the microvessel density (MVD) and improved focal cerebral blood perfusion in the rat middle cerebral artery occlusion (MCAO) model. Mechanism studies revealed that GF1-induced angiogenesis depended on IGF1R activation mediated by the autocrine IGF-1 loop in endothelial cells. Based on our findings, GF1-induced activation of the IGF-1/IGF1R pathway to promote angiogenesis is an effective approach to alleviate cerebral ischemia, and GF1 is a potential agent that improves cerebrovascular function and promotes recovery from ischemic stroke.

Pericytes in Alzheimer's Disease: Novel Clues to Cerebral Amyloid Angiopathy Pathogenesis.

Pericytes in the central nervous system attract growing attention of neurobiologists because of obvious opportunities to use them as target cells in numerous brain diseases. Functional activity of pericytes includes control of integrity of the endothelial cell layer, regeneration of vascular cells, and regulation of microcirculation. Pericytes are well integrated in the so-called neurovascular unit (NVU) serving as a platform for effective communications of neurons, astrocytes, endothelial cells, and pericytes. Contribution of pericytes to the establishment and maintaining the structural and functional integrity of blood-brain barrier is confirmed in numerous experimental and clinical studies. The review covers current understandings on the role of pericytes in molecular pathogenesis of NVU/BBB dysfunction in Alzheimer's disease with the special focus on the development of cerebral amyloid angiopathy, deregulation of cerebral angiogenesis, and progression of BBB breakdown seen in Alzheimer's type neurodegeneration.

Pentraxin 3 promotes long-term cerebral blood flow recovery, angiogenesis, and neuronal survival after stroke

Restoration of cerebral blood flow (CBF) and upregulation of angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia. Pentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke. Here, we investigated for the first time the role of PTX3 in long-term CBF, angiogenesis, and neuronal viability after ischaemic stroke induced by transient middle cerebral artery occlusion (MCAo). Lack of PTX3 had no effect on early brain damage, but significantly impaired restoration of CBF, 14 and 28 days after MCAo, compared to wild-type (WT) mice. Immunohistochemical analysis revealed that PTX3 KO mice have significantly greater neuronal loss, significantly decreased vessel diameter, vessel proliferation, vascular density, and reactive astrocytes and decreased expression of vascular endothelial growth factor receptor 2 (VEGR2), vascular extracellular matrix (ECM)-proteins (collagen IV, laminin), and integrin-β, in the ipsilateral (stroke) hemisphere compared to WT mice, 28 days after MCAo. Therefore, PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia. Collectively, these findings demonstrate the potential and clinical relevance of PTX3 as a promising therapeutic target, providing sustained long-term post-stroke neurovascular repair and reducing the loss of neurons.Key messagesPentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke.Restoration of cerebral blood flow (CBF) and angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia.PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia.

A Mesenchymal stem cell line (B10) increases angiogenesis in a rat MCAO model

A human mesenchymal stem cell line (B10) transplantation has been shown to improve ischemia-induced neurological deficits in animal stroke models. To understand the underlying mechanism, we have investigated the effects of B10 transplantation on cerebral angiogenesis in a rat middle cerebral artery occlusion (MCAO) model. B10 cells were transplanted intravenously 24 h after MCAO. Immunofluorescence staining results showed that compared to PBS-groups, vWF positive vessel and endoglin positive new vessels were increased in B10-transplanted MCAO groups in the lesion areas. The mRNA of angiogenesis factors including placental growth factor and hypoxia inducible factor (HIF)-1α were increased 3 days after MCAO in the core and IBZ areas of B10-transplanted group. Angiopoetin1 mRNA was increased only in the IBZ. Western blotting results showed that HIF-1α and vascular endothelial growth factor (VEGF) proteins were increased in B10-transplanted group. Both HIF-1α and VEGF were expressed in macrophage/microglia in the core area. In the IBZ, however, HIF-1α was expressed both in astrocytes and macrophage/microglia, while VEGF was expressed only in macrophage/microglia. Moreover, TGFβ protein levels were found to be increased in B10-transplanted group in the core and IBZ regions. Cell culture experiments using a human microglia cell line (HMO6) and B10 showed that IL-1β induced VEGF mRNA expression in both cell types. IL-1β was found to be highly expressed in B10 cells, and its co-culture with HMO6 further increased that in B10. Co-culture increased VEGF mRNA in both B10 and HMO6. In the rat brains, IL-1β was expressed in macrophage/microglia and transplanted-B10 cells in the core. IL-1β positive cell number was increased slightly, but significantly in B10-transplanted rats. To explore further, IL-1β expression was silenced in B10 cells by transfecting mRNA specific siRNA, and then transplanted in MCAO rats. Immunostaining result showed that endoglin positive area was decreased in IL-1β-silenced B10 transplanted groups compared to nonsilenced-B10 transplanted groups. Interestingly, vessel-like structure appeared as early as 3 days after MCAO in IL-1β-silenced B10-transplanted group. Thus our results demonstrated that B10 cells increased angiogenesis in MCAO rat model, through the regulation of HIF-1α and VEGF expression, where IL-1β might play a role.

Vitamin D3 promotes cerebral angiogenesis after cerebral infarction in rats by activating Shh signaling pathway.

This study aims at investigating the neuroprotective role of Vitamin D3 (VitD3) in rats with cerebral infarction and its molecular mechanisms. Male Sprague- Dawley (SD) rats were selected and randomly divided into sham operation group, middle cerebral artery occlusion (MCAO) model group, and VitD3 treatment group. The therapeutic effect of VitD3 was evaluated via neurobehavioral scoring and triphenyltetrazolium chloride (TTC) staining. For the evaluation of VitD3 influence on cerebral blood perfusion, Micro-PET imaging technique was applied. The mRNA levels of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) gene were detected via Real-Time Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Immunofluorescence staining assay was employed to determine the changes in micro-vessel density. Bromodeoxyuridine (Brdu) assay was used to count the number of new vascular endothelial cells. Protein expressions of key genes in the Shh signaling pathway were detected by Western blotting. Our results showed that VitD3 improved the score of neurological function and decreased the size of cerebral infarction in MCAO rats. VitD3 improved cerebral perfusion in the ischemic area after MCAO. VitD3 up-regulated levels of vascular growth-related factors. VitD3 elevated micro-vessel density after cerebral infarction and promoted the proliferation of vascular endothelial cells in the ischemic cortex. The sonic hedgehog (Shh) signaling pathway in the ischemic cortex of MCAO rats was activated after VitD3 treatment. We showed that VitD3 improves cerebral perfusion and reduces neurological impairment in MCAO rats via activating the Shh signaling pathway.

Chronic Cerebral Hypoperfusion Induces Alterations of Matrix Metalloproteinase-9 and Angiopoietin-2 Levels in the Rat Hippocampus

Angiogenic factors contribute to cerebral angiogenesis following cerebral hypoperfusion, and understanding these temporal changes is essential to developing effective treatments. The present study examined temporal alterations in angiogenesis-related matrix metalloproteinase-9 (MMP-9) and angiopoietin-2 (ANG-2) expression in the hippocampus following bilateral common carotid artery occlusion (BCCAo). Male Wistar rats (12 weeks of age) were randomly assigned to sham-operated control or experimental groups, and expression levels of MMP-9 and ANG-2 were assessed after BCCAo (1 week, 4 weeks, and 8 weeks), using western blotting. Protein expression increased 1 week after BCCAo and returned to control levels at 4 and 8 weeks. In addition, immunofluorescence staining demonstrated that the MMP-9- and ANG-2-positive signals were primarily observed in the NeuN-positive neurons with very little labeling in non-neuronal cells and no labeling in endothelial cells. In addition, these cellular locations of MMP-9- and ANG-2-positive signals were not altered over time following BCCAo. Other angiogenic factors such as vascular endothelial growth factor and hypoxia-inducible factor did not differ from controls at 1 week; however, expression of both factors increased at 4 and 8 weeks in the BCCAo group compared to the control group. Our findings increase understanding of alterations in angiogenic factors during the progression of cerebral angiogenesis and are relevant to developing effective temporally based therapeutic strategies for chronic cerebral hypoperfusion-associated neurological disorders such as vascular dementia.

Effects of treadmill exercise on cerebral angiogenesis and MT1-MMP expression after cerebral ischemia in rats.

IntroductionDespite the increased understanding of treadmill training on angiogenesis of stroke patients, its mechanism is not clearly known. The metalloproteinase membrane type 1‐metalloprotease (MT1‐MMP) promotes the regeneration of the peripheral vessels but seldom research on the regeneration of cerebral blood vessels. This study was designed to investigate the effects of treadmill exercise on angiogenesis and MT1‐MMP expression after cerebral ischemia in rats.MethodsThe adult male Sprague Dawley(SD) rats were randomly divided into three groups: sham operation group, the middle cerebral artery occlusion group(MCAO) and middle cerebral artery occlusion group(MCAO)+exercise group. In 4d, 7d or 14d after MCAO, respectively, the rats’ neurological function was evaluated by the modified neurologic severity scores (mNSS); the microvessel numbers in areas surrounding cerebral ischemia were counted with Microvessel Density(MVD)analysis; the levels of MT1‐MMP and reversion‐inducing cysteine‐rich protein with Kazalmotifs (RECK) were detected by Western‐blot and immunohistochemical method.ResultsCompared with MCAO group, the number of capillaries and the level of MT1‐MMP expression around the area of cerebral ischemia were significantly increased in each exercise group (p < 0.05), while the level of RECK expression and the scores of mNSS in each exercise group were significantly decreased (p < 0.05).ConclusionThis study suggested that treadmill exercise training can significantly promote angiogenesis and improve neurological function after cerebral ischemia. Its mechanism may be related to the upgraduation of the MT1‐MMP expression in brain microvessels surrounding area of the ischemic rat.

Enrichment of miR-126 Boosts the Therapeutic Effects of Endothelial Progenitor Cells Derived Exosomes on Ischemic Stroke in Diabetic Mice

We have demonstrated that endothelial progenitor cell (EPCs) have therapeutic effects on ischemic stroke in diabetic mice and that microRNA (miR)-126 modulates the function of EPC through vascular endothelial growth factor receptor 2 (VEGFR2) pathway in cell culture studies. Here, we determined the effects of EPC-released exosomes (EPC-EXs) on ischemic stroke in diabetic mice and tested whether miR-126 enriched EPC-EXs (EPC-EXsmiR126) could have enhanced efficacy. Type 2 diabetic mice subjected to filament-induced focal ischemic stroke were intravenously administrated with vehicle, or PKH26 labelled EPC-EXs or EPC-EXsmiR-126. The neurological deficit score (NDS), cerebral blood flow (CBF), infarct volume, cerebral microvascular density (MVD), cell death, angiogenesis and neurogenesis, and levels of miR-126, VEGFR2 and cleaved caspase-3 were measured. We found: 1) Injected EPC-EXs merged with brain endothelial cells, neurons and astrocytes dominantly in the peri-infarct area; 2) EPC-EXsmiR126 were more effective than EPC-EXs in decreasing NDS, ischemic damage and cell death, and increasing CBF and MVD on both day 2 and 14, and in promoting angiogenesis and neurogenesis on day 14; 3) These effects were accompanied with down-regulated cleaved caspase-3 on day 2 and prolonged VEGFR2 up-regulation till day 14. The data suggest that transfusion of EPC-EXsmiR126 has enhanced therapeutic efficacy on ischemic stroke in diabetic mice by attenuating acute injury and promoting neurological function recovery. Disclosure J. Wang: None. Q. Pan: None. H. Liu: None. B. Zhao: None. Y. Yang: None. X. Ma: None. J. Bihl: None.

High intensity exercise preconditioning provides differential protection against brain injury following experimental stroke

AimsDifferent modes of physical activity provide cerebrovascular protection against thromboembolic events. Based on recent reports high intensity exercise protocols appear to raise cerebral VEGF levels leading to efficient cerebral angiogenesis. The present study aims to address if moderate continuous training (MCT) and high intensity interval training (HIT) differ in preconditioning against ischemic stroke. MethodsWistar rats were subjected to HIT or MCT for 8 weeks before transient middle cerebral artery occlusion (tMCAO) surgery. As indexes for improved angiogenic signals, VEGF-A and its pivotal receptor VEGF-R2 were immunoblotted just before occlusive stroke. Key findingsBoth training protocols induced a remarkable protection against neurological deficit and tissue injury following stroke. Cerebral infarctions were better improved in HIT animals which explained the slightly but not significantly higher neurological function. HIT brains developed higher levels of cortical VEGF-A and striatal VEGF-R2. SignificanceThese data conclude preconditioning with high intensity protocols might excel continued moderate exercise to induce VEGF signaling and alleviate stroke outcomes. Further investigations may provide complementary mechanistic views.

Neurovascular dysfunction in dementia - human cellular models and molecular mechanisms.

From the earliest stages of development, when cerebral angiogenesis and neurogenesis are entwined, to the end of life, the interplay between vascular and neural systems of the brain is critical in health and disease. Cerebral microvascular endothelial cells constitute the blood-brain barrier and in concert with pericytes or smooth muscle cells, glia and neurons, integrate into a functional neurovascular unit (NVU). This multicellular NVU maintains homoeostasis of the brain's microenvironment by restricting the entry of systemic pathogens and neurotoxins as well as meeting the metabolic demands of neural activity. Recent evidence of cerebral microvascular pathologies in vascular diseases and dementia, including Alzheimer's disease, has challenged the notion that vascular events are merely the consequence of neuronal pathology. This review focuses on molecular mechanisms of neurovascular dysfunction in dementia and outlines currently employed in vitro models to decode such mechanisms. Deciphering neurovascular crosstalk is likely to be more important in understanding the molecular mechanisms of disease than previously anticipated and may offer novel therapeutic opportunities for dementia and related conditions.

Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion

The recent suggestion that growth differentiation factor 11 (GDF11) acts as a rejuvenation factor has remained controversial. However, in addition to its role in aging, the relationship between GDF11 and cerebral ischemia is still an important area that needs more investigation. Here we examined effects of GDF11 on angiogenesis and recovery of neurological function in a rat model of stroke.Exogenous recombinant GDF11 (rGDF11) at different doses were directly injected into the tail vein in rats subjected to cerebral ischemia/reperfusion (I/R). Neurobehavioral tests were performed, the proliferation of endothelial cells (ECs) and GDF11 downstream signal activin-like kinase 5 (ALK5) were assessed, and functional microvessels were measured.Results showed that rGDF11 at a dosage of 0.1 mg/kg/day could effectively activate cerebral angiogenesis in vivo. In addition, rGDF11 improved the modified neurological severity scores and the adhesive removal somatosensory test, promoted proliferation of ECs, induced ALK5 and increased vascular surface area and the number of vascular branch points in the peri-infarct cerebral cortex after cerebral I/R. These effects were suppressed by blocking ALK5.Our novel findings shed new light on the role of GDF11. Our results strongly suggest that GDF11 improves neurofunctional recovery from cerebral I/R injury and that this effect is mediated partly through its proangiogenic effect in the peri-infarct cerebral cortex, which is associated with ALK5. Thus, GDF11/ALK5 may represent new therapeutic targets for aiding recovery from stroke.

Abstract 61: Endothelium-Targeted Deletion of MicroRNA-15a/16-1 Cluster Promotes Post-Stroke Angiogenesis and Improves Long-Term Neurological Functions

Introduction: Angiogenesis promotes functional recovery and is associated with longer survival time in stroke patients. Accumulating studies have shown important roles for microRNAs (miRs) in regulating angiogenesis. Previously, we have demonstrated that miR-15a/16-1 cluster in endothelium negatively regulates hindlimb ischemia-induced angiogenesis. Here we further investigate its functional significance and molecular mechanism on post-ischemic cerebral angiogenesis. Hypothesis: Genetic deletion of miR-15a/16-1 cluster in endothelium increases cerebral angiogenesis and improves long-term neurological functions after ischemic stroke. Methods: EC-selective miR-15a/16-1 conditional knockout mice (EC-miR-15a/16-1 cKO) and WT controls were subjected to 1h MCAO followed by 3-28d reperfusion. Neurobehavioral outcomes were determined by the foot fault, rotarod, adhesive tape removal and Morris water maze tests. Brain capillary density and functional vessels were examined by CD31 and tomato-lectin immunofluorescent staining. In vitro angiogenesis assays, including capillary tube formation, scratch assay and BrdU cell proliferation were applied to cultured mBMECs with lentiviral loss- or gain-of-miR-15a/16-1 function. Pro-angiogenic factors were determined by 3’-UTR luciferase reporter assay, ELISA and western blotting. Results: Brain capillary density and the number of functional vessels in the ischemic penumbra of EC-miR-15a/16-1 cKO mice are higher than those of WT controls. Accordingly, EC-miR-15a/16-1 cKO mice exhibit improved sensorimotor and cognitive outcomes. Moreover, loss- or gain-of-miR-15a/16-1 function in mBMECs significantly increases or reduces tube formation, cell migration and cell proliferation, respectively. Mechanistically, gain-of miR-15a/16-1 function decreases luciferase reporter activity of VEGF, and remarkably reduces VEGF expression in mBMECs. Conclusions: Our findings suggest endothelial miR-15a/16-1 cluster is a negative regulator for post-ischemic cerebral angiogenesis and long-term functional recovery. Clinical intervention of miR-15a/16-1 mediated angiogenesis may be helpful for the development of novel neurorestorative therapies after ischemic stroke.

Nicotine promotes cerebral angiogenesis after intracerebral hemorrhage in mice

Nicotine promotes cerebral angiogenesis after intracerebral hemorrhage in mice

Reduced cerebral vascularization in experimental neuronopathic Gaucher disease.

The glycosphingolipidosis, Gaucher disease, in which a range of neurological manifestations occur, results from a deficiency of acid β-glucocerebrosidase, with subsequent accumulation of β-glucocerebroside, its upstream substrates, and the non-acylated congener β-glucosylsphingosine. However, the mechanisms by which end-organ dysfunction arise are poorly understood. Here, we report strikingly diminished cerebral microvascular density in a murine model of disease, and provide a detailed analysis of the accompanying cerebral glycosphingolipidome in these animals, with marked elevations of β-glucosylsphingosine. Further in vitro studies confirmed a concentration-dependent impairment of endothelial cytokinesis upon exposure to quasi-pathological concentrations of β-glucosylsphingosine. These findings support a premise for pathogenic disruption of cerebral angiogenesis as an end-organ effect, with potential for therapeutic modulation in neuronopathic Gaucher disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients

Background: Recent clinical studies in stroke and traumatic brain injury (TBI) victims suffering chronic neurological injury present evidence that hyperbaric oxygen therapy (HBOT) can induce neuroplasticity.Objective: To assess the neurotherapeutic effect of HBOT on prolonged post-concussion syndrome (PPCS) due to TBI, using brain microstructure imaging.Methods: Fifteen patients afflicted with PPCS were treated with 60 daily HBOT sessions. Imaging evaluation was performed using Dynamic Susceptibility Contrast-Enhanced (DSC) and Diffusion Tensor Imaging (DTI) MR sequences. Cognitive evaluation was performed by an objective computerized battery (NeuroTrax).Results: HBOT was initiated 6 months to 27 years (10.3 ± 3.2 years) from injury. After HBOT, DTI analysis showed significantly increased fractional anisotropy values and decreased mean diffusivity in both white and gray matter structures. In addition, the cerebral blood flow and volume were increased significantly. Clinically, HBOT induced significant improvement in the memory, executive functions, information processing speed and global cognitive scores.Conclusions: The mechanisms by which HBOT induces brain neuroplasticity can be demonstrated by highly sensitive MRI techniques of DSC and DTI. HBOT can induce cerebral angiogenesis and improve both white and gray microstructures indicating regeneration of nerve fibers. The micro structural changes correlate with the neurocognitive improvements.

Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice.

Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In this study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms. Male mice subjected to permanent distal middle cerebral artery occlusion were administrated with Sals, 5-bromo-2'-deoxyuridine, and JAK2 inhibitor AG490 once daily from day 1 to day 14 after distal middle cerebral artery occlusion. Compared with the control group, Sals treatment significantly improved neurological recovery at day 14 and 28 after ischemic stroke. Sals enhanced post-stroke angiogenesis, pericytes and astrocytic endfeet covered ratio in the peri-infarct area. The JAK2/STAT3 signaling pathway was activated by Sals in the angiogenesis process, and inhibition of JAK2/STAT3 signaling blocked the effects of Sals on post-stroke angiogenesis and neurological recovery as well as abolished the mediation of proangiogenic factors. In summary, these data suggest that Sals administration enhances cerebral angiogenesis and promotes neurological recovery after ischemic stroke, mediated by the activation of JAK2/STAT3 signaling pathway.

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.