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1.  Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials 
Progress in neurobiology  2013;115:138-156.
The brain vasculature has been increasingly recognized as a key player that directs brain development, regulates homeostasis, and contributes to pathological processes. Following ischemic stroke, the reduction of blood flow elicits a cascade of changes and leads to vascular remodeling. However, the temporal profile of vascular changes after stroke is not well understood. Growing evidence suggests that the early phase of cerebral blood volume (CBV) increase is likely due to the improvement in collateral flow, also known as arteriogenesis, whereas the late phase of CBV increase is attributed to the surge of angiogenesis. Arteriogenesis is triggered by shear fluid stress followed by activation of endothelium and inflammatory processes, while angiogenesis induces a number of pro-angiogenic factors and circulating endothelial progenitor cells (EPCs). The status of collaterals in acute stroke has been shown to have several prognostic implications, while the causal relationship between angiogenesis and improved functional recovery has yet to be established in patients. A number of interventions aimed at enhancing cerebral blood flow including increasing collateral recruitment are under clinical investigation. Transplantation of EPCs to improve angiogenesis is also underway. Knowledge in the underlying physiological mechanisms for improved arteriogenesis and angiogenesis shall lead to more effective therapies for ischemic stroke.
PMCID: PMC4295834  PMID: 24291532
arteriogenesis; angiogenesis; collateral flow; fluid shear stress; pro-angiogenic factors; inflammation; macrophage polarization
2.  MicroRNAs in Cerebral Ischemia 
Stroke Research and Treatment  2013;2013:276540.
The risk of ischemic stroke increases substantially with age, making it the third leading cause of death and the leading cause of long-term disability in the world. Numerous studies demonstrated that genes, RNAs, and proteins are involved in the occurrence and development of stroke. Current studies found that microRNAs (miRNAs or miRs) are also closely related to the pathological process of stroke. miRNAs are a group of short, noncoding RNA molecules playing important role in posttranscriptional regulation of gene expression and they have emerged as regulators of ischemic preconditioning and ischemic postconditioning. Here we give an overview of the expression and function of miRNAs in the brain, miRNAs as biomarkers during cerebral ischemia, and clinical applications and limitations of miRNAs. Future prospects of miRNAs are also discussed.
PMCID: PMC3606790  PMID: 23533957
3.  Differences of Circulating Inflammatory Markers between Large- and Small Vessel Disease in Patients with Acute Ischemic Stroke 
Background: The difference of inflammatory response between the pathogenesis of cerebral large- and small vessel disease after stroke remains unclear. In present study, we aim to determine the association of circulating inflammatory markers with different stroke subtype.
Methods: 99 patients with non-cardioembolic stroke were divided into large artery atherosclerosis (LAA) and small-artery occlusion (SAO) according to TOAST classification. A panel of plasma inflammatory markers including leukocyte, lymphocyte, CRP, fibrinogen, D-dimer, CD40L, IFN-γ, IL-1α, IL-1β, IL-6, IL-8, IL-17 and TNF-α were measured within 72 hours following cerebral ischemia. The relation of their levels in plasma with stroke subtype was further studied. All statistical data analysis was performed by SPSS 17.0 software.
Results: We found that only CRP were closely associated with stroke subtype (p<0.05). Compared to SAO subgroup, the plasma levels of CRP was higher in LAA subgroup (p<0.05). The predictive efficiency of CRP more than 3.2 for LAA was 85.7% sensitivity. The influencing factor of CRP includes IL-6, lymphocyte, fibrinogen and D-dimer.
Conclusion: LAA had a stronger activation of inflammation than SAO in the pathogenesis, which was associated with the changes of CRP.
PMCID: PMC3753418  PMID: 23983602
CRP; Cytokine; Inflammation; Stroke subtype
4.  Reorganization of Brain Networks in Aging and Age-related Diseases 
Aging and Disease  2011;3(2):181-193.
Aging is associated with reorganization of brain in both structure and function. In recent years, graph theoretical analysis of brain organization has drawn increasing attention, and reorganization of brain in aging has been investigated in terms of connectivity and networks in topology such as modular organization, global and local efficiency, and small-worldness. Beyond studying on abnormity in local brain regions, connectivity quantifies alternations of correlation between two regions that may be spatially far separated, and graph theoretical analysis of brain network examines the complex interactions among multiple regions. This article reviewed complex brain networks of human in normal aging or with age-related diseases such as stroke and Alzheimer’s disease after a technical introduction of brain networks and graph theoretical analysis. We further discussed the relationship between the functional and the structural brain networks of subjects in aging or with age-related diseases. Finally, we proposed several interesting topics for future research in this field.
PMCID: PMC3377830  PMID: 22724079
Aging; Brain network; Connectivity; Functional; Neuroimaging; Small-world; Structural
5.  Surgical treatment and pathologic analysis of posterior lentiglobus with cataract 
PMCID: PMC3340720  PMID: 22553723
6.  Endothelial progenitor cell transplantation improves long-term outcome in mice 
Annals of neurology  2010;67(4):488-497.
Endothelial progenitor cells (EPCs) have been implicated in playing an important role in vascular repair and revascularization in ischemic organs including brain tissue. However, the cause of EPC migration and the function of EPC playing following post-ischemia are unclear. Here, we reported EPC therapy in a mouse model of transient middle cerebral artery occlusion (tMCAO) to explore the roles of EPC following ischemic brain injury.
Human EPCs were cultured, characterized, and confirmed with flow cytometry. Ex vivo expanded EPCs (1×106) were injected via jugular vein after 1 hour of tMCAO. Histological and behavioral analyses were performed from day 1 to 28 days after tMCAO.
EPCs were detected in ischemic brain region 24 hours after MCAO. EPC transplantation significantly reduced ischemic infarct volume at 3 days following MCAO compared to the control (p<0.05). CXCR4 was expressed on majority of EPCs and SDF-1-induced EPC migration was blocked by AMD3100 in vitro. SDF-1 was up-regulated in ischemic brain and AMD3100 could reduce EPCs migration to the ischemic region in vivo, suggesting that SDF-1/CXCR4 was involved in EPC-mediated neuroprotection. Compared to the control, EPC therapy reduced mouse cortex atrophy 4 weeks after tMCAO, which was accompanied by improved neurobehavioral outcomes (p<0.05). In addition, EPC injection potently increased angiogenesis in the peri-infarction area (p<0.05).
We conclude that systemic delivery of EPC protect against cerebral ischemic injury, promote neurovascular repair, and improve long-term neurobehavioral outcomes. Our data suggests that SDF-1/CXCR4 plays a critical role in EPC-mediated neuroprotection.
PMCID: PMC3026588  PMID: 20437584
angiogenesis; EPCs; ischemia; mice; neuroprotection
7.  Restoring HOXA5 Expression Inhibits the Growth of Experimental Hemangiomas in the Brain 
Hemangiomas are vascular tumors that are angiogenesis-dependent. We previously showed that the transcription factor HoxA5, which is absent in activated, angiogenic endothelial cells (ECs), can block angiogenesis, and thus investigated whether restoring expression of HoxA5 blocks hemangioma growth in the mouse brain. We thus transplanted the murine hemangioma cell line EOMA or HoxA5 expressing EOMA cells into mice brain. Transplantation of EOMA cells into the mouse brain successfully induced brain hemangioma (BH) characterized by large, cyst-like spaces lined by thin walls of ECs surrounded by scant smooth muscle cell coverage. We also measured growth of vascular lesions and characterized the BH morphology. When EOMA cells expressing HoxA5 were injected, the volume of the lesions was reduced between 5 and 20-fold compared to the EOMA control group (p<0.05). Restoration of HoxA5 was associated with increased TSP-2, which inhibits angiogenesis and reduced HIF-1α expression. Our data suggest that restoring HoxA5 can attenuate experimental BH development.
PMCID: PMC2728585  PMID: 19458547
Angiogenesis; Brain; EOMA; Hemangioma; Homeobox A5; Mouse
8.  Overexpression of Netrin-1 Induces Neovascularization in the Adult Mouse Brain 
Netrin-1 is a critical molecule for axonal pathfinding during embryo development, and because of its structural homology to the endothelial mitogens, it may share its effects on vascular network formation. Using an adeno-associated viral netrin-1 vector (AAV-NT-1) gene transfer, we demonstrated that netrin-1 was able to stimulate the proliferation and migration of human cerebral endothelial cells (HCECs) and human aortic smooth muscle cells (HASMCs) compared to the control (p<0.05), and could also promote HCEC tube formation on matrigel (p<0.05) in vitro. Moreover, netrin-1 hyper-stimulation could promote focal neovascularization (p<0.05) in the adult brain in vivo. Unlike VEGF-induced microvessel increase, Netrin-1-induced newly formed vessels that showed an artery-like phenotype, with an intact endothelial cell monolayer surrounded by multiple cell layers, including smooth muscle cells and an astrocyte-connected outer layer. Our findings suggest that netrin-1 plays an important role in promoting blood vessel formation in the adult rodent central nervous system, and could have broad implication in cerebrovascular development and remodeling.
PMCID: PMC2581494  PMID: 18461079
adeno-associated viral vector; angiogenesis; brain; mouse; netrin-1; neovascularization; vascular endothelial growth factor
9.  Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages 
We investigated the role of bone marrow-derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation.
Methods and Results
BM from GFP donor mice was isolated and transplanted into lethally irradiated recipients. Four weeks after transplantation, groups of mice received adeno-associated viral vector (AAV)-VEGF or AAV-lacZ gene (control) injection and were sacrificed at 1 to 24 weeks. BMDCs were characterized by double-labeled immunostaining. BMDCs’ function was further examined through matrix metalloproteinase-2, -9 (MMP-2, -9) activity. We found that capillary density increased after 2 weeks, peaked at 4 weeks (p<0.01), and sustained up to 24 weeks after gene transfer. GFP-positive BMDCs’ infiltration in the angiogenic focus began 1 week, peaked at 2 weeks, and decreased thereafter. The GFP-positive BMDCs were co-localized with CD45 (94%), CD68 (71%), 5% Vimentin (5%), CD31/vWF (1%), and alpha-smooth muscle actin (α-SMA, 0.5%). Infiltrated BMDCs expressed MMP-9. MMP-9 KO mice confirmed the dependence of the angiogenic response on MMP-9 availability.
Nearly all BMDCs in the angiogenic focus showed expression for leukocytes/macrophages, indicating that BMDCs minimally incorporated into the neovasculature. Co-localization of MMPs with GFP suggests that BMDCs play a critical role in VEGF-induced angiogenic response through up-regulation of MMPs.
PMCID: PMC2610019  PMID: 18802012
adeno-associated virus; angiogenesis; BMDCs; MMPs; VEGF
Normal vasculature development of the central nervous system is extremely important because patients with vascular malformations are at life-threatening risk of intracranial hemorrhage or cerebral ischemia. The etiology and pathogenesis of abnormal vasculature development in the central nervous system are unknown, and progress is hampered by the lack of animal models of the human cerebrovascular diseases. Here, we reported our current study on cerebral microvascular dysplasia (CMVD) development. Using vascular endothelial growth factor hyper-stimulation, we demonstrated that aberrant microvessels could be developed in the rodent brain in certain conditions (such as genetic deficient background, local cytokine and chemokine release, or exogenous vessel dilating stimulation) that may speed up focal angiogenesis and lead to cerebral vascular dysplasia.
PMCID: PMC2677755  PMID: 19066107
cerebral; dysplasia; microvascular; mice; VEGF
11.  Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro 
Circulating blood endothelial progenitor cells (EPCs) contribute to postnatal vasculogenesis, providing a novel therapeutic target for vascular diseases. However, the molecular mechanism of EPC-induced vasculogenesis is unknown. Interleukin-6 (IL-6) plays multiple functions in angiogenesis and vascular remodeling. Our previous study demonstrated that the polymorphism (174G>C) in IL-6 gene promoter was associated with brain vascular disease. In this study, we investigated if IL-6 receptor is expressed in human endothelial progenitor cells (EPCs) derived from circulating mononuclear cells, and if IL-6 stimulates EPC angiogenesis in vitro.
First, we isolated and cultured mononuclear cells from adult human circulating blood. We obtained EPC clones that were further cultured and expended for the angiogenesis study. We found that the EPCs possessed human mature endothelial cell phenotypes; however, they proliferated much faster than mature endothelial cells (p<0.05). We then found that IL-6 receptor (gp-80) was expressed in the EPCs, and that administration of IL-6 could activate receptor gp80/gp130 signaling pathways including downstream ERK1/2 and STAT-3 phosphorylation in EPCs. Furthermore, IL-6 stimulated EPC proliferation, migration and matrigel tube formation in a dose-dependent manner (p<0.05); anti-IL-6 antibodies or IL-6 receptor could abolish these effects (P<0.05). These results suggest that IL-6 plays a crucial role in the biological behavior of blood-derived EPCs, which may help clarify the mechanism of IL-6 inflammatory-related diseases.
PMCID: PMC2581498  PMID: 17519976
angiogenesis; endothelial progenitor cell; ERK 1/2; interleukin-6; proliferation; migration; tube formation
12.  Adeno-associated viral vector-mediated hypoxia-regulated VEGF gene transfer promotes angiogenesis following focal cerebral ischemia in mice 
Gene therapy  2007;15(1):30-39.
Uncontrolled expression of VEGF in vivo may cause unexpected side effects, such as brain hemangioma, or tumor growth. Because hypoxia-inducible factor-1 (HIF-1) is up-regulated during cerebral ischemia and regulates gene expression by binding to a cis-acting hypoxia-responsive element (HRE), we therefore used a novel HRE, originating in the 3′ end of the erythropoietin (Epo) gene, to control gene expression in the ischemic brain. A concatemer of 9 copies (H9) of the consensus sequence of HRE was used to mediate hypoxia induction. Three groups of adult CD-1 mice received AAVH9-VEGF, AAVH9-lacZ or saline injection, and then underwent 45 minutes of transient middle cerebral artery occlusion (tMCAO). Results show that HIF-1 was persistently expressed in the ischemic brain. VEGF was overexpressed in the ischemic perifocal region in AAVH9-VEGF-transduced mice. Double-labeled immunostaining showed that VEGF expressed in neurons and astrocytes but not endothelial cells, suggesting that AAV vectors transduced neurons and astrocytes predominantly. The total number of microvessels/enlarged microvessels was greatly increased in the AAVH9-VEGF-transduced mice (180±29/27±4) compared to the AAVH9-lacZ (118±19/14±3) or saline-treated (119±20/14±2) mice after tMCAO (p<0.05). Cell proliferation examination demonstrated that these microvessels were newly formed. Regional cerebral blood flow recovery in the AAVH9-VEGF-transduced mice was also better than in AAVH9-lacZ or saline-treated mice (p<0.05). Our data indicated that HRE is a novel trigger for the control of VEGF expression in the ischemic brain. VEGF overexpression through AAVH9-VEGF gene transfer showed stable focal angiogenic effects in post-ischemic repair process, providing an opportunity to rebuild injured brain tissue.
PMCID: PMC2586392  PMID: 17960159
Adeno-associated viral vectors; angiogenesis; hypoxia-responsive element; ischemia; VEGF
13.  Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration 
Neurochemistry international  2006;50(3):524-530.
Smooth muscle migration plays an important role during angiogenesis and vascular remodeling. In this study, we examined the effects of doxycycline and minocycline on vascular endothelial growth factor (VEGF)-induced human aortic smooth muscle cell (HASMCs) migration, and explored the mechanisms in which doxycycline or minocycline inhibit HASMC migration. We demonstrated that both doxycycline and minocycline attain consistent anti-angiogenic effects in the inhibition of HASMC migration via a different signal pathway (p<0.05). This effect is through attenuating VEGF-induced matrix metalloproteinase-9 (MMP-9) activity (p<0.05). Doxycycline could increase tissue inhibitors of metalloproteinases-1 (TIMP-1) expression while minocycline down-regulated PI3K/Akt phosphorylation in HASMC. Our study suggests that doxycycline has a stronger ability to inhibit MMP secretion in HASMC by up-regulating endogenous MMPs inhibitor TIMP-1, while minocycline implements anti-angiogenic effect through inhibiting HASMC migration by down-regulating PI3K/Akt pathway.
PMCID: PMC1876824  PMID: 17145119
Doxycycline; Matrix metalloproteinase; Minocycline; Migration; Smooth muscle cell; Vascular endothelial growth factor
14.  Neural stem cell protects aged rat brain from ischemia–reperfusion injury through neurogenesis and angiogenesis 
Neural stem cells (NSCs) show therapeutic potential for ischemia in young-adult animals. However, the effect of aging on NSC therapy is largely unknown. In this work, NSCs were transplanted into aged (24-month-old) and young-adult (3-month-old) rats at 1 day after stroke. Infarct volume and neurobehavioral outcomes were examined. The number of differentiated NSCs was compared in aged and young-adult ischemic rats and angiogenesis and neurogenesis were also determined. We found that aged rats developed larger infarcts than young-adult rats after ischemia (P<0.05). The neurobehavioral outcome was also worse for aged rats comparing with young-adult rats. Brain infarction and neurologic deficits were attenuated after NSC transplantation in both aged and young-adult rats. The number of survived NSCs in aged rats was similar to that of the young-adult rats (P>0.05) and most of them were differentiated into glial fibrillary acidic protein+ (GFAP+) cells. More importantly, angiogenesis and neurogenesis were greatly enhanced in both aged and young-adult rats after transplantation compared with phosphate-buffered saline (PBS) control (P<0.05), accompanied by increased expression of vascular endothelial growth factor (VEGF). Our results showed that NSC therapy reduced ischemic brain injury, along with increased angiogenesis and neurogenesis in aged rats, suggesting that aging-related microenvironment does not preclude a beneficial response to NSCs transplantation during cerebral ischemia.
PMCID: PMC4083376  PMID: 24714034
aged rats; behavioral recovery; ischemia; neural stem cell transplantation
15.  Netrin-1 overexpression promotes white matter repairing and remodeling after focal cerebral ischemia in mice 
Damage of oligodendrocytes after ischemia has negative impact on white matter integrity and neuronal function. In this work, we explore whether Netrin-1 (NT-1) overexpression facilitates white matter repairing and remodeling. Adult CD-1 mice received stereotactic injection of adeno-associated virus carrying NT-1 gene (AAV-NT-1). One week after gene transfer, mice underwent 60 minutes of middle cerebral artery occlusion. The effect of NT-1 on neural function was evaluated by neurobehavioral tests. Proliferated oligodendrocyte progenitor cells (OPCs), newly matured oligodendrocytes, and remyelination were semi-quantified by immunohistochemistry. The role of NT-1 in oligodendrogenesis was further explored by examining specific NT-1 receptors and their function. Netrin-1 overexpression was detected in neurons and astrocytes 2 weeks after AAV-NT-1 gene transfer and significantly improved the neurobehavioral outcomes compared with the control (P<0.05). In comparison with the control, proliferated OPCs, newly matured oligodendrocytes, and remyelination were greatly increased in the ipsilateral hemisphere of AAV-NT-1-transduced mice. Furthermore, both NT-1 receptors deleted in colorectal carcinoma and UNC5H2 were expressed on OPCs whereas only UNC5H2 was expressed in myelinated axons. Our study indicated that NT-1 promoted OPC proliferation, differentiation, and increased remyelination, suggesting that NT-1 is a promising factor for white matter repairing and remodeling after ischemia.
PMCID: PMC3851901  PMID: 23963365
ischemia; netrin-1; oligodendrocyte progenitor cells; remyelination; white matter
16.  Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion 
Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms.
Ninety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways.
Infarct volume was reduced in metformin-treated mice compared to the control group following tMCAO (P < 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice (P < 0.05). MPO+ cells, Gr1+ cells, MPO activity and BBB permeability were decreased after metformin administration (P < 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF-κB activation, down-regulated cytokine (IL-1β, IL-6, TNF-α) and ICAM-1 expression following tMCAO (P < 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells (P < 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect.
Metformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-014-0177-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4201919  PMID: 25315906
Blood-brain barrier; ICAM-1; Inflammation; Ischemic stroke; Metformin
17.  Neurovascular Recovery via Cotransplanted Neural and Vascular Progenitors Leads to Improved Functional Restoration after Ischemic Stroke in Rats 
Stem Cell Reports  2014;3(1):101-114.
The concept of the “neurovascular unit,” emphasizing the interactions between neural and vascular components in the brain, raised the notion that neural progenitor cell (NPC) transplantation therapy aimed at neural repair may be insufficient for the treatment of ischemic stroke. Here, we demonstrate that enhanced neurovascular recovery via cotransplantation of NPCs and embryonic stem cell-derived vascular progenitor cells (VPCs) in a rat stroke model is correlated with improved functional recovery after stroke. We found that cotransplantation promoted the survival, migration, differentiation, and maturation of neuronal and vascular cells derived from the cotransplanted progenitors. Furthermore, it triggered an increased generation of VEGF-, BDNF-, and IGF1-expressing neural cells derived from the grafted NPCs. Consistently, compared with transplantation of NPCs alone, cotransplantation more effectively improved the neurobehavioral deficits and attenuated the infarct volume. Thus, cotransplantation of NPCs and VPCs represents a more effective therapeutic strategy for the treatment of stroke than transplantation of NPCs alone.
•Neural and vascular progenitor cell cotransplantation therapy for ischemic stroke•Better neurovascular recovery by cotransplanted progenitor cells in the infarct area•Better infarction reduction and functional restoration by cotransplantation•Neurovascular recovery likely mediated by neural production of growth/trophic factors
Gao, Yang, and colleagues demonstrate a more favorable neurovascular recovery and functional restoration after cotransplantation of neural progenitor cells (NPCs) and embryonic stem cell-derived vascular progenitor cells than after transplantation of NPCs alone in a rat stroke model. Cotransplantation not only reciprocally enhances the survival and differentiation of the transplanted progenitors but also preserves the host brain from further degeneration, likely by increasing neural production of VEGF, BDNF, and IGF1.
PMCID: PMC4110773  PMID: 25068125
18.  Increase of circulating miR-223 and insulin-like growth factor-1 is associated with the pathogenesis of acute ischemic stroke in patients 
BMC Neurology  2014;14:77.
The relationship between circulating microRNA-223 and pathogenesis of acute ischemic stroke is unknown. Here we investigated the roles and possible targets of circulating microRNA-223 in human ischemic stroke within the first 72 hours.
Blood samples were collected from patients within 72 hours after cerebral ischemia (n = 79) and compared with healthy control samples (n = 75). The level of possible downstream factors of microRNA-223 including insulin-like growth factor-1, insulin-like growth factor-1 receptor and interleukin-6 was examined by ELISA assay. The relationship between the microRNA-223 level and NIHSS scores, TOAST subtypes, and infarct volume was analyzed respectively. In addition, twelve adult male CD-1 mice underwent middle cerebral artery occlusion using the suture technique. Circulating blood and brain tissue in the ischemic ipsilateral hemisphere were collected at 24 hours after middle cerebral artery occlusion. microRNA-223 was detected by real-time polymerase chain reactions.
microRNA-223 levels in the circulating blood of acute ischemic stroke patients were greatly increased compared to the control (p < 0.05). microRNA-223, which were negatively correlated with NIHSS scores (r = −0.531, p < 0.01) and infarct volume (r = −0.265, p = 0.039), was significantly up-regulated in large artery and small artery strokes. The plasma level of insulin-like growth factor-1 was positively associated with that of microRNA-223 (r = 0.205, p = 0.022). Moreover, microRNA-223 in blood and brain were positively correlated (r = 0.834, p < 0.05), and they were up-regulated significantly in mice that underwent middle cerebral artery occlusion (p < 0.05).
Our results suggest that microRNA-223 is associated with acute ischemic stroke and possibly plays a role in stroke through up-regulating growth factor such as insulin-like growth factor-1 gene.
PMCID: PMC4234389  PMID: 24708646
Human; Ischemia; microRNA-223; Stroke
19.  Therapeutic Benefit of Bone Marrow–Derived Endothelial Progenitor Cell Transplantation after Experimental Aneurysm Embolization with Coil in Rats 
PLoS ONE  2014;9(2):e90069.
Aneurysm embolization with coil is now widely used clinically. However, the recurrence of aneurysms after embolization has always plagued neurosurgeons because the endothelial layer of the aneurysm neck loses its integrity after being embolized by coil. Bone marrow–derived endothelial progenitor cells (BM-EPCs) could be incorporated into injured endothelium and differentiate into mature endothelial cells during vascular repairing processes. The aim of our study is to explore the effects of BM-EPCs on aneurysm repairing and remodeling in a rat embolization model of abdominal aortic aneurysm. BM-EPC proliferation, migration and tube formation were not affected by super-paramagnetic iron oxide nanoparticle (SPIO) labeling compared to the controls (p>0.05). The number of SPIO-labeled cells greatly increased in EPC transplanted rats compared to that of phosphate buffered saline treated rats. SPIO-labeled EPC (SPIO-EPC) are mainly located in the aneurysm neck and surrounded by fibrous tissue. A histology study showed that the aneurysm orifice was closed with neointima and the aneurysm was filled with newly formed fibrous tissue. The SPIO-EPC accumulated in the aneurysm neck, which accelerated focal fibrous tissue remodeling, suggesting that BM-EPCs play a crucial role in repairing and remodeling the aneurysm neck orifice.
PMCID: PMC3938595  PMID: 24587209
20.  Correction: Genetic Associations of Angiotensin-Converting Enzyme with Primary Intracerebral Hemorrhage: A Meta-analysis 
PLoS ONE  2014;9(1):10.1371/annotation/7f2d85e0-c41a-40cf-80e1-6ce4b0470eff.
PMCID: PMC3883730
21.  microRNAs: innovative targets for cerebral ischemia and stroke 
Current drug targets  2013;14(1):90-101.
Stroke is one of the leading causes of death and disability worldwide. Because stroke is a multifactorial disease with a short therapeutic window many clinical stroke trials have failed and the only currently approved therapy is thrombolysis. MicroRNAs (miRNA) are endogenously expressed noncoding short single-stranded RNAs that play a role in the regulation of gene expression at the post-transcriptional level, via degradation or translational inhibition of their target mRNAs. The study of miRNAs is rapidly growing and recent studies have revealed a significant role of miRNAs in ischemic disease. miRNAs are especially important candidates for stroke therapeutics because of their ability to simultaneously regulate many target genes and since to date targeting single genes for therapeutic intervention has not yet succeeded in the clinic. Although there are already quite a few review articles about miRNA in ischemic heart disease, much less is currently known about miRNAs in cerebral ischemia. This review summarizes current knowledge about miRNAs and cerebral ischemia, focusing on the role of miRNAs in ischemia, both changes in expression and identification of potential targets, as well as the potential of miRNAs as biomarkers and therapeutic targets in cerebral ischemia.
PMCID: PMC3673881  PMID: 23170800
BCL2 family; cerebral ischemia; heat shock protein; microRNA; mitochondria
22.  In-Line Phase Contrast Imaging of Hepatic Portal Vein Embolization with Radiolucent Embolic Agents in Mice: A Preliminary Study 
PLoS ONE  2013;8(12):e80919.
It is crucial to understand the distribution of embolic agents inside target liver during and after the hepatic portal vein embolization (PVE) procedure. For a long time, the problem has not been well solved due to the radiolucency of embolic agents and the resolution limitation of conventional radiography. In this study, we first reported use of fluorescent carboxyl microspheres (FCM) as radiolucent embolic agents for embolizing hepatic portal veins. The fluorescent characteristic of FCM could help to determine their approximate location easily. Additionally, the microspheres were found to be fairly good embolizing agents for PVE. After the livers were excised and fixed, they were imaged by in-line phase contrast imaging (PCI), which greatly improved the detection of the radiolucent embolic agents as compared to absorption contrast imaging (ACI). The preliminary study has for the first time shown that PCI has great potential in the pre-clinical investigation of PVE with radiolucent embolic agents.
PMCID: PMC3851775  PMID: 24324646
23.  Surgery-Related Thrombosis Critically Affects the Brain Infarct Volume in Mice Following Transient Middle Cerebral Artery Occlusion 
PLoS ONE  2013;8(9):e75561.
Transient middle cerebral artery occlusion (tMCAO) model is widely used to mimic human focal ischemic stroke in order to study ischemia/reperfusion brain injury in rodents. In tMCAO model, intraluminal suture technique is widely used to achieve ischemia and reperfusion. However, variation of infarct volume in this model often requires large sample size, which hinders the progress of preclinical research. Our previous study demonstrated that infarct volume was related to the success of reperfusion although the reason remained unclear. The aim of present study is to explore the relationship between focal thrombus formation and model reproducibility with respect to infarct volume. We hypothesize that suture-induced thrombosis causes infarct volume variability due to insufficient reperfusion after suture withdrawal. Seventy-two adult male CD-1 mice underwent 90 minutes of tMCAO with or without intraperitoneal administration of heparin. Dynamic synchrotron radiation microangiography (SRA) and laser speckle contrast imaging (LSCI) were performed before and after tMCAO to observe the cerebral vascular morphology and to measure the cerebral blood flow in vivo. Infarct volume and neurological score were examined to evaluate severity of ischemic brain injury. We found that the rate of successful reperfusion was much higher in heparin-treated mice compared to that in heparin-free mice according to the result of SRA and LSCI at 1 and 3 hours after suture withdrawal (p<0.05). Pathological features and SRA revealed that thrombus formed in the internal carotid artery, middle cerebral artery or anterior cerebral artery, which blocked reperfusion following tMCAO. LSCI showed that cortical collateral circulation could be disturbed by thrombi. Our results demonstrated that suture-induced thrombosis was a critical element, which affects the success of reperfusion. Appropriate heparin management provides a useful approach for improving reproducibility of reperfusion model in mice.
PMCID: PMC3782513  PMID: 24086572
24.  CO2-based in-line phase contrast imaging of small intestine in mice 
Scientific Reports  2013;3:2313.
The objective of this study was to explore the potential of CO2 single contrast in-line phase contrast imaging (PCI) for pre-clinical small intestine investigation. The absorption and phase contrast images of CO2 gas production were attained and compared. A further increase in image contrast was observed in PCI. Compared with CO2-based absorption contrast imaging (ACI), CO2-based PCI significantly enhanced the detection of mucosal microstructures, such as pits and folds. The CO2-based PCI could provide sufficient image contrast for clearly showing the intestinal mucosa in living mice without using barium. We concluded that CO2-based PCI might be a novel and promising imaging method for future studies of gastrointestinal disorders.
PMCID: PMC3727055  PMID: 23896957
25.  Genetic Associations of Angiotensin-Converting Enzyme with Primary Intracerebral Hemorrhage: A Meta-analysis 
PLoS ONE  2013;8(6):e67402.
A number of studies have reported an association of angiotensin-converting enzyme (ACE) gene polymorphism with primary intracerebral hemorrhage (PICH), however the reports have demonstrated inconclusive results. To clarify this conflict, we updated the previously performed meta-analysis by Peck et al., which revealed negative results, by investigating the ACE polymorphism and its correlation to PICH.
PubMed and Embase databases (through Dec 2012) were searched for English articles on the relationship of the I/D polymorphism in ACE with PICH in humans. Summary odds ratios (ORs) were estimated and potential sources of heterogeneity and bias were explored.
A total of 805 PICH cases and 1641 control cases obtained from 8 case-control studies were included. The results suggest that in dominant genetic models, the ACE I/D polymorphic variant was associated with a 58% increase in susceptibility risk of PICH (OR = 1.58; 95% CI = 1.07–2.35 for DD vs. DI+II). However, in the subgroup analysis based on race, a significant increased risk was found in Asian DD homozygote carriers (OR = 1.76 and 95% CI = 1.16–2.66 for DD vs. DI+II), but not in Caucasian DD homozygote carriers (OR = 1.18, 95% CI = 0.36–3.88, P = 0.784 for DD vs. DI+II). The heterogeneity between studies was remarkable, and its major sources of heterogeneity were due to the year in which the study was published. No potential publication bias was observed in dominant genetic models.
These data demonstrated evidence of a positive association between ACE I/D polymorphism with PICH, and suggested that the ACE gene is a PICH susceptible gene in Asian populations.
PMCID: PMC3694901  PMID: 23826288

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