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bmp3 is Required for Integrity of Blood Brain Barrier by Promoting Pericyte Coverage in Zebrafish Embryos. Lei D,Jin X,Wen L,Dai H,Ye Z,Wang G Current molecular medicine BACKGROUND:The compromise of blood brain barrier (BBB) integrity is often associated with human hemorrhage stroke and neurodegeneration diseases, including retina diseases, such as age-related macular degeneration and diabetic retinopathy. Brain pericytes play pivotal roles in regulation and maintenance of BBB integrity. However, the mechanisms underlying brain pericyte development to establish BBB integrity remain unclear. METHODS:Zebrafish transgenic lines Tg(flk1:GFP; gata1:dsRed), Tg(flk1:GFP), Tg(fli1:GFP) and Tg(BRE:GFP) were used in this work. The functional studies of bmp3 were performed by mopholino oligonucleotide (MO) injection, dye-based permeability assay, RT-PCR, in vivo imaging, immunofluorescence staining and statics analysis. RESULTS:Here we report that bmp3 regulates BBB integrity in zebrafish brain by promoting pericyte development. Knockdown of bmp3 with injection of bmp3-MO causes intracerebral hemorrhage in zebrafish embryos. Meanwhile, disruption of bmp3 function by bmp3-MO injection impairs cerebral pericyte coverage in zebrafish embryos. Mechanistically, knockdown of bmp3 disrupts the pattern and activities of BMP signaling in zebrafish brain, thus probably disrupting the balance of TGFβ/BMP signaling in zebrafish embryos. CONCLUSION:In summary, our data shows that bmp3 regulates BBB integrity potentially by promoting pericyte development. 10.2174/1566524017666171106114234
Admission blood glucose and short term survival in primary intracerebral haemorrhage: a population based study. Fogelholm R,Murros K,Rissanen A,Avikainen S Journal of neurology, neurosurgery, and psychiatry BACKGROUND:The role of admission blood glucose level on the prognosis of patients with intracerebral haemorrhage has not been elucidated. OBJECTIVE:To examine this association on the basis of an epidemiologically representative patient material. METHODS:249 500 people living in the catchment area of the Central Hospital of Central Finland. The diagnosis of ICH was established if verified by cranial computed tomography (CT) or autopsy. RESULTS:Of the 416 patients who fulfilled the diagnostic criteria, 30 died before admission and 386 were admitted to the Central Hospital. All 329 patients (290 nondiabetics and 39 diabetics) with both admission blood glucose and cranial CT data were included in the study. The mean blood glucose level was 10.6 mmol/l for nondiabetics who died on the day of onset, 8.6 mmol/l for those dying during days 1 to 28, and 6.8 mmol/l for the 28 day survivors. The corresponding figures for diabetics were 13.9 mmol/l, 12.5 mmol/l, and 9.3 mmol/l. In both nondiabetics and diabetics, patients who died had significantly higher mean glucose than the 28 day survivors (p<0.0001 versus p = 0.029). However, blood glucose of the surviving diabetics was as high as that of the deceased nondiabetics (9.3 mmol/l versus 9.1 mmol/l). In nondiabetics, admission blood glucose was associated with parameters signifying severe stroke; disturbed consciousness, large haematoma volume and shift of cerebral midline structures, and high admission mean arterial pressure. In logistic regression analysis, high admission blood glucose in nondiabetics was a significant predictor of death during the first 28 days of onset (odds ratio 1.22, 95% CI 1.07 to 1.40). CONCLUSIONS:High admission blood glucose predicts increased 28 day case fatality rate in both nondiabetic and diabetic patients with ICH. Because high admission blood glucose was associated with markers of severe stroke, we are inclined to support the stress theory; high admission blood glucose is the result of a serious ICH. 10.1136/jnnp.2003.034819
The specific VPAC2 agonist Bay 55-9837 increases neuronal damage and hemorrhagic transformation after stroke in type 2 diabetic rats. Darsalia Vladimer,Mansouri Shiva,Wolbert Petra,Barde Swapnali,Sjöholm Ake,Patrone Cesare Neuropeptides VPAC2 receptor is a potential target for the treatment of type 2 diabetes and may also convey neuroprotective effects. The aim of this study was to determine the potential efficacy of the VPAC2 receptor agonist Bay 55-9837 against stroke in type-2 diabetic Goto-Kakizaki (GK) rats. GK rats were treated intravenously once daily for 7 days with 0.25 or 0.025 nmol/kg Bay 55-9837 or vehicle before inducing stroke by transient middle cerebral artery occlusion. Treatments were then continued for 7 further days. The glycemic effects of Bay 55-9837 were assessed by measuring fasting blood glucose and oral glucose tolerance. The severity of stroke was measured by assessing ischemic volume. The results show that Bay 55-9837 is not effective in lowering fasting glycemia and does not facilitate glucose disposal. The highest dose of Bay 55-9837 (0.25 nmol/kg) led to increased mortality and brain hemorrhage when compared to control. The lower dose of Bay 55-9837 (0.025 nmol/kg) did not increase mortality rate but caused a threefold increase of the ischemic lesion size with signs of brain hemorrhages as compared to control. In conclusion, Bay 55-9837 did not show antidiabetic or antistroke efficacy in the type 2 diabetic GK rat. Contrarily, Bay 55-9837 treatment led to increased mortality and worsening of the severity of stroke. 10.1016/j.npep.2012.08.008
Cerebrovascular responses to pathophysiological insult in diabetic rats. Fouyas I P,Kelly P A T,Ritchie I M,Lammie G A,Whittle I R Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Diabetes mellitus is associated with altered cerebrovascular responsiveness and this could contribute to the pathology of stroke in diabetic patients. In these studies, we used a model of haemorrhagic stroke (intrastriatal injection of 50 microl blood) to examine subacute perilesional perfusion and blood-brain barrier (BBB) integrity in spontaneously diabetic rats. Volumes of striatal oligaemia (blood flow < 35 ml 100 g(-1) min(-1)) were significantly increased (>300%) in diabetic rats with intrastriatal blood, compared to either non-diabetic rats with blood or control diabetic rats with striatal injection of silicon oil. However, the increase in BBB permeability was both qualitatively and quantitatively similar in diabetic and control rats. Poorer outcomes following haemorrhagic stroke in diabetic patients may thus result from dysfunctional cerebrovascular control, and particularly decreased dilatatory reserve. 10.1016/s0967-5868(02)00247-3
Highly glycosylated CD147 promotes hemorrhagic transformation after rt-PA treatment in diabetes: a novel therapeutic target? Xie Yanan,Wang Yingzhe,Ding Hongyan,Guo Min,Wang Xun,Dong Qiang,Cui Mei Journal of neuroinflammation BACKGROUND:Diabetes is known to be a main risk factor of post-stroke hemorrhagic transformation following recombinant tissue plasminogen activator (rt-PA) therapy. However, the mechanism through which diabetes exacerbates hemorrhagic transformation is insufficiently understood. We aimed to verify that CD147, the extracellular matrix metalloproteinase (MMP) inducer, played a vital role in the progress. METHODS:We performed middle cerebral artery occlusion on diabetic and non-diabetic rats, with or without rt-PA treatment, and then compared the glycosylation level of CD147, caveolin-1, MMPs activities, and blood-brain barrier (BBB) permeability. In vitro, tunicamycin treatment and genetic tools were used to produce non-glycosylated and lowly glycosylated CD147. An endogenous glucagon-like peptide-1 receptor (GLP-1R) agonist was used to downregulate the glycosylation of CD147 in vivo. RESULTS:Compared with non-diabetic rats, diabetic rats expressed higher levels of highly glycosylated CD147 in endothelium and astrocytes following rt-PA treatment accompanied by higher activity of MMPs and BBB permeability, in the middle cerebral artery occlusion model. Caveolin-1 was also overexpressed and co-localized with CD147 in astrocytes and endothelium in diabetic rats. In vitro, advanced glycation end products increased the expression of highly glycosylated CD147 in astrocytes and endothelial cells. Downregulating the glycosylation of CD147 lowered the activity of MMPs and promoted the expression of tight junction proteins. The expression of caveolin-1 in endothelial cells and astrocytes was not inhibited by tunicamycin, which revealed that caveolin-1 was an upstream of CD147. In vivo, GLP-1R agonist downregulated the glycosylation of CD147 and further reduced the activity of MMPs and protected the BBB in diabetic rats. CONCLUSION:CD147 is essential for diabetes-associated rt-PA-induced hemorrhagic transformation, and downregulation of CD147 glycosylation is a promising therapy for neurovascular-unit repair after rt-PA treatment of patients with diabetes. 10.1186/s12974-019-1460-1
The role of endothelin in the cerebrovascular response following intracerebral haemorrhage: experimental studies using the endothelin antagonist SB209670. Fouyas I P,Brennan P,Kelly P A T,Whittle I R British journal of neurosurgery Primary intracerebral haemorrhage (ICH) is associated with considerable morbidity and mortality. Local endothelin release following ICH may contribute to the pathophysiology of perilesional ischaemia. In diabetics, endothelin release can be enhanced by hyperglycaemia and cerebrovascular dilation may be inhibited by vascular endothelial dysfunction. To examine the effects of endothelin-mediated vasoconstriction after spontaneous ICH in the normal and diabetic brain, regional cerebral blood flow (rCBF) was examined in insulin dependent BB-rats and non-diabetic BB control rats. These experiments were performed 24 h following experimental ICH in both groups of animals that were either given the endothelin antagonist SB209670 or saline. Perilesional oligaemia was similar in control and SB209670 treated diabetic rats, but SB209670 reduced perilesional oligaemia in normal rats. In brain contralateral to the experimental ICH, rCBF was increased by SB209670 in diabetic rats, but not in non-diabetic rats. These studies show that there are differences in the cerebrovascular effects of endothelin in perilesional and contralateral brain in non-diabetic and diabetic rats following ICH. 10.1080/02688690701595913
Endothelin-1-mediated cerebrovascular remodeling is not associated with increased ischemic brain injury in diabetes. Li Weiguo,Kelly-Cobbs Aisha I,Mezzetti Erin M,Fagan Susan C,Ergul Adviye Canadian journal of physiology and pharmacology Diabetes increases the risk of as well as poor outcome after stroke. Matrix metalloprotease (MMP) activation disrupts blood-brain barrier integrity after cerebral ischemia. We have previously shown that type 2 diabetes promotes remodeling of middle cerebral arteries (MCA) characterized by increased media/lumen (M/L) ratio and MMP activity in an endothelin (ET)-1-dependent manner in the Goto-Kakizaki (GK) rat model. In the present study, we examined the effects of ET-1-mediated vascular remodeling on neurovascular damage following cerebral ischemic injury in GK rats 5 and 12 weeks after the onset of diabetes. The MCA structure, cerebral perfusion as well as infarct size, and hemorrhage were measured in control and diabetic rats subjected to transient MCA occlusion. M/L ratio was increased after 12 but not 5 weeks of diabetes. The baseline cerebral perfusion was lower and the infarct volume smaller in diabetic rats in both age groups. The incidence of hemorrhagic transformation was higher after 5 weeks of diabetes as compared to that after 12 weeks or in the control groups. These findings provide evidence that ET-1-mediated cerebrovascular remodeling does not worsen the neurovascular damage of ischemic brain injury in diabetes. It is possible that this early remodeling response is compensatory in nature to regulate vascular tone and integrity, especially when ischemia is layered on diabetic vascular disease. 10.1139/Y10-040
A rat model of studying tissue-type plasminogen activator thrombolysis in ischemic stroke with diabetes. Fan Xiang,Qiu Jianhua,Yu Zhanyang,Dai Haibin,Singhal Aneesh B,Lo Eng H,Wang Xiaoying Stroke BACKGROUND AND PURPOSE:Poststroke hyperglycemia and diabetes mellitus are associated with lower thrombolytic efficacy and an increased risk of postischemic cerebral hemorrhage. We aimed to develop a rodent model of thrombolysis in diabetic stroke that mimics the clinical situation. Method- Male 6-week Type I diabetic rats (14 weeks old) were subjected to embolic focal stroke and treated with tissue-type plasminogen activator at 1.5 hours. Reperfusion and 24-hour neurological outcomes were measured and compared with nondiabetic control rats. RESULTS:Diabetic rats exhibited resistance to thrombolytic reperfusion, larger infarction volumes, and increased intracerebral hemorrhage. CONCLUSIONS:This animal model would be relevant to future studies investigating pathophysiological mechanisms and in developing new therapeutic approaches to enhance the efficacy of tissue-type plasminogen activator thrombolysis in stroke patients with diabetes or poststroke hyperglycemia. 10.1161/STROKEAHA.111.635250
Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. Liu Jia,Gao Ben-Bo,Clermont Allen C,Blair Price,Chilcote Tamie J,Sinha Sukanto,Flaumenhaft Robert,Feener Edward P Nature medicine Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis. 10.1038/nm.2295
Angiotensin-converting enzyme (rs4646994) and α ADDUCIN (rs4961) gene polymorphisms' study in primary spontaneous intracerebral hemorrhage. Kalita J,Misra U K,Bindu I S,Kumar B,Mittal B Neurology India BACKGROUND:Primary spontaneous intracerebral hemorrhage (PSICH) is common in Asia and may have a genetic basis. OBJECTIVE:To report the role of angiotensin-converting enzyme (ACE) and a ADDUCIN (ADD1) gene polymorphisms in patients with PSICH. SETTING:Tertiary care teaching referral hospital. PATIENTS AND METHODS:Study subjects included 104 patients with PSICH diagnosed by computed tomography (CT) brain scan and 198 controls. The vascular risk factors of stroke were noted. The location and size of the hematoma on CT scan were recorded. ACE (rs4646994) and a ADDUCIN (rs4961) gene polymorphisms were analyzed by polymerase chain reaction (PCR). The genotype and allele frequency were compared between patients and controls and within the PSICH group. RESULTS:The median age of the PSICH group was 58 years, 17 (16.3%) patients were aged above 70 years and 40 (38%) were females. Ninety-three (91.2%) patients were hypertensive and 17 (16.5%) were diabetic. Hematoma was putaminal in 88 (84.5%), pontine in 5 (4.9%), cerebellar in 2 (1.9%), lobar in seven (6.8%) and multiple and primary intraventricular in one (1%) patient each. In the patients with PSICH, ACE DD genotype was present in 44 (42.8%) and ID in 40 (38.4%) whereas in controls these were 22 (11.1%) and 103 (52%) respectively. ADD1- WW genotype was found in two patients (1.9%), and GW in 44 patients (42.7%). In the controls these were found in nine (4.5%) and 65 (32.8%) respectively. DD genotype had 7.4 times higher risk of PSICH. ADD1 variant genotypes were not associated with increased risk but in association with ACE DD genotype resulted in significantly higher risk of PSICH. ACE and ADD1 variant genotypes were associated with nonlobar hematoma. CONCLUSION:ACE DD genotype in isolation or in combination with ADD1 GW genotype is associated with PSICH, especially nonlobar hematoma. 10.4103/0028-3886.76856
Increased Spontaneous Central Bleeding and Cognition Impairment in APP/PS1 Mice with Poorly Controlled Diabetes Mellitus. Ramos-Rodriguez Juan José,Infante-Garcia Carmen,Galindo-Gonzalez Lucia,Garcia-Molina Yaiza,Lechuga-Sancho Alfonso,Garcia-Alloza Mónica Molecular neurobiology Alzheimer's disease (AD) and vascular dementia (VaD) are the most common causes of dementia, and borderlines are blurred in many cases. Aging remains the main risk factor to suffer dementia; however, epidemiological studies reveal that diabetes may also predispose to suffer AD. In order to further study this relationship, we have induced hypoinsulinemic diabetes to APPswe/PS1dE9 (APP/PS1) mice, a classical model of AD. APP/PS1 mice received streptozotocin (STZ) ip at 18 weeks of age, when AD pathology is not yet established in this animal model. Cognition was evaluated at 26 weeks of age in the Morris water maze and the new object discrimination tests. We observed that STZ-induced episodic and working memory impairment was significantly worsened in APP/PS1 mice. Postmortem assessment included brain atrophy, amyloid-beta and tau pathology, spontaneous bleeding, and increased central inflammation. Interestingly, in APP/PS1-STZ diabetic mice, we detected a shift in Aβ soluble/insoluble levels, towards more toxic soluble species. Phospho-tau levels were also increased in APP/PS1-STZ mice, accompanied by an exacerbated inflammatory process, both in the close proximity to senile plaque (SP) and in SP-free areas. The presence of hemorrhages was significantly higher in APP/PS1-STZ mice, and although pericytes and endothelium were only partially affected, it remains possible that blood-brain barrier alterations underlie observed pathological features. Our data support the implication of the diabetic process in AD and VaD, and it is feasible that improving metabolic control could delay observed central pathology. 10.1007/s12035-015-9311-2
Recombinant adiponectin peptide promotes neuronal survival after intracerebral haemorrhage by suppressing mitochondrial and ATF4-CHOP apoptosis pathways in diabetic mice via Smad3 signalling inhibition. Wu Xun,Luo Jianing,Liu Haixiao,Cui Wenxing,Guo Wei,Zhao Lei,Guo Hao,Bai Hao,Guo Kang,Feng Dayun,Qu Yan Cell proliferation OBJECTIVE:Low levels of adiponectin (APN), a biomarker of diabetes mellitus, have been implicated in the poor outcome of intracerebral haemorrhage (ICH). Herein, we aimed to demonstrate the neuroprotective effects of a blood-brain barrier-permeable APN peptide (APNp) on ICH injury in diabetic mice and explore the underlying mechanisms. MATERIALS AND METHODS:Recombinant APNp was administrated intraperitoneally to mice with collagenase-induced ICH. Neurological deficits, brain water content and neural apoptosis were assessed. Western blotting, immunofluorescence staining, quantitative RT-PCR and transmission electron microscopy were used to determine the signalling pathways affected by APNp. RESULTS:Adiponectin peptide significantly alleviated neural apoptosis, neurological deficits and brain oedema following ICH in diabetic mice. Mechanistically, APNp promoted the restoration of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α related mitochondrial function and suppressed activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)-induced neural apoptosis. Furthermore, Smad3 signalling was found to play a regulatory role in this process by transcriptionally regulating the expression of PGC-1α and ATF4. APNp significantly suppressed the elevated phosphorylation and nuclear translocation of Smad3 after ICH in diabetic mice, while the protective effects of APNp on mitochondrial and ATF4-CHOP apoptosis pathways were counteracted when Smad3 was activated by exogenous transforming growth factor (TGF)-β1 treatment. CONCLUSIONS:Our study provided the first evidence that APNp promoted neural survival following ICH injury in the diabetic setting and revealed a novel mechanism by which APNp suppressed mitochondrial and ATF4-CHOP apoptosis pathways in a Smad3 dependent manner. 10.1111/cpr.12759
Early Increased Bradykinin 1 Receptor Contributes to Hemorrhagic Transformation After Ischemic Stroke in Type 1 Diabetic Rats. Sang Hongfei,Qiu Zhongming,Cai Jin,Lan Wenya,Yu Linjie,Zhang Hao,Li Min,Xie Yi,Guo Ruibing,Ye Ruidong,Liu Xinfeng,Liu Ling,Zhang Renliang Translational stroke research Hemorrhagic transformation (HT) is a major complication of ischemic stroke and further deteriorates neurological outcomes. Bradykinin 1 receptor (B1R) has been proven to mediate vasculo-toxicity in various experimental models. However, its role in the development of HT after stroke remains unclear. We detected the B1R expression in brain tissues with or without HT in a rat model of cerebral ischemia/reperfusion (I/R) with type 1 diabetes, showing higher B1R expression in the hemorrhagic areas than the ischemic tissues. Then, B1R agonist or antagonist was administrated intravenously just before reperfusion to investigate its effect on HT and the underlying molecular mechanism. Administration of low (300 nmol/kg) or high (1 μmol/kg) dose of B1R antagonist mitigated hemorrhage, improved neurobehavioral deficits, and preserved blood-brain-barrier (BBB) integrity after reperfusion for 8 h whereas the 300 nmol/kg of B1R agonist aggravated these outcomes, though only the high does of B1R antagonist affected the infarction volume. Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was increased by B1R activation but decreased by B1R inhibition, which mediated B1R toxicity on BBB disruption and ischemia-related HT. Furthermore, B1R activation facilitated the mRNA and protein expressions of MMP-9 in the hemorrhagic tissues, and these increases were blocked by both ERK inhibitor U0126 and NF-κB inhibitor PDTC. U0126 also remarkably decreased the B1R-induced NF-κB/p65 activation. We concluded that upregulated B1R may contribute to early HT after I/R in type 1 diabetic rats via ERK1/2/NF-κB/MMP-9 pathway. B1R inhibition could be an encouraging therapeutic strategy to withstand HT after ischemic stroke in diabetic patients. 10.1007/s12975-017-0552-4