Endothelial Nitric Oxide Synthase Mediates Endogenous Protection Against Subarachnoid Hemorrhage-Induced Cerebral Vasospasm

Vellimana, Ananth K.; Milner, Eric; Azad, Tej D.; Harries, Michael D.; Zhou, Meifang; Gidday, Jeffrey M.; Han, Byung Hee; Zipfel, Gregory J.

doi:10.1161/strokeaha.110.607200

Cited by 95 publications

(86 citation statements)

References 36 publications

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“…In vitro, EPCs can differentiated into endothelial lineage cells, and in animal models of ischemia, EPCs are shown to incorporate into sites of active neovascularization [10,11,12]. Endothelial nitric oxide synthase (eNOS) and its bioactive product nitric oxide (NO) are well-established proangiogenic molecules [13]. eNOS-derived NO regulates cardiac myocyte function, myocardial neovascularization, and myocardial perfusion.…”

Section: Introductionmentioning

confidence: 99%

Deterioration of Cardiac Function After Acute Myocardial Infarction is Prevented by Transplantation of Modified Endothelial Progenitor Cells Overexpressing Endothelial NO Synthases

Chen

Zhao

et al. 2013

Cell Physiol Biochem

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Background/Aims: Stem cell transplantation and gene therapies have been shown to attenuate myocardial dysfunction after myocardial infarction (AMI) in different acute and chronic animal models. The aim of this study was to assess the potential therapeutic efficacy of endothelial NO synthases (eNOS)-expressing endothelial progenitor cells (EPCs) on infarcted hearts. Methods: Lentiviral eNOS-infected EPCs were injected after 1 h of ligation of the left anterior descending artery (LAD). The pro-inflammatory cytokines TNF-α and IL-1β levels in cardiac tissue were measured by ELISA at 3 days after transplantation. 28 days post AMI (before sacrifice), Left ventricular function of each group was determined by echocardiography and pressure-volume system. Cardiac tissues were analyzed with hematoxylin and eosin (H&E) staining and immunohistochemisty. eNOS expression in cardiac tissues was detected by western blot, and NO production of cardiac tissues was determined using an NO assay kit. Results: TNF-α and IL-1β levels in cardiac tissue were decreased significantly at 3 days after transplantation of lentiviral with eNOS infected EPCs compared to medium control, eNOS lentiviral vector and normal EPCs. At the 28 day after AMI, echocardiography and hemodynamic measurements, and isolated heart studies showed great therapeutic efficacy in improvement of cardiac function, reduction of infarcted size and improvement of vascular densities in the peri-infarct region after intramyocardial application of lentiviral eNOS-infected EPCs compared to medium control, eNOS lentiviral vector and normal EPCs. The eNOS over-expression in cardiac tissue was observed in the eNOS-EPCs and eNOS lentiviral vector group, and NO levels were increased significantly in the eNOS-EPCs and eNOS lentiviral vector group compared to the other three groups (sham operated group, transplantation of medium or EPCs group). Conclusion: EPCs can be an attractive vehicle for the exogenous eNOS expression into heart after infarction, which is beneficial to prevent deterioration and promote restoration of cardiac function after AMI by improving angiogenesis.

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Section: Introductionmentioning

confidence: 99%

Deterioration of Cardiac Function After Acute Myocardial Infarction is Prevented by Transplantation of Modified Endothelial Progenitor Cells Overexpressing Endothelial NO Synthases

Chen

Zhao

et al. 2013

Cell Physiol Biochem

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“…19,27 Decreased functionality of this pathway following SAH has been linked to the pathophysiology of DCI including CVS. 58,69,71,77,85 Studies investigating the eNOS-NO-cGMP pathway have shown that inhibition of PDE-V has substantial beneficial effects. In animal SAH studies, PDE-V inhibition (mainly via administration of sildenafil, an FDA-approved selective PDE-V inhibitor) acutely reverses SAH-induced CVS, 2,28,31,32,34,42 reduces neuronal cell death, 32 restores impaired autoregulatory mechanisms, 73 and improves neurological outcomes.…”

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confidence: 99%

A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

Washington

Derdeyn

Dhar

et al. 2016

JNS

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A neurysmal subarachnoid hemorrhage (SAH) is a significant health care problem with high morbidity and mortality; up to 70% of patients will die or be permanently disabled.33 Prognosis is dependent on a number of factors such as age, presenting neurological status, and development of delayed cerebral ischemia (DCI). 4,6,74 Occurring in 30%-40% of patients, DCI is the most common and potentially treatable contributor to outcome. 6,57,78 Though the mechanisms underlying DCI are multifactorial, the processes considered most responsible are delayed cerebrovascular vasospasm (CVS), cerebrovascular autoregulatory dysfunction, and cortical spreading ischemia. 6,47 Unfortunately, to date few therapies have proven effective for the prevention and treatment of DCI. 4,82 A significant predictor of developing DCI is angiographic CVS of intracranial vessels. 6,7,47 Approximately abbreviatioNs cGMP = cyclic guanosine monophosphate; CVS = cerebrovascular vasospasm; DCI = delayed cerebral ischemia; DSA = digital subtraction angiography; DSMB = Data Safety Monitoring Board; eNOS = endothelial nitric oxide synthase; ICA = internal carotid artery; ICP = intracranial pressure; MAP = mean arterial pressure; MCA = middle cerebral artery; NNICU = Neurology/Neurosurgery ICU; NO = nitric oxide; PDE-V = phosphodiesterase-V; SAH = subarachnoid hemorrhage. obJective Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients. methods A 2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as "improvement" or "no improvement" in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms. results Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the highdose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0-2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%-200%). coNclusioNs The results from this Phas...

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“…Inducible NOS (iNOS) was found to be involved in isoflurane PC-induced neuroprotection in in vivo and in vitro conditions, as well as during IPC [16,63,64]. eNOS has been recently implicated as a mediator of neurovascular protection against subarachnoid hemorrhage (SAH)-induced vasospasm, through HPC in mice, showing for the first time that PC is beneficial for other forms of stroke as well [65].…”

Section: Nitric Oxide (No) Synthasementioning

confidence: 99%

Cerebral Ischemic Preconditioning: the Road So Far…

Sangwan

Sharma

et al. 2015

Mol Neurobiol

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Cerebral preconditioning constitutes the brain's adaptation to lethal ischemia when first exposed to mild doses of a subtoxic stressor. The phenomenon of preconditioning has been largely studied in the heart, and data from in vivo and in vitro models from past 2-3 decades have provided sufficient evidence that similar machinery exists in the brain as well. Since preconditioning results in a transient protective phenotype labeled as ischemic tolerance, it can open many doors in the medical warfare against stroke, a debilitating cerebrovascular disorder that kills or cripples thousands of people worldwide every year. Preconditioning can be induced by a variety of stimuli from hypoxia to pharmacological anesthetics, and each, in turn, induces tolerance by activating a multitude of proteins, enzymes, receptors, transcription factors, and other biomolecules eventually leading to genomic reprogramming. The intracellular signaling pathways and molecular cascades behind preconditioning are extensively being investigated, and several first-rate papers have come out in the last few years centered on the topic of cerebral ischemic tolerance. However, translating the experimental knowledge into the clinical scaffold still evades practicality and faces several challenges. Of the various preconditioning strategies, remote ischemic preconditioning and pharmacological preconditioning appears to be more clinically relevant for the management of ischemic stroke. In this review, we discuss current developments in the field of cerebral preconditioning and then examine the potential of various preconditioning agents to confer neuroprotection in the brain.

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Endothelial Nitric Oxide Synthase Mediates Endogenous Protection Against Subarachnoid Hemorrhage-Induced Cerebral Vasospasm

Cited by 95 publications

References 36 publications

Deterioration of Cardiac Function After Acute Myocardial Infarction is Prevented by Transplantation of Modified Endothelial Progenitor Cells Overexpressing Endothelial NO Synthases

Deterioration of Cardiac Function After Acute Myocardial Infarction is Prevented by Transplantation of Modified Endothelial Progenitor Cells Overexpressing Endothelial NO Synthases

A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

Cerebral Ischemic Preconditioning: the Road So Far…

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