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Neurology Research International
Volume 2013 (2013), Article ID 291895, 11 pages
Genetics of Cerebral Vasospasm
1Vanderbilt University School of Medicine, Nashville, TN 37212, USA
2Department of Neurological Surgery, Vanderbilt University School of Medicine, Nashville, TN 37212, USA
Received 7 November 2012; Accepted 10 March 2013
Academic Editor: William Mack
Copyright © 2013 Travis R. Ladner et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cerebral vasospasm (CV) is a major source of morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). It is thought that an inflammatory cascade initiated by extravasated blood products precipitates CV, disrupting vascular smooth muscle cell function of major cerebral arteries, leading to vasoconstriction. Mechanisms of CV and modes of therapy are an active area of research. Understanding the genetic basis of CV holds promise for the recognition and treatment for this devastating neurovascular event. In our review, we summarize the most recent research involving key areas within the genetics and vasospasm discussion: (1) Prognostic role of genetics—risk stratification based on gene sequencing, biomarkers, and polymorphisms; (2) Signaling pathways—pinpointing key inflammatory molecules responsible for downstream cellular signaling and altering these mediators to provide therapeutic benefit; and (3) Gene therapy and gene delivery—using viral vectors or novel protein delivery methods to overexpress protective genes in the vasospasm cascade.
Cerebral vasospasm (CV) is the narrowing of the major cerebral arteries following aneurysmal subarachnoid hemorrhage (aSAH) and is a leading contributor to the morbidity and mortality associated with aSAH. The annual incidence of aSAH in the United States is between 21,000 and 33,000 people . Of these, approximately 67% will develop vasospasm [2, 3]. In the setting of aSAH, CV has a biphasic course, with an acute and chronic phase. The acute phase typically begins 3 to 4 hours after hemorrhage, with rapid, spontaneous resolution. In contrast, the chronic phase begins 3 to 5 days later, with maximum narrowing between days 6 and 8, resolving after about 14 days .
CV can be diagnosed angiographically or clinically. Angiographic vasospasm refers to the observed narrowing of contrast medium in the major cerebral arteries. Radiologic modalities used to diagnose CV include computed tomography angiography (CTA), magnetic resonance angiography (MRA), and catheter angiography. Clinical vasospasm is the sequelae of neurocognitive deficits presumably as a result of a prolonged ischemic state. Both angiographic and clinical vasospasms can lead to cerebral infarction. Angiographic and clinical vasospasms appear to be distinct phenomena, with aSAH patients presenting with angiographic CV only (43% of patients), both angiographic and clinical CV (33% of patients), or none of them (24% of patients) .
Although there are many hypotheses on the pathogenesis of CV, it still remains a poorly understood phenomenon. In 1944, Zucker observed that lysed erythrocytes incited smooth muscle contraction of cerebral arteries in mammals . A later clinical angiographic study by Ecker and Riemenschneider in 1951 found that the degree of vasospasm is directly related to the volume of subarachnoid blood observed on head CTs , leading to the use of the Fisher Grade in predicting vasospasm onset .
The inciting event of CV is likely an inflammatory response to extravasated blood products in the subarachnoid space, leading to prolonged and deregulated contraction of vascular smooth muscle cells (VSMCs) . Lysed RBCs in subarachnoid space surrounding the cerebral vasculature can generate inflammatory downstream effects that result in endothelial damage and smooth muscle contraction . In particular, extracorpuscular oxyhemoglobin is the potent inflammatory compound and has been shown to increase the formation of reactive oxygen species (ROS), decrease nitric oxide (NO) concentration, increase prostaglandin synthesis, and increase lipid peroxidation [9, 11–13]. Such changes in the vascular equilibrium can lead to the activation of pro-vasospasm signaling pathways and the synthesis of inflammatory gene products. This process occurs in parallel to the delayed cerebral ischemia (DCI) resulting from microthromboses and cortical spreading ischemia [14, 15].
2. Genetics in CV
While much work has been done to characterize the signaling pathways implicated in CV, the field still lacks a definitive explanatory model with robust predictability and therapeutic targets. Several presumptive targets have been proposed with only modest gains. For example, clazosentan, an endothelin receptor antagonist, has shown great attenuation of angiographic vasospasm in preclinical and clinical studies but no improvement in neurological outcomes . In contrast, nimodipine, a calcium channel blocker, improves functional outcomes without a parallel reduction in angiographic vasospasm . However, the field of genetics offers a new insight.
An active area of research is the exploration of the genetic basis for CV, which has previously been supported by population studies . New advances in molecular genetics have revealed several genes whose products are presumptive mediators of CV and genetic polymorphisms that portend increased CV risk and/or poorer outcomes. Understanding the genetic mechanism of disease generation may provide insight into novel therapeutic avenues. In this review, we will summarize the most recent research in the following areas regarding genetics and CV: (1) prognostic role of genetics, (2) key signaling mediators involved, and (3) gene therapy and gene delivery.
2.1. Prognostic Factors
Stratifying risk based on next generation sequencing is gradually becoming integrated into medical practice . In cardiovascular medicine, indications on the use of drugs such as clopidogrel, warfarin, and statins have already been made based on the patient’s genotype [32–34]. Genetic screening of family members of patients diagnosed with familial hypercholesterolemia is currently recommended in the UK .
Genetic risk stratification for CV holds great potential. Close family members of patients with aneurysms may be screened for their own susceptibility for aneurysm formation and rupture. Genomic biomarkers may also be used to stratify SAH patients for more intensive monitoring according to vasospasm risk, as well as informing medication administration.
Genomewide and other gene association studies have identified several genes that may play a larger role in developing quick and inexpensive screening protocols in SAH. This represents an update on a genetics review by Ducruet and colleagues , with attention to recent discoveries reported in the literature. The following is a summary of genetic markers associated with SAH and CV, with evidence for disease mechanisms as well as implicated polymorphisms (Table 1).
2.1.1. Catechol-O-methyltransferase (COMT)
Catecholamines have been implicated in the development of acute CV following SAH [37, 38]. COMT, a key enzyme in the degradation of catecholamines, has been shown to play a role in acute CV. A rat model has shown increased expression of COMT and catecholamines following SAH induction . A study of 167 Chinese Han SAH patients showed that patients with the COMT-A allele, A/A genotype were more likely to develop acute CV . This polymorphism may be a biomarker for predicting poor outcomes in patients with aneurysms that may later rupture.
2.1.2. Endothelial Nitric Oxide Synthase (eNOS) Gene
Endothelial nitric oxide synthase (eNOS) gene, which is found on chromosome 7q35, plays an important role in CV and other cardiovascular diseases . eNOS is present in the endothelium of the major cerebral arteries and produces nitric oxide (NO), a potent vasodilator. Constitutive levels of NO inhibit platelet aggregation, vascular smooth muscle proliferation, and inflammation [9, 23, 42–44]. Perivascular oxyhemoglobin released after SAH scavenges NO generated by eNOS, decreasing NO-mediated vasorelaxation and contributing to the onset of vasospasm [45–47].
Clinically, decreased levels of NO in the CSF have been reported in aSAH patients. Overexpression of the eNOS gene has been shown to be vasoprotective in humans and canines in the setting of SAH [48, 49]. Polymorphisms of the eNOS genes are linked to intracranial aneurysm formation [50, 51] and coronary vasospasm . Genetic association studies have shown that eNOS 7-786 gene SNPs predispose aSAH patients for vasospasm [19–23]. However, the various findings are contradictory, showing either an effect with the T allele, C allele, or no clear association. This apparent discrepancy is likely attributable to the heterogeneity of vasospasm definition as well as the complex regulation of the eNOS gene.
The activity of eNOS is tightly regulated at many stages, including transcription, substrate availability, cofactors, protein-protein interactions, posttranslational modifications, and dimerization [59, 60]. The literature is mixed on whether eNOS activity is increased , decreased , or unchanged [63–66] following SAH. Further, it is still unclear what role SAH plays in the phosphorylation of eNOS .
eNOS is physiologically a homodimer but under pathological conditions decouples and forms a ferrous-dioxygen complex which has a tendency to form superoxide radicals instead of NO . Recent studies by Sabri and colleagues have shown that SAH leads to increased phosphorylation of eNOS on Ser1177 and subsequent uncoupling, which decreases NO availability while simultaneously increasing the production of superoxide. Superoxide may further react with remaining NO to form peroxynitrite, which continues to deplete residual NO . While it is known that simvastatin can mitigate vasospasm [63, 68], recent work suggests that simvastatin may work by recoupling eNOS to increase NO production and decrease the production of superoxide . This may further explain its mechanism of attenuating vasospasm clinically and in other animal models [63, 64].
Another recent study showed that preconditioning (PC) of mice in hypoxic chambers prior to induction of SAH selectively increases the expression and activity of eNOS, increasing NO levels and reducing vasospasm . These results suggest that PC-induced vasoprotection is mediated by upregulation of eNOS. In addition, decreased NO availability with no change in eNOS activity was observed in SAH, which may also support the pathologic uncoupling hypothesis.
Haptoglobin (Hp) is a serum protein produced primarily by hepatocytes  that binds to free hemoglobin released by lysed erythrocytes . The bound complex is taken up by macrophages through the CD163 receptor, presumably reducing extracorpuscular hemoglobin toxicity . It is composed of an alpha subunit and a beta subunit, which are encoded by the haptoglobin alpha gene and haptoglobin beta gene, respectively. The gene complex is found on human chromosome 16q22 .
The Hp gene exists in 2 alleles in humans, and 3 genotypes are possible: Hp 1-1, Hp 2-2, or Hp 2-2. The Hp 1 product is a linear dimer, the Hp 2-1 product is a linear polymer, and the Hp 2-2 product is a cyclical polymer [73, 74]. These structural differences confer different binding affinities, with greater binding and clearing of hemoglobin in Hp 1-1 individuals and weaker binding and clearance in Hp 2-2 individuals [45, 75]. As a result, the Hp 2-2 allele is thought to be more proinflammatory than the Hp 1-1 allele, leading to increased inflammation, immune response, oxidation, and vasoconstriction [9, 47].
As such, the Hp 2-2 allele may be a mediator of CV as well. The Hp gene has been shown to be upregulated in a canine model of CV . A study of 32 Fisher Grade 3 SAH patients conducted in 2006 showed that individuals with the Hp 2 allele had greater likelihood than Hp 1 individuals of developing vasospasm . Clinically, the allelic distribution of Hp in Western patients roughly corresponds to the prevalence of CV in Western SAH patients [5, 77]. In recent years the Hp 2-2 mouse has been investigated as a novel animal model for CV and its treatment [78, 79]. Mice with the Hp 2-2 genotype display greater arterial narrowing and neurological deficits compared to Hp 1-1 mice following experimental SAH .
2.1.4. Plasminogen Activator Inhibitor-1 (PAI-1)
PAI-1 is a protein encoded by the SERPINEI gene, found on the 7q21.3-q22 chromosome . It is antifibrinolytic, functioning as the principal inhibitor of tissue plasminogen activator and urokinase, which themselves activate plasmin. A common polymorphism is the 4G/5G SNP on the promoter region . The 4G allele has been previously associated with higher plasma concentrations of PAI-1 in the acute setting and poorer survival after trauma  as well as increased PAI-1 activity in myocardial infarction . PAI-1 has also been investigated in the setting of SAH for a possible link to thrombosis-related DCI, thought to contribute to the neurological deficits resulting from CV . A study of 126 aSAH patients in 2004 found that the presence of the 4G allele in the 4G/5G promoter SNP is associated with increased risk for cerebral ischemia and poorer 3-month GOS outcomes relative to the 5G allele . However, another study of 183 aSAH patients in 2009 found no association between the PAI-1 SNP and poor outcomes on the 1-year GOS-E scale . Given the multifactorial nature of vasospasm, more work must be done to characterize this apparent discrepancy.
2.1.5. Apolipoprotein E (ApoE)
ApoE, a polymorphic protein encoded by the ApoE gene, is associated with plasma lipoproteins and is involved in lipid transport and metabolism in the central nervous system . ApoE has been studied extensively in the literature for its significance to cerebrovascular disease. Three common alleles have been reported in humans (, , and ) on the 19p13 chromosome, encoding 3 different isoforms (ApoE2, ApoE3, and ApoE4) . The allele predisposes patients to poor neurological outcomes in CV, traumatic brain injury, and ischemic stroke [27, 86–88]. However, the purported role of this allele in vasospasm following aSAH is still unclear. While this polymorphism does not appear to play a role in generating vasospasm, it seems to inhibit normal neuronal plasma membrane repair following cerebral ischemia, ostensibly worsening outcomes for the patients that do end up developing vasospasm .
Within the past decade the promoter region of ApoE has come under more scrutiny for its role in CV after SAH. Polymorphisms in the promoter region have previously been associated with poorer outcomes in traumatic brain injury. A study in 2003 found that carriers of the G-219T allele had more unfavorable GOS functional scores . Another study reported that in e4 carriers the 491AA SNP contributed to poor outcomes in traumatic brain injury . A study of 101 SAH patients in China in 2010 showed that patients carrying the −219T allele had an increased risk of CV . This effect is possibly mediated through decreased transcriptional activity of ApoE, which decreases its protective effect in the setting of inflammation .
A recent study of ApoE knockout mice  observed enhanced vasoconstriction in response to endothelin-1, a vasoconstrictive compound associated with CV . Administration of cilostazol was reported to decrease endothelial dysfunction in knockout mice, which likely increases eNOS phosphorylation . This suggests that ApoE may play a vasoprotective role in CV and that underexpression of the gene may be overcome with medication for patients with normal eNOS expression in the setting of SAH.
Ryanodine receptors (RyRs) are a family of intracellular calcium channels that mediate the calcium-induced calcium release (CICR). There are three subtypes (RyR1, RyR2, and RyR3), which are all present in vascular smooth muscle [94, 95]. Activation of these receptors facilitates sparks, which promote vasorelaxation through hyperpolarizing VSMCs [96–98]. RyRs are involved in the regulation of cerebral artery luminal diameter [99, 100], and recent evidence indicates that RyRs may play a role in the pathogenesis of vasospasm after SAH. Koide and colleagues found a 50% reduction in spark activity coupled with a 65% reduction in RyR2 expression following induced SAH in rabbits . These changes appear to come from a combination of reduced RyR2 expression as well as increased FKBP12.6 expression, a stabilizer of RyR2 channels. Clinically, polymorphisms in genes encoding RyRs are related to vasospasm onset. A 2011 study of 46 patients in Germany revealed that SAH patients who were heterozygous for the c.6178G>T polymorphism of the RyR1 gene were more likely to develop symptomatic vasospasm .
2.1.7. Cystathionine β-Synthase
Cystathionine β-synthase (CBS) is an enzyme that converts homocysteine and serine to form cystathionine, releasing in the process . is a vasodilator and neuromodulator and is known to function in the cerebral circulation, although the nature of its interaction warrants further study [30, 102, 103]. CBS is the predominant source of in the brain and therefore may play a role in cerebrovascular disease. A study of 87 aSAH patients found that those with the 699CT and TT (gain of function) genotypes had increased angiographic vasospasm, but no increase in delayed cerebral ischemia . Delayed cerebral ischemia was more frequent in 1080TT (decline of function) populations. This study suggests that -mediated signaling is neuroprotective in aSAH, and this protection may not be dependent on vasoprotection.
More work must be done to characterize these prognostic genes and generate more consistent findings on their role in vasospasm. Differences in study designs, sample sizes, and vasospasm-monitoring modalities must be reconciled for more definitive explanations. However, these remain the most studied genes and may therefore play a role in future stratification of SAH patients.
2.2. Signaling Pathways
Inflammatory molecules generated from the breakdown of blood products following SAH incite several known cascades of cellular signaling enzymes. In particular, compounds such as endothelin-1, oxyhemoglobin, bilirubin oxidation products (BOXes), and ROS activate cytokine and cellular signaling pathways [9, 104, 105]. These can lead to the alteration of expression of CV-related genes, the mechanisms of which are still currently being investigated. Preliminary studies have shown that alteration of these pathways may provide therapeutic benefit. The following is a summary of 3 important known pathways in CV.
The MAPK signaling pathway is important in the generation of vasospasm . It is hypothesized that spasmogens, when released from lysed blood cells surrounding vascular tissue, lead to the sequential activation of phospholipase C (PLC), inositol-1,4,5-trisphosphate (), and diacylglycerol (DAG). This pathway mobilizes and activates protein kinase C (PKC), which together activate protein tyrosine kinase (TK). TK phosphorylates Ras to form the GTP-bound activated form of Ras, which is associated with cell cycle regulation, cell adhesion, and migration . ROS, as those generated following SAH, have also been associated with Ras activation .
Ras has been shown to be activated in a rabbit model of SAH, peaking at day 3 . GTP-bound (activated) Ras interacts with Raf-1 to phosphorylate downstream effectors such as extracellular signal-regulated kinase (ERK). As such, inhibition of the Ras-ERK pathway is associated with a reduction in vasospasm in rabbit and canine models of SAH [107, 109, 110].
MAPK is associated with vasoconstriction, impaired vasorelaxation, tissue proliferation, apoptosis, and inflammation [106, 111]. An in vitro model using human vascular smooth muscle cells found that inhibition of p38 MAPK resulted in decreased vasospasm and cytokine production . It is hypothesized that caldesmon and calponin, which are substrates for MAPK, are associated with vasoconstriction, but the exact interaction has not yet been determined [106, 113]. These proteins are inhibitors of -dependent smooth muscle contraction, and inhibition of them by MAPK may lead to sustained vascular smooth muscle contraction .
2.2.2. JAK/STAT Signaling
The JAK/STAT signaling pathway is an important mediator of downstream cytokine and growth factor activity  and may be involved in the pathogenesis of CV. Cytokines such as IL-6 are known to be elevated in SAH patients and are also known activators of JAKs. JAK1 has been shown to be activated in a rat model of SAH following production of IL-6 . JAK2 has also been shown to be activated in a rabbit model of SAH . Activated JAKs subsequently phosphorylate STAT proteins. STAT proteins have been shown to be activated in the basilar artery in a rat model of SAH, with STAT3 expressed in the intima and media and STAT1 expressed in the adventitia . While STAT3 is activated in response to cytokines, STAT1 is activated by the free radicals generated by oxyhemoglobin metabolism following SAH .
JAK2/STAT3 signaling is associated with the expression of the apoptotic genes bcl-2 and bcl-xL in the intima of the basilar arteries in rabbits . JAK1/STAT3 signaling in rats upregulates the inflammatory COX-2 protein in the intima . These early gene products may mediate the generation of vasospasm, as fibrosis of the cerebral arteries is associated with vasospasm following SAH . Endothelial cell death promotes thrombosis and decreases vasodilator expression [119–121]. COX-2 products, including prostaglandins and thromboxanes, are known to lead to endothelial dysfunction through endothelial-dependent contractions . Inflammatory changes in the adventitia may result in decreased vessel compliance and may contribute to the vessel stiffness observed in CV . Taken together, these findings suggest that the JAK/STAT pathway may be an important mediator of vasospasm.
Rho proteins are small G proteins that are commonly expressed in mammals . Rho-kinase, the effector of Rho, plays an important role in the cardiovascular system through its interaction with the myosin light chain (MLC) in VSMC contractions. Rho-kinase phosphorylates and inhibits myosin light chain phosphatase and therefore increases contractility . Rho-kinase also phosphorylates myosin light chain directly, generating sustained contraction in a similar manner as the /calmodulin-dependent MLC kinase pathway . Rho-kinase has been shown to be involved in the pathogenesis of both coronary and cerebral vasospasm [124, 126–131]. Oxyhemoglobin from SAH activates Rho/Rho-kinase signaling . In addition, the Rho/Rho-kinase pathway decreases NO production through the production of cyclophilin A (CyPA), which decreases eNOS expression . CyPA itself stimulates ERK1/2, Akt, and JAK in VSMCs, which contributes to increased ROS production [133, 134]. Rho-kinase is also known to play a role in vascular smooth muscle through increasing vascular smooth muscle proliferation, ROS production, inflammation, and endothelial damage [123, 134]. Fasudil, an inhibitor of Rho-kinase, has shown some benefit in treating vasospasm in SAH patients .
2.3. Gene Therapy and Delivery
We summarize the current status of gene therapy in CV (Table 2). Within the past decade viral vector-mediated gene therapy has been explored in the context of vasospasm and other vascular diseases [136, 137]. In a proof-of-concept experiment reported in 1997, Muhonen and colleagues demonstrated that β-galactosidase could be transferred to cerebral blood vessels and surrounding tissue during vasospasm using a virus vector . In 2002 Ono and colleagues showed that the HMOX1 gene can be transferred to the rat basilar artery adventitia through adenovirus using transcisternal injection. Overexpression of heme oxygenase-1 attenuated vasospasm in this model. This was associated with increased heme oxygenase-1 mRNA and activity, with increased basilar artery diameter and CBF [55, 138]. In the last decade this method has shown efficacy in preclinical SAH models using genes such as calcitonin gene-related peptide (CGRP) , eNOS , and superoxide dismutase . There are no published clinical models of such therapy to date in CV. However, overexpression of the SERCA2a gene by viral transfer has shown success in improving outcomes in heart failure patients [139–141]. Intramuscular injection of VEGF-carrying adenovirus has improved peripheral artery occlusive disease and coronary artery disease in clinical trials [137, 142].
Despite the promise gene therapy holds, there are several challenges to the translation of preclinical protocols to humans in the setting of CV . The route of administration is typically through the cisterna magna, which requires more invasive procedures in critically ill patients; however, external ventricular drains may provide appropriate CSF access. It is difficult to ensure adequate and accurate tissue distribution, especially to the endothelium. In addition, humans have increased body weight relative to small laboratory animals. Therefore, greater loads of gene-carrying viruses will be required. As CV is a polygenic disorder, single gene therapy alone may not be sufficient. It may be more difficult to express genes within deeper layers of blood vessels with perivascular administration. Perhaps the development of endovascular administration with vectors with enhanced transfer efficiency may be a solution. There have also been problems with expressed genes remaining functional for only short periods of time, perhaps from weeks to months. However, given the relatively short time course of vasospasm, this may not matter as much.
Safety concerns such as inflammation, viral cytotoxicity, and random viral DNA integration into host cells still persist . These events may be especially problematic in CV, as an increase in inflammation may exacerbate existing vasospasm, and such responses have been shown in adenovirus gene therapy . Fortunately in human trials of angiogenesis gene transfer for vascular disease, no increases in tumors, retinopathy, kidney failure, or cardiovascular endpoints have been reported .
There are other potential approaches to targeting CV-related genes which involve delivering gene products to vascular tissue. Two recent developments are summarized below.
2.3.3. Arginine-Conjugated Gene Delivery
Presumptive gene products can be conjugated with 10–20 amino acid polypeptides and delivered into somatic cells . This form of protein therapy can be used for therapeutic overexpression of genes in CV. In 2011 Ogawa and colleagues demonstrated that HMOX1 can be conjugated with an 11 arginine polypeptide and introduced by transcisternal injection in a rat model. They found that this method transduced the HMOX1 gene into all layers of the basilar artery and was vasoprotective in an experimental SAH model . Such a method may be applicable to transduction of other vasoprotective genes previously discussed in order to mitigate CV. However, concerns such as short time course of action, the need for continuous administration, imprecise delivery, and the need for large doses may make this less practical. In addition, this study reported no neurological differences in treated rats.
2.3.4. Intranasal Protein Delivery
Advances in drug delivery have made targeted therapy even more attractive. Crossing the blood-brain barrier (BBB) has been a historical challenge in neurotherapeutics. In addition, decreased cerebral blood flow (CBF) in the perivasospasm period decreases the delivery of intra-arterial administered drugs. In 2011 Ogawa and colleagues demonstrated that intranasal delivery of calcitonin gene-related protein (CGRP) can be an effective and minimally invasive way of bypassing the BBB . This study, performed in a rat model of SAH, attenuated vasospasm of the basilar artery as well as neurological deficits. More work will need to be done to see if this method is amenable to other known medications and gene products.
Within the past decade there has been increased knowledge in the genetic basis of CV along with refinements in gene therapy. Advances in genetic technology could add genetic screening and gene delivery to the armamentarium of future providers caring for SAH patients. While further study will be required to translate the available knowledge into clinical practice, the field of genetics holds great promise for the management of cerebral vasospasm.
Conflict of Interests
The authors report no conflict of interests concerning the materials or methods used in this study or the findings specified in this paper.
- J. I. Suarez, R. W. Tarr, and W. R. Selman, “Aneurysmal subarachnoid hemorrhage,” The New England Journal of Medicine, vol. 354, no. 4, pp. 387–396, 2006.
- N. W. C. Dorsch and M. T. King, “A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage Part I: incidence and effects,” Journal of Clinical Neuroscience, vol. 1, no. 1, pp. 19–26, 1994.
- N. F. Kassell, T. Sasaki, A. R. T. Colohan, and G. Nazar, “Cerebral vasospasm following aneurysmal subarachnoid hemorrhage,” Stroke, vol. 16, no. 4, pp. 562–572, 1985.
- B. Weir, M. Grace, J. Hansen, and C. Rothberg, “Time course of vasospasm in man,” Journal of Neurosurgery, vol. 48, no. 2, pp. 173–178, 1978.
- N. W. C. Dorsch, “Cerebral arterial spasm-a clinical review,” British Journal of Neurosurgery, vol. 9, no. 3, pp. 403–412, 1995.
- M. B. Zucker, “A study of the substances in blood serum and platelets which stimulate smooth muscle,” American Journal of Physiology, vol. 142, no. 1, pp. 12–26, 1944.
- A. Ecker and P. A. Riemenschneider, “Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms,” Journal of neurosurgery, vol. 8, no. 6, pp. 660–667, 1951.
- C. M. Fisher, J. P. Kistler, and J. M. Davis, “Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning,” Neurosurgery, vol. 6, no. 1, pp. 1–9, 1980.
- K. L. Chaichana, G. Pradilla, J. Huang, and R. J. Tamargo, “Role of inflammation (leukocyte-endothelial cell interactions) in vasospasm after subarachnoid hemorrhage,” World Neurosurgery, vol. 73, no. 1, pp. 22–41, 2010.
- M. Zimmermann and V. Seifert, “Endothelin and subarachnoid hemorrhage: an overview,” Neurosurgery, vol. 43, no. 4, pp. 863–876, 1998.
- D. H. Edwards, T. M. Griffith, H. C. Ryley, and A. H. Henderson, “Haptoglobin-haemoglobin complex in human plasma inhibits endothelium dependent relaxation: evidence that endothelium derived relaxing factor acts as a local autocoid,” Cardiovascular Research, vol. 20, no. 8, pp. 549–556, 1986.
- S. A. Saeed, N. Ahmad, and S. Ahmed, “Dual inhibition of cyclooxygenase and lipoxygenase by human haptoglobin: its polymorphism and relation to hemoglobin binding,” Biochemical and Biophysical Research Communications, vol. 353, no. 4, pp. 915–920, 2007.
- A. Agil, C. J. Fuller, and I. Jialal, “Susceptibility of plasma to ferrous iron/hydrogen peroxide-mediated oxidation: demonstration of a possible Fenton reaction,” Clinical Chemistry, vol. 41, no. 2, pp. 220–225, 1995.
- M. D. I. Vergouwen, M. Vermeulen, B. A. Coert, E. S. G. Stroes, and Y. B. W. E. M. Roos, “Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 11, pp. 1761–1770, 2008.
- J. P. Dreier, J. Woitzik, M. Fabricius et al., “Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations,” Brain, vol. 129, no. 12, pp. 3224–3237, 2006.
- R. L. Macdonald, R. T. Higashida, E. Keller et al., “Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling,” Stroke, vol. 43, no. 6, pp. 1463–1469, 2012.
- F. G. Barker II and C. S. Ogilvy, “Efficacy of prophylactic nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis,” Journal of Neurosurgery, vol. 84, no. 3, pp. 405–414, 1996.
- J. Mocco, E. R. Ransom, R. J. Komotar et al., “Racial differences in cerebral vasospasm: a systematic review of the literature,” Neurosurgery, vol. 58, no. 2, pp. 305–312, 2006.
- V. G. Khurana, Y. R. Sohni, W. I. Mangrum et al., “Endothelial nitric oxide synthase gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage and cerebral vasospasm,” Journal of Cerebral Blood Flow and Metabolism, vol. 24, no. 3, pp. 291–297, 2004.
- V. G. Khurana, D. J. Fox, I. Meissner, F. B. Meyer, and R. F. Spetzler, “Update on evidence for a genetic predisposition to cerebral vasospasm,” Neurosurgical Focus, vol. 21, no. 3, article E3, 2006.
- M. K. Song, M. K. Kim, T. S. Kim et al., “Endothelial nitric oxide gene T-786C polymorphism and subarachnoid hemorrhage in Korean population,” Journal of Korean Medical Science, vol. 21, no. 5, pp. 922–926, 2006.
- N. U. Ko, P. Rajendran, H. Kim et al., “Endothelial nitric oxide synthase polymorphism (-786T→C) and increased risk of angiographic vasospasm after aneurysmal subarachnoid hemorrhage,” Stroke, vol. 39, no. 4, pp. 1103–1108, 2008.
- R. M. Starke, G. H. Kim, R. J. Komotar et al., “Endothelial nitric oxide synthase gene single-nucleotide polymorphism predicts cerebral vasospasm after aneurysmal subarachnoid hemorrhage,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 6, pp. 1204–1211, 2008.
- M. Borsody, A. Burke, W. Coplin, R. Miller-Lotan, and A. Levy, “Haptoglobin and the development of cerebral artery vasospasm after subarachnoid hemorrhage,” Neurology, vol. 66, no. 5, pp. 634–640, 2006.
- M. D. I. Vergouwen, C. J. M. Frijns, Y. B. W. E. M. Roos, G. J. E. Rinkel, F. Baas, and M. Vermeulen, “Plasminogen activator inhibitor-1 4G allele in the 4G/5G promoter polymorphism increases the occurrence of cerebral ischemia after aneurysmal subarachnoid hemorrhage,” Stroke, vol. 35, no. 6, pp. 1280–1283, 2004.
- C. Ladenvall, L. Csajbok, K. Nylén, K. Jood, B. Nellgård, and C. Jern, “Association between factor XIII single nucleotide polymorphisms and aneurysmal subarachnoid hemorrhage: clinical article,” Journal of Neurosurgery, vol. 110, no. 3, pp. 475–481, 2009.
- M. J. Gallek, Y. P. Conley, P. R. Sherwood, M. B. Horowitz, A. Kassam, and S. A. Alexander, “APOE genotype and functional outcome following aneurysmal subarachnoid hemorrhage,” Biological Research for Nursing, vol. 10, no. 3, pp. 205–212, 2009.
- H. T. Wu, J. Ruan, X. D. Zhang, H. J. Xia, Y. Jiang, and X. C. Sun, “Association of promoter polymorphism of apolipoprotein e gene with cerebral vasospasm after spontaneous SAH,” Brain Research, vol. 1362, pp. 112–116, 2010.
- H. Rueffert, A. Gumplinger, C. Renner et al., “Search for genetic variants in the ryanodine receptor 1 gene in patients with symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage,” Neurocritical Care, vol. 15, no. 3, pp. 410–415, 2011.
- B. T. Grobelny, A. F. Ducruet, P. A. Derosa et al., “Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage: clinical article,” Journal of Neurosurgery, vol. 115, no. 1, pp. 101–107, 2011.
- J. S. Ware, A. M. Roberts, and S. A. Cook, “Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist,” Heart, vol. 98, no. 4, pp. 276–281, 2012.
- F. Sofi, B. Giusti, R. Marcucci, A. M. Gori, R. Abbate, and G. F. Gensini, “Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis,” Pharmacogenomics Journal, vol. 11, no. 3, pp. 199–206, 2011.
- J. L. Anderson, B. D. Horne, S. M. Stevens et al., “Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation,” Circulation, vol. 116, no. 22, pp. 2563–2570, 2007.
- L. R. Brunham, P. J. Lansberg, L. Zhang et al., “Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin,” Pharmacogenomics Journal, vol. 12, no. 3, pp. 233–237, 2012.
- R. M. Ned and E. J. G. Sijbrands, “Cascade screening for familial hypercholesterolemia (FH),” PLoS Currents, vol. 3, 2011.
- A. F. Ducruet, P. R. Gigante, Z. L. Hickman et al., “Genetic determinants of cerebral vasospasm, delayed cerebral ischemia, and outcome after aneurysmal subarachnoid hemorrhage,” Journal of Cerebral Blood Flow and Metabolism, vol. 30, no. 4, pp. 676–688, 2010.
- A. Dilraj, J. H. Botha, V. Rambiritch, R. Miller, J. R. Van Dellen, and J. H. Wood, “Levels of catecholamine in plasma and cerebrospinal fluid in aneurysmal subarachnoid hemorrhage,” Neurosurgery, vol. 31, no. 1, pp. 42–51, 1992.
- S. Naredi, G. Lambert, P. Friberg et al., “Sympathetic activation and inflammatory response in patients with subarachnoid haemorrhage,” Intensive Care Medicine, vol. 32, no. 12, pp. 1955–1961, 2006.
- Z. He, X. Sun, Z. Guo, and J. H. Zhang, “Expression and role of COMT in a rat subarachnoid hemorrhage model,” Acta Neurochirurgica, vol. 110, part 1, pp. 181–187, 2011.
- Z. He, X. Sun, Z. Guo, and J. H. Zhang, “The correlation between COMT gene polymorphism and early cerebral vasospasm after subarachnoid hemorrhage,” Acta Neurochirurgica, vol. 110, no. 1, pp. 233–238, 2011.
- P. A. Marsden, H. H. Heng, S. W. Scherer et al., “Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene,” The Journal of Biological Chemistry, vol. 268, no. 23, pp. 17478–17488, 1993.
- M. Y. Tseng, M. Czosnyka, H. Richards, J. D. Pickard, and P. J. Kirkpatrick, “Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial,” Stroke, vol. 36, no. 8, pp. 1627–1632, 2005.
- S. Moncada, R. M. J. Palmer, and E. A. Higgs, “Nitric oxide: physiology, pathophysiology, and pharmacology,” Pharmacological Reviews, vol. 43, no. 2, pp. 109–142, 1991.
- S. Moncada and E. A. Higgs, “The discovery of nitric oxide and its role in vascular biology,” British Journal of Pharmacology, vol. 147, supplement 1, pp. S193–S201, 2006.
- I. Azarov, X. He, A. Jeffers et al., “Rate of nitric oxide scavenging by hemoglobin bound to haptoglobin,” Nitric Oxide, vol. 18, no. 4, pp. 296–302, 2008.
- S. Nishizawa and I. Laher, “Signaling mechanisms in cerebral vasospasm,” Trends in Cardiovascular Medicine, vol. 15, no. 1, pp. 24–34, 2005.
- K. L. Chaichana, A. P. Levy, R. Miller-Lotan, S. Shakur, and R. J. Tamargo, “Haptoglobin 2-2 genotype determines chronic vasospasm after experimental subarachnoid hemorrhage,” Stroke, vol. 38, no. 12, pp. 3266–3271, 2007.
- V. G. Khurana, L. A. Smith, D. A. Weiler et al., “Adenovirus-mediated gene transfer to human cerebral arteries,” Journal of Cerebral Blood Flow and Metabolism, vol. 20, no. 9, pp. 1360–1371, 2000.
- V. G. Khurana, L. A. Smith, T. A. Baker, D. Eguchi, T. O'Brien, and Z. S. Katusic, “Protective vasomotor effects of in vivo recombinant endothelial nitric oxide synthase gene expression in a canine model of cerebral vasospasm,” Stroke, vol. 33, no. 3, pp. 782–789, 2002.
- V. G. Khurana, Y. R. Sohni, W. I. Mangrum et al., “Endothelial nitric oxide synthase T-786C single nucleotide polymorphism: a putative genetic marker differentiating small versus large ruptured intracranial aneurysms,” Stroke, vol. 34, no. 11, pp. 2555–2559, 2003.
- V. G. Khurana, I. Meissner, and F. B. Meyer, “Update on genetic evidence for rupture-prone compared with rupture-resistant intracranial saccular aneurysms,” Neurosurgical Focus, vol. 17, no. 5, article E7, 2004.
- M. Yoshimura, M. Nakayama, Y. Shimasaki et al., “A T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene and coronary arterial vasomotility,” American Journal of Cardiology, vol. 85, no. 6, pp. 710–714, 2000.
- M. G. Muhonen, H. Ooboshi, M. J. Welsh, B. L. Davidson, and D. D. Heistad, “Gene transfer to cerebral blood vessels after subarachnoid hemorrhage,” Stroke, vol. 28, no. 4, pp. 822–829, 1997.
- K. Toyoda, F. M. Faraci, A. F. Russo, B. L. Davidson, and D. D. Heistad, “Gene transfer of calcitonin gene-related peptide to cerebral arteries,” American Journal of Physiology, vol. 278, no. 2, pp. H586–H594, 2000.
- S. Ono, T. Komuro, and R. L. Macdonald, “Heme oxygenase-1 gene therapy for prevention of vasospasm in rats,” Journal of Neurosurgery, vol. 96, no. 6, pp. 1094–1102, 2002.
- Y. Watanabe, Y. Chu, J. J. Andresen, H. Nakane, F. M. Faraci, and D. D. Heistad, “Gene transfer of extracellular superoxide dismutase reduces cerebral vasospasm after subarachnoid hemorrhage,” Stroke, vol. 34, no. 2, pp. 434–440, 2003.
- B. L. Sun, F. P. Shen, Q. J. Wu et al., “Intranasal delivery of calcitonin gene-related peptide reduces cerebral vasospasm in rats,” Frontiers in Bioscience, vol. 2, pp. 1502–1513, 2010.
- T. Ogawa, D. Hänggi, Y. Wu et al., “Protein therapy using heme-oxygenase-1 fused to a polyarginine transduction domain attenuates cerebral vasospasm after experimental subarachnoid hemorrhage,” Journal of Cerebral Blood Flow & Metabolism, vol. 31, no. 11, pp. 2231–2242, 2011.
- D. N. Atochin, A. Wang, V. W. T. Liu et al., “The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo,” Journal of Clinical Investigation, vol. 117, no. 7, pp. 1961–1967, 2007.
- D. M. Dudzinski, J. Igarashi, D. Greif, and T. Michel, “The regulation and pharmacology of endothelial nitric oxide synthase,” Annual Review of Pharmacology and Toxicology, vol. 46, pp. 235–276, 2006.
- M. Sabri, J. Ai, B. Knight et al., “Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage,” Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 1, pp. 190–199, 2011.
- A. V. R. Santhanam, L. A. Smith, M. Akiyama, A. G. Rosales, K. R. Bailey, and Z. S. Katusic, “Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm,” Stroke, vol. 36, no. 12, pp. 2731–2737, 2005.
- M. J. McGirt, J. R. Lynch, A. Parra et al., “Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage,” Stroke, vol. 33, no. 12, pp. 2950–2956, 2002.
- T. Sugawara, R. Ayer, V. Jadhav, W. Chen, T. Tsubokawa, and J. H. Zhang, “Simvastatin attenuation of cerebral vasospasm after subarachnoid hemorrhage in rats via increased phosphorylation of Akt and endothelial nitric oxide synthase,” Journal of Neuroscience Research, vol. 86, no. 16, pp. 3635–3643, 2008.
- K. Osuka, Y. Watanabe, N. Usuda, K. Atsuzawa, J. Yoshida, and M. Takayasu, “Modification of endothelial nitric oxide synthase through AMPK after experimental subarachnoid hemorrhage,” Journal of Neurotrauma, vol. 26, no. 7, pp. 1157–1165, 2009.
- A. K. Vellimana, E. Milner, T. D. Azad et al., “Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm,” Stroke, vol. 42, no. 3, pp. 776–782, 2011.
- U. Förstermann, “Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal,” Biological Chemistry, vol. 387, no. 12, pp. 1521–1533, 2006.
- J. R. Lynch, H. Wang, M. J. McGirt et al., “Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial,” Stroke, vol. 36, no. 9, pp. 2024–2026, 2005.
- D. C. Hooper, C. J. Steer, C. A. Dinarello, and A. C. Peacock, “Haptoglobin and albumin synthesis in isolated rat hepatocytes. Response to potential mediators of the acute-phase reaction,” Biochimica et Biophysica Acta, vol. 653, no. 1, pp. 118–129, 1981.
- D. J. McCormick and M. Z. Atassi, “Hemoglobin binding with haptoglobin: delineation of the haptoglobin binding site on the α-chain of human hemoglobin,” Journal of Protein Chemistry, vol. 9, no. 6, pp. 735–742, 1990.
- M. Kristiansen, J. H. Graversen, C. Jacobsen et al., “Identification of the haemoglobin scavenger receptor,” Nature, vol. 409, no. 6817, pp. 198–201, 2001.
- J. R. McGill, F. Yang, and W. D. Baldwin, “Localization of the haptoglobin α and β genes (HPA and HPB) to human chromosome 16q22 by in situ hybridization,” Cytogenetics and Cell Genetics, vol. 38, no. 2, pp. 155–157, 1984.
- J. C. Wejman, D. Hovsepian, J. S. Wall, J. F. Hainfeld, and J. Greer, “Structure and assembly of haptoglobin polymers by electron microscopy,” Journal of Molecular Biology, vol. 174, no. 2, pp. 343–368, 1984.
- J. C. Wejman, D. Hovsepian, and J. S. Wall, “Structure of haptoglobin and the haptoglobin-hemoglobin complex by electron microscopy,” Journal of Molecular Biology, vol. 174, no. 2, pp. 319–341, 1984.
- J. JAVID, “The effect of haptoglobin polymer size on hemoglobin binding capacity,” Vox Sanguinis, vol. 10, no. 3, pp. 320–325, 1965.
- A. Sasahara, H. Kasuya, B. Krischek et al., “Gene expression in a canine basilar artery vasospasm model: a genome-wide network-based analysis,” Neurosurgical Review, vol. 31, no. 3, pp. 283–290, 2008.
- B. H. Bowman and A. Kurosky, “Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation,” Advances in Human Genetics, vol. 12, pp. 189–453, 1982.
- G. Pradilla, T. Garzon-Muvdi, J. J. Ruzevick et al., “Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage,” Neurosurgery, vol. 70, no. 3, pp. 747–757, 2012.
- M. T. Froehler, A. Kooshkabadi, R. Miller-Lotan et al., “Vasospasm after subarachnoid hemorrhage in haptoglobin 2-2 mice can be prevented with a glutathione peroxidase mimetic,” Journal of Clinical Neuroscience, vol. 17, no. 9, pp. 1169–1172, 2010.
- P. E. Morange, N. Saut, M. C. Alessi et al., “Association of plasminogen activator inhibitor (PAI)-1 (SERPINE1) SNPs with myocardial infarction, plasma PAI-1, and metabolic parameters: the HIFMECH study,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 10, pp. 2250–2257, 2007.
- W. Koch, M. Schrempf, A. Erl et al., “4G/5G polymorphism and haplotypes of SERPINE1 in atherosclerotic diseases of coronary arteries,” Thrombosis and Haemostasis, vol. 103, no. 6, pp. 1170–1180, 2010.
- T. Menges, P. W. M. Hermans, S. G. Little et al., “Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients,” Lancet, vol. 357, no. 9262, pp. 1096–1097, 2001.
- S. Ye, F. R. Green, P. Y. Scarabin et al., et al., “The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Etude CasTemoins de I'nfarctus du Mycocarde,” Thrombosis and Haemostasis, vol. 74, no. 3, pp. 837–841, 1995.
- W. J. Strittmatter and C. Bova Hill, “Molecular biology of apolipoprotein,” Current Opinion in Lipidology, vol. 13, no. 2, pp. 119–123, 2002.
- M. I. Kamboh, “Apolipoprotein E polymorphism and susceptibility to Alzheimer’s disease,” Human Biology, vol. 67, no. 2, pp. 195–215, 1995.
- R. Rao, V. Tah, J. P. Casas et al., “Ischaemic stroke subtypes and their genetic basis: a comprehensive meta-analysis of small and large vessel stroke,” European Neurology, vol. 61, no. 2, pp. 76–86, 2009.
- X. Sun and Y. Jiang, “Genetic susceptibility to traumatic brain injury and apolipoprotein E gene,” Chinese Journal of Traumatology, vol. 11, no. 4, pp. 247–252, 2008.
- Z. D. Guo, X. C. Sun, and J. H. Zhang, “The role of apolipoprotein e in the pathological events following subarachnoid hemorrhage: a review,” Acta Neurochirurgica, vol. 110, part 2, pp. 5–7, 2011.
- C. L. Lendon, J. M. Harris, A. L. Pritchard, J. A. R. Nicoll, G. M. Teasdale, and G. Murray, “Genetic variation of the APOE promoter and outcome after head injury,” Neurology, vol. 61, no. 5, pp. 683–685, 2003.
- Y. Jiang, X. Sun, L. Gui et al., “Correlation between APOE-491AA promoter in ε4 carriers and clinical deterioration in early stage of traumatic brain injury,” Journal of Neurotrauma, vol. 24, no. 12, pp. 1802–1810, 2007.
- K. Yamashiro, A. B. Milsom, J. Duchene et al., “Alterations in nitric oxide and endothelin-1 bioactivity underlie cerebrovascular dysfunction in ApoE-deficient mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 30, no. 8, pp. 1494–1503, 2010.
- M. Chow, A. S. Dumont, N. F. Kassell et al., “Endothelin receptor antagonists and cerebral vasospasm: an update,” Neurosurgery, vol. 51, no. 6, pp. 1333–1342, 2002.
- A. Hashimoto, G. Miyakoda, Y. Hirose, and T. Mori, “Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism,” Atherosclerosis, vol. 189, no. 2, pp. 350–357, 2006.
- M. W. Ledbetter, J. K. Preiner, C. F. Louis, and J. R. Mickelson, “Tissue distribution of ryanodine receptor isoforms and alleles determined by reverse transcription polymerase chain reaction,” Journal of Biological Chemistry, vol. 269, no. 50, pp. 31544–31551, 1994.
- V. Sorrentino, “The Ryanodine Receptor Family of Intracellular Calcium Release Channels,” Advances in Pharmacology, vol. 33, pp. 67–90, 1995.
- M. Koide, M. A. Nystoriak, G. Krishnamoorthy et al., “Reduced Ca2+ spark activity after subarachnoid hemorrhage disables BK channel control of cerebral artery tone,” Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 1, pp. 3–16, 2011.
- M. T. Nelson, H. Cheng, M. Rubart et al., “Relaxation of arterial smooth muscle by calcium sparks,” Science, vol. 270, no. 5236, pp. 633–637, 1995.
- G. C. Wellman and M. T. Nelson, “Signaling between SR and plasmalemma in smooth muscle: sparks and the activation of Ca2+-sensitive ion channels,” Cell Calcium, vol. 34, no. 3, pp. 211–229, 2003.
- G. C. Wellman, D. J. Nathan, C. M. Saundry et al., “Ca2+ sparks and their function in human cerebral arteries,” Stroke, vol. 33, no. 3, pp. 802–808, 2002.
- H. J. Knot, N. B. Standen, and M. T. Nelson, “Ryanodine receptors regulate arterial diameter and wall [Ca2+] in cerebral arteries of rat via Ca2+-dependent K+ channels,” Journal of Physiology, vol. 508, part 1, pp. 211–221, 1998.
- K. Abe and H. Kimura, “The possible role of hydrogen sulfide as an endogenous neuromodulator,” Journal of Neuroscience, vol. 16, no. 3, pp. 1066–1071, 1996.
- C. W. Leffler, H. Parfenova, J. H. Jaggar, and R. Wang, “Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation,” Journal of Applied Physiology, vol. 100, no. 3, pp. 1065–1076, 2006.
- G. Yang, L. Wu, B. Jiang et al., “H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase,” Science, vol. 322, no. 5901, pp. 587–590, 2008.
- A. Zubkov, L. Miao, and J. Zhang, “Signal transduction of ET-1 in contraction of cerebral arteries,” Journal of Cardiovascular Pharmacology, vol. 44, supplement 1, pp. S24–S26, 2004.
- J. F. Clark, M. Reilly, and F. R. Sharp, “Oxidation of bilirubin produces compounds that cause prolonged vasospasm of rat cerebral vessels: a contributor to subarachnoid hemorrhage-induced vasospasm,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 4, pp. 472–478, 2002.
- H. Suzuki, Y. Hasegawa, K. Kanamaru, and J. H. Zhang, “Mitogen-activated protein kinases in cerebral vasospasm after subarachnoid hemorrhage: a review,” Acta Neurochirurgica, vol. 110, part 1, pp. 133–139, 2011.
- X. D. Zhao, Y. T. Zhou, Y. Wu et al., “Potential role of Ras in cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits,” Journal of Clinical Neuroscience, vol. 17, no. 11, pp. 1407–1411, 2010.
- H. M. Lander, J. S. Ogiste, K. K. Teng, and A. Novogrodsky, “p21(ras) as a common signaling target of reactive free radicals and cellular redox stress,” Journal of Biological Chemistry, vol. 270, no. 36, pp. 21195–21198, 1995.
- M. Yamaguchi, C. Zhou, A. Nanda, and J. H. Zhang, “Ras protein contributes to cerebral vasospasm in a canine double-hemorrhage model,” Stroke, vol. 35, no. 7, pp. 1750–1755, 2004.
- G. Kusaka, H. Kimura, I. Kusaka, E. Perkins, A. Nanda, and J. H. Zhang, “Contribution of Src tyrosine kinase to cerebral vasospasm after subarachnoid hemorrhage,” Journal of Neurosurgery, vol. 99, no. 2, pp. 383–390, 2003.
- J. H. Laher IZhang, “Protein kinase C and cerebral vasospasm,” Journal of Cerebral Blood Flow & Metabolism, vol. 21, no. 8, pp. 887–906, 2001.
- T. Sasaki, H. Kasuya, H. Onda et al., “Role of p38 mitogen-activated protein kinase on cerebral vasospasm after subarachnoid hemorrhage,” Stroke, vol. 35, no. 6, pp. 1466–1470, 2004.
- Q. Jiang, R. Huang, S. Cai, and C. L. A. Wang, “Caldesmon regulates the motility of vascular smooth muscle cells by modulating the actin cytoskeleton stability,” Journal of Biomedical Science, vol. 17, no. 1, article 6, 2010.
- J. S. Rawlings, K. M. Rosler, and D. A. Harrison, “The JAK/STAT signaling pathway,” Journal of Cell Science, vol. 117, no. 8, pp. 1281–1283, 2004.
- K. Osuka, Y. Watanabe, K. Yamauchi et al., “Activation of the JAK-STAT signaling pathway in the rat basilar artery after subarachnoid hemorrhage,” Brain Research, vol. 1072, no. 1, pp. 1–7, 2006.
- G. Chen, J. Wu, C. Sun et al., “Potential role of JAK2 in cerebral vasospasm after experimental subarachnoid hemorrhage,” Brain Research, vol. 1214, pp. 136–144, 2008.
- K. Osuka, Y. Watanabe, N. Usuda, K. Atsuzawa, T. Wakabayashi, and M. Takayasu, “Oxidative stress activates STAT1 in basilar arteries after subarachnoid hemorrhage,” Brain Research, vol. 1332, pp. 12–19, 2010.
- J. M. Findlay, B. K. A. Weir, K. Kanamaru et al., “Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: dosage study in a primate model and review of the literature,” Canadian Journal of Neurological Sciences, vol. 16, no. 1, pp. 28–40, 1989.
- B. R. Clower, Y. Yamamoto, L. Cain, D. E. Haines, and R. R. Smith, “Endothelial injury following experimental subarachnoid hemorrhage in rats: effects on brain blood flow,” Anatomical Record, vol. 240, no. 1, pp. 104–114, 1994.
- C. O. Borel, A. McKee, A. Parra et al., “Possible role for vascular cell proliferation in cerebral vasospasm after subarachnoid hemorrhage,” Stroke, vol. 34, no. 2, pp. 427–432, 2003.
- R. M. Pluta, E. H. Oldfield, and R. J. Boock, “Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage,” Journal of Neurosurgery, vol. 87, no. 5, pp. 746–751, 1997.
- M. Félétou, Y. Huang, and P. M. Vanhoutte, “Endothelium-mediated control of vascular tone: COX-1 and COX-2 products,” British Journal of Pharmacology, vol. 164, no. 3, pp. 894–912, 2011.
- K. Satoh, Y. Fukumoto, and H. Shimokawa, “Rho-kinase: important new therapeutic target in cardiovascular diseases,” American Journal of Physiology, vol. 301, no. 2, pp. H287–H296, 2011.
- M. Sato, E. Tani, H. Fujikawa, and K. Kaibuchi, “Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm,” Circulation Research, vol. 87, no. 3, pp. 195–200, 2000.
- M. Amano, M. Ito, K. Kimura et al., “Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase),” Journal of Biological Chemistry, vol. 271, no. 34, pp. 20246–20249, 1996.
- G. J. Pyne-Geithman, S. G. Nair, D. N. Caudell, and J. F. Clark, “PKC and Rho in vascular smooth muscle: activation by BOXes and SAH CSF,” Frontiers in Bioscience, vol. 13, no. 4, pp. 1526–1534, 2008.
- G. Wickman, C. Lan, and B. Vollrath, “Functional roles of the Rho/Rho kinase pathway and protein kinase C in the regulation of cerebrovascular constriction mediated by hemoglobin: relevance to subarachnoid hemorrhage and vasospasm,” Circulation Research, vol. 92, no. 7, pp. 809–816, 2003.
- H. Shimokawa and A. Takeshita, “Rho-kinase is an important therapeutic target in cardiovascular medicine,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 9, pp. 1767–1775, 2005.
- Y. Watanabe, F. M. Faraci, and D. D. Heistad, “Activation of rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage,” American Journal of Physiology, vol. 288, no. 6, pp. H2653–H2658, 2005.
- K. Obara, S. Nishizawa, M. Koide et al., “Interactive role of protein kinase C-δ with Rho-kinase in the development of cerebral vasospasm in a canine two-hemorrhage model,” Journal of Vascular Research, vol. 42, no. 1, pp. 67–76, 2005.
- C. Lan, D. Das, A. Wloskowicz, and B. Vollrath, “Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C,” American Journal of Physiology, vol. 286, no. 1, pp. H165–H173, 2004.
- P. Nigro, K. Satoh, M. R. O’Dell et al., “Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E-deficient mice,” The Journal of Experimental Medicine, vol. 208, no. 1, pp. 53–66, 2011.
- K. Satoh, T. Matoba, J. Suzuki et al., “Cyclophilin a mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation,” Circulation, vol. 117, no. 24, pp. 3088–3098, 2008.
- K. Satoh, P. Nigro, and B. C. Berk, “Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin A,” Antioxidants and Redox Signaling, vol. 12, no. 5, pp. 675–682, 2010.
- S. Iwabuchi, T. Yokouchi, M. Hayashi et al., “Intra-arterial administration of fasudil hydrochloride for vasospasm following subarachnoid haemorrhage: experience of 90 cases,” Acta Neurochirurgica, vol. 110, part 2, pp. 179–181, 2011.
- H. Ooboshi, “Gene therapy as a novel pharmaceutical intervention for stroke,” Current Pharmaceutical Design, vol. 17, no. 5, pp. 424–433, 2011.
- T. Van-Assche, V. Huygelen, M. J. Crabtree, and C. Antoniades, “Gene therapy targeting inflammation in atherosclerosis,” Current Pharmaceutical Design, vol. 17, no. 37, pp. 4210–4223, 2011.
- S. Ono, T. Komuro, and R. L. Macdonald, “Adenovirus-mediated heme oxygenase-1 gene transfection prevents hemoglobin-induced contraction of rat basilar artery,” Acta Neurochirurgica, vol. 77, pp. 93–96, 2001.
- B. E. Jaski, M. L. Jessup, D. M. Mancini et al., “Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID trial), a first-in-human phase 1/2 clinical trial,” Journal of Cardiac Failure, vol. 15, no. 3, pp. 171–181, 2009.
- M. Jessup, B. Greenberg, D. Mancini et al., “Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure,” Circulation, vol. 124, no. 3, pp. 304–313, 2011.
- Y. Kawase, D. Ladage, and R. J. Hajjar, “Rescuing the failing heart by targeted gene transfer,” Journal of the American College of Cardiology, vol. 57, no. 10, pp. 1169–1180, 2011.
- F. Sedighiani and S. Nikol, “therapy in vascular disease,” Surgeon, vol. 9, no. 6, pp. 326–335, 2011.
- S. R. Schwarze, A. Ho, A. Vocero-Akbani, and S. F. Dowdy, “In vivo protein transduction: delivery of a biologically active protein into the mouse,” Science, vol. 285, no. 5433, pp. 1569–1572, 1999.