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Hindawi Publishing Corporation Neurology Research International Volume 2013, Article ID 291895, 11 pages http://dx.doi.org/10.

1155/2013/291895

Review Article Genetics of Cerebral Vasospasm
Travis R. Ladner,1 Scott L. Zuckerman,2 and J Mocco2
1 2

Vanderbilt University School of Medicine, Nashville, TN 37212, USA Department of Neurological Surgery, Vanderbilt University School of Medicine, Nashville, TN 37212, USA

Correspondence should be addressed to J. Mocco; j.mocco@vanderbilt.edu 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.

1. Introduction
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 [1]. 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 [4]. 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) [5]. 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 [6]. 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 [7], leading to the use of the Fisher Grade in predicting vasospasm onset [8]. 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) [9]. Lysed RBCs in subarachnoid space surrounding the cerebral vasculature can generate inflammatory downstream effects that result in endothelial damage and smooth muscle contraction [10]. In particular, extracorpuscular oxyhemoglobin is the potent inflammatory compound and has been shown to increase the formation of reactive oxygen species (ROS), decrease nitric

or no clear association. 64]. Constitutive levels of NO inhibit platelet aggregation. an endothelin receptor antagonist. Genomic biomarkers may also be used to stratify SAH patients for more intensive monitoring according to vasospasm risk. and inflammation [9. 38]. This polymorphism may be a biomarker for predicting poor outcomes in patients with aneurysms that may later rupture. 49]. The following is a summary of genetic markers associated with SAH and CV. 60]. Close family members of patients with aneurysms may be screened for their own susceptibility for aneurysm formation and rupture. COMT. which decreases NO availability while simultaneously increasing the production of superoxide. which is found on chromosome 7q35. decreasing NO-mediated vasorelaxation and contributing to the onset of vasospasm [45–47]. warfarin. Superoxide may further react with remaining NO to form peroxynitrite. and increase lipid peroxidation [9. recent work suggests that simvastatin may work by recoupling eNOS to increase NO production and decrease the production of superoxide [61]. with attention to recent discoveries reported in the literature. improves functional outcomes without a parallel reduction in angiographic vasospasm [17]. 15]. posttranslational modifications. 42–44]. 11–13]. increase prostaglandin synthesis. Cate-chol-ami-nes have been implicated in the development of acute CV following SAH [37. The literature is mixed on whether eNOS activity is increased [61]. plays an important role in CV and other cardiovascular diseases [41]. Understanding the genetic mechanism of disease generation may provide insight into novel therapeutic avenues. Genetic risk stratification for CV holds great potential. 2. . the various findings are contradictory. 2. and statins have already been made based on the patient’s genotype [32–34].1. nimodipine. C allele. 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 [67]. A/A genotype were more likely to develop acute CV [40]. protein-protein interactions. An active area of research is the exploration of the genetic basis for CV. 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. Genetic screening of family members of patients diagnosed with familial hypercholesterolemia is currently recommended in the UK [35].1. showing either an effect with the T allele. This process occurs in parallel to the delayed cerebral ischemia (DCI) resulting from microthromboses and cortical spreading ischemia [14. A study of 167 Chinese Han SAH patients showed that patients with the COMT-A allele. we will summarize the most recent research in the following areas regarding genetics and CV: (1) prognostic role of genetics. and (3) gene therapy and gene delivery.2 oxide (NO) concentration. as well as informing medication administration. This may further explain its mechanism of attenuating vasospasm clinically and in other animal models [63. or unchanged [63–66] following SAH. Clinically. has shown great attenuation of angiographic vasospasm in preclinical and clinical studies but no improvement in neurological outcomes [16]. which has previously been supported by population studies [18]. The activity of eNOS is tightly regulated at many stages. eNOS is present in the endothelium of the major cerebral arteries and produces nitric oxide (NO). However. Neurology Research International 2. 2. indications on the use of drugs such as clopidogrel. decreased [62]. Polymorphisms of the eNOS genes are linked to intracranial aneurysm formation [50. has been shown to play a role in acute CV. vascular smooth muscle proliferation. cofactors. (2) key signaling mediators involved. In contrast. 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. substrate availability. the field still lacks a definitive explanatory model with robust predictability and therapeutic targets. This apparent discrepancy is likely attributable to the heterogeneity of vasospasm definition as well as the complex regulation of the eNOS gene. it is still unclear what role SAH plays in the phosphorylation of eNOS [66]. While it is known that simvastatin can mitigate vasospasm [63. Overexpression of the eNOS gene has been shown to be vasoprotective in humans and canines in the setting of SAH [48. In cardiovascular medicine.1.1. the field of genetics offers a new insight. Perivascular oxyhemoglobin released after SAH scavenges NO generated by eNOS. However. In this review. Recent studies by Sabri and colleagues have shown that SAH leads to increased phosphorylation of eNOS on Ser1177 and subsequent uncoupling. clazosentan. Genetic association studies have shown that eNOS 7-786 gene SNPs predispose aSAH patients for vasospasm [19–23]. Such changes in the vascular equilibrium can lead to the activation of provasospasm signaling pathways and the synthesis of inflammatory gene products. This represents an update on a genetics review by Ducruet and colleagues [36]. and dimerization [59. 68]. 23. Further. Stratifying risk based on next generation sequencing is gradually becoming integrated into medical practice [31]. with evidence for disease mechanisms as well as implicated polymorphisms (Table 1). which continues to deplete residual NO [61]. Endothelial Nitric Oxide Synthase (eNOS) Gene. a key enzyme in the degradation of catecholamines. a calcium channel blocker. 51] and coronary vasospasm [52]. Catechol-O-methyltransferase (COMT). including transcription. Prognostic Factors. Genetics in CV While much work has been done to characterize the signaling pathways implicated in CV.2. For example. Endothelial nitric oxide synthase (eNOS) gene. Several presumptive targets have been proposed with only modest gains. A rat model has shown increased expression of COMT and catecholamines following SAH induction [39]. decreased levels of NO in the CSF have been reported in aSAH patients. a potent vasodilator.

with greater binding and clearing of hemoglobin in Hp 1-1 individuals and weaker binding and clearance in Hp 2-2 individuals [45. leading to increased inflammation. 77]. A common polymorphism is the 4G/5G SNP on the promoter region [81]. is associated with plasma lipoproteins and is involved in lipid transport and metabolism in the central nervous system [84]. which may also support the pathologic uncoupling hypothesis. 𝜀3. oxidation. encoding 3 different isoforms (ApoE2. 47]. but no increase in delayed cerebral ischemia. decreased NO availability with no change in eNOS activity was observed in SAH. The Hp gene has been shown to be upregulated in a canine model of CV [76]. Gene eNOS eNOS eNOS eNOS eNOS Hp PAI-1 PAI-1 ApoE ApoE RyR1 CBS Reference [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] 𝑁 141 51 136 347 77 32 126 183 206 101 46 87 3 Finding T-786C promoter → clinical/angiographic and/or TCD vasospasm T-786C SNP → symptomatic/asymptomatic angiographic vasospasm No relationship T-786C SNP → angiographic vasospasm T-786C SNP → angiographic vasospasm Hp 2 allele → angiographic and/or TCD vasospasm 4G allele → DCI and poor 3-month GOS No relationship b/w allele and 1-year GOS-E ApoE4 allele → poor GOS −219T → clinical and TCD vasospasm GT c. These structural differences confer different binding affinities. As such. another study of 183 aSAH patients in 2009 found no association between the PAI1 SNP and poor outcomes on the 1-year GOS-E scale [26]. the Hp 2-2 allele may be a mediator of CV as well. PAI-1 has also been investigated in the setting of SAH for a possible link to thrombosis-related DCI. 2. respectively. 79]. 2. While this polymorphism does not appear to play a role in generating vasospasm. which are encoded by the haptoglobin alpha gene and haptoglobin beta gene.1. a polymorphic protein encoded by the ApoE gene. and the Hp 2-2 product is a cyclical polymer [73. or Hp 2-2. more work must be done to characterize this apparent discrepancy. Mice with the Hp 2-2 genotype display greater arterial narrowing and neurological deficits compared to Hp 1-1 mice following experimental SAH [47]. The Hp gene exists in 2 alleles in humans. Clinically. it seems to inhibit normal neuronal plasma membrane repair . Plasminogen Activator Inhibitor-1 (PAI-1). found on the 7q21. 2. 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 [25]. thought to contribute to the neurological deficits resulting from CV [14]. It is composed of an alpha subunit and a beta subunit. and vasoconstriction [9. These results suggest that PC-induced vasoprotection is mediated by upregulation of eNOS. ApoE. The 𝜀4 allele predisposes patients to poor neurological outcomes in CV. ApoE has been studied extensively in the literature for its significance to cerebrovascular disease. Apolipoprotein E (ApoE). The Hp 1 product is a linear dimer. Given the multifactorial nature of vasospasm.3q22 chromosome [80].Neurology Research International Table 1: Summary of prognostic genes in cerebral vasospasm.4. Haptoglobin. 74]. It is antifibrinolytic. immune response. Haptoglobin (Hp) is a serum protein produced primarily by hepatocytes [69] that binds to free hemoglobin released by lysed erythrocytes [70]. ApoE3. 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 [24]. 1080TT → DCI 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. and ischemic stroke [27. However. traumatic brain injury. As a result. In recent years the Hp 2-2 mouse has been investigated as a novel animal model for CV and its treatment [78. and 3 genotypes are possible: Hp 1-1. increasing NO levels and reducing vasospasm [66]. Hp 2-2.3.5. Three common alleles have been reported in humans (𝜀2.1. the allelic distribution of Hp in Western patients roughly corresponds to the prevalence of CV in Western SAH patients [5. However. functioning as the principal inhibitor of tissue plasminogen activator and urokinase. and ApoE4) [85]. and 𝜀4) on the 19p13 chromosome. 75]. the Hp 2-2 allele is thought to be more proinflammatory than the Hp 1-1 allele. The bound complex is taken up by macrophages through the CD163 receptor. PAI-1 is a protein encoded by the SERPINEI gene. presumably reducing extracorpuscular hemoglobin toxicity [71].6178G → T → symptomatic vasospasm 699CT and TT → angiographic vasospasm.1. 86– 88]. the purported role of this allele in vasospasm following aSAH is still unclear. the Hp 2-1 product is a linear polymer. In addition. which themselves activate plasmin. The gene complex is found on human chromosome 16q22 [72]. The 4G allele has been previously associated with higher plasma concentrations of PAI-1 in the acute setting and poorer survival after trauma [82] as well as increased PAI-1 activity in myocardial infarction [83].

the mechanisms of which are still currently being investigated. impaired vasorelaxation.5-trisphosphate (IP3 ). as those generated following SAH. inhibition of the Ras-ERK pathway is associated with a reduction in vasospasm in rabbit and canine models of SAH [107.2. More work must be done to characterize these prognostic genes and generate more consistent findings on their role in vasospasm. 2. This study suggests that H2 S-mediated signaling is neuroprotective in aSAH.1. Another study reported that in e4 carriers the 491AA SNP contributed to poor outcomes in traumatic brain injury [90]. which are substrates for MAPK.2. There are three subtypes (RyR1. 104. Ras has been shown to be activated in a rabbit model of SAH. Cystathionine 𝛽-synthase (CBS) is an enzyme that converts homocysteine and serine to form cystathionine. and ROS activate cytokine and cellular signaling pathways [9. Administration of cilostazol was reported to decrease endothelial dysfunction in knockout mice. Delayed cerebral ischemia was more frequent in 1080TT (decline of Neurology Research International function) populations. and inflammation [106. Within the past decade the promoter region of ApoE has come under more scrutiny for its role in CV after SAH. bilirubin oxidation products (BOXes). A 2011 study of 46 patients in Germany revealed that SAH patients who were heterozygous for the c. inositol-1.2. which decreases its protective effect in the setting of inflammation [28]. 2. 2. The following is a summary of 3 important known pathways in CV. Ryanodine. releasing H2 S in the process [101]. H2 S is a vasodilator and neuromodulator and is known to function in the cerebral circulation. As such. 95]. which likely increases eNOS phosphorylation [93].4 following cerebral ischemia. which together activate protein tyrosine kinase (TK). TK phosphorylates Ras to form the GTP-bound activated form of Ras. 2. and this protection may not be dependent on vasoprotection.1.6 expression. 105]. A recent study of ApoE knockout mice [91] observed enhanced vasoconstriction in response to endothelin-1. and vasospasm-monitoring modalities must be reconciled for more definitive explanations. tissue proliferation. cell adhesion. a stabilizer of RyR2 channels. and RyR3). These can lead to the alteration of expression of CV-related genes. ostensibly worsening outcomes for the patients that do end up developing vasospasm [36]. It is hypothesized that spasmogens. 109. 103]. An in vitro model using human vascular smooth muscle cells found that inhibition of p38 MAPK resulted in decreased vasospasm and cytokine production [112]. A study in 2003 found that carriers of the G-219T allele had more unfavorable GOS functional scores [89]. when released from lysed blood cells surrounding vascular tissue. and inhibition of them by MAPK may lead to sustained vascular smooth muscle contraction [106]. ROS. and diacylglycerol (DAG). these remain the most studied genes and may therefore play a role in future stratification of SAH patients. and migration [107]. oxyhemoglobin. but no increase in delayed cerebral ischemia [30].6178G>T polymorphism of the RyR1 gene were more likely to develop symptomatic vasospasm [29]. 2. 110]. have also been associated with Ras activation [108]. Inflammatory molecules generated from the breakdown of blood products following SAH incite several known cascades of cellular signaling enzymes. compounds such as endothelin-1. Differences in study designs. The MAPK signaling pathway is important in the generation of vasospasm [106]. apoptosis. but the exact interaction has not yet been determined [106. Signaling Pathways. MAPK is associated with vasoconstriction. It is hypothesized that caldesmon and calponin. and recent evidence indicates that RyRs may play a role in the pathogenesis of vasospasm after SAH.1. A study of 101 SAH patients in China in 2010 showed that patients carrying the −219T allele had an increased risk of CV [28]. Ryanodine receptors (RyRs) are a family of Ca2+ intracellular calcium channels that mediate the calciuminduced calcium release (CICR). which promote vasorelaxation through hyperpolarizing VSMCs [96–98]. although the nature of its interaction warrants further study [30. 102. a vasoconstrictive compound associated with CV [92]. Ras/MAPK. RyRs are involved in the regulation of cerebral artery luminal diameter [99. sample sizes. JAK/STAT Signaling. However. Cystathionine 𝛽-Synthase. GTP-bound (activated) Ras interacts with Raf-1 to phosphorylate downstream effectors such as extracellular signal-regulated kinase (ERK). peaking at day 3 [107]. RyR2.7. are associated with vasoconstriction. which are all present in vascular smooth muscle [94.6. which is associated with cell cycle regulation. These proteins are inhibitors of Ca2+ -dependent smooth muscle contraction. This effect is possibly mediated through decreased transcriptional activity of ApoE. The JAK/STAT signaling pathway is an important mediator of downstream cytokine and growth factor activity [114] and may be involved in the pathogenesis . 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. Polymorphisms in the promoter region have previously been associated with poorer outcomes in traumatic brain injury. 113]. 111]. polymorphisms in genes encoding RyRs are related to vasospasm onset. Clinically. Preliminary studies have shown that alteration of these pathways may provide therapeutic benefit. Activation of these receptors facilitates Ca2+ sparks. A study of 87 aSAH patients found that those with the 699CT and TT (gain of function) genotypes had increased angiographic vasospasm. These changes appear to come from a combination of reduced RyR2 expression as well as increased FKBP12. Koide and colleagues found a 50% reduction in Ca2+ spark activity coupled with a 65% reduction in RyR2 expression following induced SAH in rabbits [96]. lead to the sequential activation of phospholipase C (PLC). 100].4. This pathway mobilizes Ca2+ and activates protein kinase C (PKC). In particular.2. CBS is the predominant source of H2 S in the brain and therefore may play a role in cerebrovascular disease.

JAK1 has been shown to be activated in a rat model of SAH following production of IL-6 [115].3. Challenges. In addition.3. However. Gene Therapy and Delivery. In addition. and perivascular tissue Adenovirus Rat HO-1 mRNA and protein in BA adventitia Adenovirus Canine BA adventitia Adenovirus Rabbit BA adventitia Protein Rat — Arginine Rat All layers of BA 5 Effect — Attenuation of vasoconstriction Attenuation of vasoconstriction Attenuation of vasoconstriction Attenuation of vasoconstriction Attenuation of vasoconstriction Attenuation of vasoconstriction of CV. Gene Reference 𝛽-galactosidase [53] CGRP [54] HMOX [55] eNOS [49] Superoxide dismutase [56] CGRP [57] HMOX [58] Method Organism Expression Adenovirus Canine Leptomeninges. the effector of Rho. There are no published clinical models of such therapy to date in CV. As CV is a polygenic disorder. including prostaglandins and thromboxanes. Rho-kinase has been shown to be involved in the pathogenesis of both coronary and cerebral vasospasm [124. 138]. Rho proteins are small G proteins that are commonly expressed in mammals [123]. eNOS [49]. and endothelial damage [123. there are several challenges to the translation of preclinical protocols to humans in the setting of CV [136]. 126–131]. Cytokines such as IL-6 are known to be elevated in SAH patients and are also known activators of JAKs. While STAT3 is activated in response to cytokines. STAT proteins have been shown to be activated in the basilar artery in a rat model of SAH.1. the Rho/Rho-kinase pathway decreases NO production through the production of cyclophilin A (CyPA). BA adventitia. greater loads of genecarrying viruses will be required. In 2002 Ono and colleagues showed that the HMOX1 gene can be transferred to the rat basilar artery adventitia through adenovirus using transcisternal injection. and superoxide dismutase [56]. are known to lead to endothelial dysfunction through endothelial-dependent contractions [122]. with STAT3 expressed in the intima and media and STAT1 expressed in the adventitia [115]. Despite the promise gene therapy holds. 134]. which contributes to increased ROS production [133. Rho-kinase also phosphorylates myosin light chain directly. an inhibitor of Rho-kinase. It is difficult to ensure adequate and accurate tissue distribution. Activated JAKs subsequently phosphorylate STAT proteins. which decreases eNOS expression [132]. Akt. 2. single gene therapy alone may not be sufficient. Therefore. Endothelial cell death promotes thrombosis and decreases vasodilator expression [119–121]. The route of administration is typically through the cisterna magna. We summarize the current status of gene therapy in CV (Table 2). overexpression of the SERCA2a gene by viral transfer has shown success in improving outcomes in heart failure patients [139–141]. This was associated with increased heme oxygenase-1 mRNA and activity. In the last decade this method has shown efficacy in preclinical SAH models using genes such as calcitonin gene-related peptide (CGRP) [54]. generating sustained contraction in a similar manner as the Ca2+ /calmodulindependent MLC kinase pathway [125]. CyPA itself stimulates ERK1/2. Rho/Rho-Kinase. COX-2 products. Rho-kinase. Oxyhemoglobin from SAH activates Rho/Rho-kinase signaling [127]. has shown some benefit in treating vasospasm in SAH patients [135]. 142]. however. STAT1 is activated by the free radicals generated by oxyhemoglobin metabolism following SAH [117]. In a proof-of-concept experiment reported in 1997. and JAK in VSMCs. Within the past decade viral vector-mediated gene therapy has been explored in the context of vasospasm and other vascular diseases [136. especially to the endothelium. It may be more difficult to express genes within deeper layers of blood vessels with perivascular administration. JAK2 has also been shown to be activated in a rabbit model of SAH [116]. Muhonen and colleagues demonstrated that 𝛽-galactosidase could be transferred to cerebral blood vessels and surrounding tissue during vasospasm using a virus vector [53]. Fasudil. 134]. with increased basilar artery diameter and CBF [55.3. Overexpression of heme oxygenase1 attenuated vasospasm in this model. humans have increased body weight relative to small laboratory animals. 2.Neurology Research International Table 2: Summary of preclinical in vivo gene therapy experiments. 2. which requires more invasive procedures in critically ill patients. as fibrosis of the cerebral arteries is associated with vasospasm following SAH [118]. Rho-kinase phosphorylates and inhibits myosin light chain phosphatase and therefore increases contractility [124]. Inflammatory changes in the adventitia may result in decreased vessel compliance and may contribute to the vessel stiffness observed in CV [120]. 137]. Taken together. inflammation. 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 [116]. these findings suggest that the JAK/STAT pathway may be an important mediator of vasospasm. plays an important role in the cardiovascular system through its interaction with the myosin light chain (MLC) in VSMC contractions. and BA adventitia Adenovirus Rabbit CSF. ROS production. These early gene products may mediate the generation of vasospasm. Rho-kinase is also known to play a role in vascular smooth muscle through increasing vascular smooth muscle proliferation. Intramuscular injection of VEGFcarrying adenovirus has improved peripheral artery occlusive disease and coronary artery disease in clinical trials [137. JAK1/STAT3 signaling in rats upregulates the inflammatory COX-2 protein in the intima [115]. external ventricular drains may provide appropriate CSF access. ependyma. Perhaps the development of endovascular administration with vectors .2.

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