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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Acta Neurochir Suppl. Author manuscript; available in PMC 2012 January 1.
Published in final edited form as:
Acta Neurochir Suppl. 2011; 111: 83–92.
doi:  10.1007/978-3-7091-0693-8_14
PMCID: PMC3187860

Brain Arteriovenous Malformation Pathogenesis: A Response-to-Injury Paradigm

Helen Kim, PhD,1,4,5 Hua Su, MD,1 Shantel Weinsheimer, PhD,1 Ludmila Pawlikowska, PhD,1,5 and William L. Young, MD1,2,3


Brain arteriovenous malformations (AVMs) are a rare but important cause of intracranial hemorrhage (ICH) in young adults. In this paper, we review both human and animal studies of brain AVM, focusing on the: (1) natural history of AVM hemorrhage; (2) genetic and expression studies of AVM susceptibility and hemorrhage; and (3) strategies for development of a brain AVM model in adult mice. These data target various mechanisms which must act in concert to regulate normal angiogenic response to injury. Based on the various lines of evidence reviewed in this paper, we propose a “response-to-injury” model of brain AVM pathogenesis.

Keywords: Brain arteriovenous malformations, Intracranial hemorrhage, Gene expression, Genetics, Angiogenesis, Inflammation, Animal models

Brain arteriovenous malformations (AVM) represent a relatively infrequent but important source of neurological morbidity in relatively young adults [5]. Brain AVMs have a population prevalence of 10–18 per 100,000 adults [4, 7], and a new detection rate (incidence) of ~1.3 per 100,000 person-years [12, 53]. The basic morphology is of a vascular mass, called the nidus, that directly shunts blood between the arterial and venous circulations without a true capillary bed. There is usually high flow through the feeding arteries, nidus and draining veins. The nidus is a complex tangle of abnormal, dilated channels, not clearly artery or vein, with intervening gliosis.

Seizures, mass effect and headache are causes of associated morbidity, but prevention of new or recurrent intracranial hemorrhage (ICH) is the primary rationale to treat AVMs, usually with some combination of surgical resection, embolization and stereotactic radiotherapy. The risk of spontaneous ICH has been estimated in retrospective and prospective observational studies to range from 2–4% per year [26], but approximately 50% of patients present initially with a bleed. Other than non-specific control of symptoms, e.g., headache and seizures, primary medical therapy is lacking.

Treatment of unruptured AVMs is controversial and has led to an ongoing randomized clinical trial to test whether best medical therapy has better outcomes than procedural intervention ( Due to the complexity of AVM treatment and a wide range of expert opinions, it is unlikely that a single clinical trial can settle all of the questions related to management strategies. Thus, understanding the pathogenesis of AVM formation and progression to ICH will be important for informing patient management decisions.

In this review, we propose a novel “response-to-injury” paradigm to explain sporadic brain AVM pathogenesis, based on findings from clinical research studies of AVM patients and animal models investigating AVM formation to date. Figure 1 shows a speculative synthesis of pathways involved in AVM pathogenesis. Inciting event(s), while not known, might include sequelae of even modest injury from an otherwise unremarkable episode of trauma, infection, inflammation, irradiation, or a mechanical stimulus such as compression. The normal response to these inciting events would involve angiogenesis, endothelial mitogenesis, and vascular stabilization. However, when superimposed on an underlying structural defect, such as a microscopic developmental venous anomaly or some sort of venous outflow restriction in a microcirculatory bed, or an underlying genetic background, such as mutations in key angiogenic genes, the normal injury response is shifted towards an abnormal dysplastic response. In the next few sections, we will review the available data on factors involved in the abnormal “response-to-injury” in AVMs.

Fig. 1
Speculative synthesis of pathways involved in AVM pathogenesis

Evidence for Abnormal Angiogenesis and Inflammation in AVM

Studies of surgically-resected AVM tissue suggest an active angiogenic and inflammatory lesion rather than a static congenital anomaly. Several groups [21, 43] have shown that a prominent feature of the AVM phenotype is relative overexpression of vascular endothelial growth factor (VEGF-A), at both the mRNA and protein level. Extrapolating from animal models, VEGF may contribute to the hemorrhagic tendency of AVMs [30]. The vascular phenotype of AVM tissue may be explained, in part, by an inadequate recruitment of peri-endothelial support structures, which is mediated by angiopoietins and TIE-2 signaling. For example, angiopoietin-2 (ANG-2), which allows loosening of cell-to-cell contacts, is overexpressed in the perivascular region in AVM vascular channels [20].

A key downstream consequence of VEGF and ANG-2 signaling, contributing to the angiogenic phenotype, is matrix metalloproteinase (MMP) expression. MMP-9 expression, in particular, appears to be at least an order of magnitude higher in AVM than in control tissue [8, 22] with levels of naturally occurring MMP inhibitors, TIMP-1 and TIMP-3, also increased, but to a lesser degree. Additional inflammatory markers that are overexpressed include myeloperoxidase (MPO) and interleukin 6 (IL-6), both of which are highly correlated with MMP-9 [8, 9]. MMP-9 expression is correlated with the lipocalin-MMP-9 complex, suggesting neutrophils as a major source. In a subset of unruptured, non-embolized AVMs, neutrophils (MPO) and macrophages/microglia (CD68) were all prominent in the vascular wall and intervening stroma of AVM tissue, whereas T and B lymphocytes were present but rarely observed [10]. Higher immunoglobulin levels have been reported in AVM tissue than in control brain [48].

Exactly how the dysplastic response propagates is not known, but recruitment of progenitor cell populations may be one source influencing AVM growth and development and is an area in need of further exploration. For example, endothelial progenitor cells (EPCs) are present in the nidus of brain and spinal cord AVMs, and may mediate pathological vascular remodeling and impact the clinical course of AVMs. Gao et al. demonstrated that both brain and spinal AVM tissues displayed more CD133, SDF-1, and CD68-positive signals than epilepsy and basilar artery control tissues [14]. EPCs, identified as CD133 and KDR double stained-positive cells, were increased in the brain and spinal cord AVM nidus, mainly at the edge of the vessel wall. The expression of SDF-1 was co-localized with CD31-positive and α-smooth muscle cell expression, and was predominantly found within the vessel wall. More generally, circulating bone-marrow derived cells have a major role in both microcirculatory angiogenesis [16, 17] and conductance vessel remodeling [35, 36]. If AVM pathogenesis involves these two processes, it is reasonable to infer that bone-marrow derived cells may have an underappreciated role in lesion formation and growth. An unresolved issue with all stem cell interactions is the extent to which progenitor cells actually integrate into existing tissue compartments, or whether they provide a nursing function by supplying critical components of the repair response such as cytokines, growth factors and enzymes to the tissue, i.e., do progenitor cells supply “troops” or merely “ordinance”.

Evidence for Genetic Influences in AVMs

Candidate genes and pathways for brain AVM pathogenesis have been suggested by Mendelian disorders, which exhibit AVMs as part of their clinical phenotype, and gene expression studies. AVMs in various organs, including the brain, are highly prevalent in patients with hereditary hemorrhagic telangiectasia (HHT, OMIM#187300), an autosomal dominant disorder of mucocutaneous fragility. Compared to sporadic lesions, brain AVMs in HHT tend to be smaller and are more likely to have single draining veins, be located superficially, and be multiple. However, they are generally similar to the sporadic lesions and cannot be distinguished individually on the basis of their angioarchitecture.

The two main subtypes of HHT (HHT1 and 2) are caused by loss-of-function mutations in two genes [33] originally implicated in TGF-β signaling pathways (Figure 1). The first is endoglin (ENG), which encodes an accessory protein of TGF-β receptor complexes. The second is activin-like kinase 1 (ALK1, or ACVLR1), which codes for a transmembrane kinase also thought to participate in TGF-β signaling. There are hundreds of reported mutations in ALK1 and ENG [1], but the functional effect appears to be haploinsufficiency rather than a mutation-specific set of dysfunctions. A third candidate gene for AVM pathogenesis is SMAD4, encoding a downstream participant in TGF-β and bone morphogenic protein (BMP) signaling. SMAD4 is mutated in a combined syndrome of juvenile polyposis and HHT [13]. These HHT mutations can be viewed as risk factors for brain AVM since the prevalence in HHT1 (ENG) is 1000-fold higher and HHT2 (ALK1) is 100-fold higher compared to the prevalence of brain AVMs in the general population (10/100,000) [24].

At the earliest stages of vascular development, mice lacking Alk-1 (Acvrl1) form systemic A-V fistulae from fusion of major arteries and veins [57]. Endothelial cell-specific ablation of the murine Alk-1 gene causes vascular malformations to form during development, whereas mice harboring an EC-specific knockout of Alk-5 (the type I TGF-β receptor) or Tgfbr2 show neither vascular malformation formation nor any other perturbation in vascular morphogenesis [37]. The exact signaling pathways for ALK-1 and ENG are complex, interrelated and their relative importance and cellular specificity are controversial [55]. ENG interacts with multiple TGF-β related signaling pathways and interacts with TGFBR2 (the type II TGF-β receptor) as well as with type I TGF-β receptors, ALK-1 and ALK-5 [31]. ENG can also bind ligands besides TGF-β, including activins and BMP family members [6, 45]. Regardless of the exact signaling mechanism leading to vascular malformation, it is clear that mutations and likely genetic variation in TGF-beta signaling genes are important players in the “response-to-injury” paradigm of AVM pathogenesis.

Candidate Gene Studies in non-HHT AVM Patients

The mechanism of AVM initiation is as yet unknown. Even if it involves a structural aberration, or mechanical insult—per se not a heritable trait—the subsequent growth and behavior of the lesion may still be influenced by genetic variation. For example, multiple genetic loci influence VEGF-induced angiogenesis [42, 46]. Therefore, a pathogenesis that involves a “response-to-injury” at any level may be at least partially influenced by heritable aspects of such a response.

Candidate gene studies of sporadic AVM cases have identified single nucleotide polymorphisms (SNPs) in several genes associated with risk of AVM susceptibility and/or progression to ICH. Previously, SNPs in ALK1 (IVS3–35A>G) and ENG (207G>A) were found to be associated with an increased risk of AVM [40]. The ALK1 finding was later replicated in an independent cohort of AVM patients from Germany [49, 50]. Additionally, common SNPs in interleukin (IL) genes have been associated with increased risk of AVM among certain race-ethnic groups. Among Hispanics, a promoter SNP in IL-6 (−174G>C) was associated with a 2-fold increased risk of AVM after adjusting for age, sex, and genetic ancestry. Among self-reported Caucasians, common SNPs in IL-1β, 2 promoter (−31T>C and −511C>T) and 1 exonic (+3953C>T), were also associated with increased risk of AVM susceptibility [23]. The IL-1β promoter polymorphisms have also been reported to have functional effects on IL-1β transcription. Thus, genetic variation in these cytokines may contribute to AVM pathogenesis by enhancing or maintaining a pro-inflammatory state necessary for lesion formation.

Evidence for genetic influences on clinical course of AVM rupture resulting in intracranial hemorrhage (ICH) have also been reported in three different settings: presentation with ICH [23, 41, 60], new ICH after diagnosis [3, 39], and ICH after treatment [2]. The same IL-6 promoter polymorphism (−174G>C) was associated with clinical presentation of ICH [41], and the high-risk G allele correlated with increasing IL-6 mRNA and protein levels in AVM tissue [9]. More recently, SNPs in the EPHB4 gene, encoding a tyrosine kinase receptor involved in embryogenic arterial-venous determination, were also reported to be associated with increased risk of ICH presentation [60]. Loss of function mutations in EphB4 (receptor) and Efnb2 (ligand) cause vascular defects and AVM formation in mice similar to that observed in Notch1 gain of function mutants, but these results suggest that different mechanisms can lead to the same phenotype [28].

Not surprisingly, SNPs in inflammatory genes also appear to influence risk of ICH in the natural course of AVMs, including promoter SNPs in TNF-α (−238G>A) [3] and IL1B (−31T>C and −511C>T) [23]. In addition to their association with spontaneous ICH in the natural, untreated course, both APOEε2 [39] and TNF-α −238 A [3] alleles appear to confer greater risk for post-radiosurgical and post-surgical hemorrhage [2].

Genome-wide SNP and Expression Studies in AVM Patients

A drawback of candidate gene studies is that, while they are hypothesis driven, they represent at best an educated guess as to which genes are involved. An alternative approach is to conduct a genome-wide association (GWAS) or expression profiling study. The GWAS approach relies upon scanning all common variation in the genome utilizing microarrays that feature hundreds of thousands to millions of SNPs or probes covering known genes. GWAS can identify associated genes if the causal variants are common in the general population and have shown moderate success for several common complex diseases. An advantage of the GWAS approach is the ability to uncover completely novel biological mechanisms. For example, inflammation was not previously known to be causally involved in age-related macular degeneration (AMD), but a series of studies published in 2005, including the first successful example of GWAS [27], implicated the Y204H polymorphism in the complement factor H gene with risk of AMD [11]. These genetic findings were subsequently replicated in several independent cohorts and have paved the way for development of new therapeutic interventions [11]. Preliminary results from the first GWAS study in Caucasian brain AVM patients have recently been reported [25].

Genome-wide expression profiling can also be used to identify genes that are likely to have a functional role in the disease process. The basic premise is that different patient groups (diseases) can be distinguished by their gene expression “signature”, defined as the unique and consistent pattern of up- and down-regulation of genes. Two small genome-wide expression studies of brain AVM tissue have identified overexpression of inflammatory and angiogenesis-related genes, including VEGFA, ENG, ANGPT2, ITGAV, VEGFR1 (FLT1), and MMP9 [21, 47]. Decreased expression was observed for TIE1, TEK (TIE2), and ANGPT1 [21, 47].

Increasingly, there is interest in performing genome-wide expression profiling of peripheral blood to identify vascular disease-specific gene expression signatures that may serve as clinically useful molecular biomarkers [15, 51, 59, 63]. Identifying blood biomarkers for ICH may have clinical utility in identifying high-risk AVM patients, especially those who come to clinical attention without ICH. The first such study in brain AVM patients has recently been published in abstract form [61], demonstrating differential blood expression profiles in ruptured compared to unruptured brain AVM patients. Pathway analysis of differentially expressed genes implicated inflammatory pathways and VEGF, MAPK, and Wnt signaling, which has relevance for AVM model development as discussed below. Integration of data from multiple genome-wide approaches, including both SNP genotype and gene expression data, may offer additional insight into disease mechanisms.

Experimental AVM Models

Model systems for studying AVM are needed to test mechanistic hypotheses and develop novel therapies. We have previously discussed development of cerebral microvascular dysplasia, a surrogate model for brain AVM [54]. There has been considerable progress in AVM model development during the past year.

A logical approach to animal models is to focus on genes that are clearly related to the human disease phenotype, which for AVM are those genes described above leading to HHT. It is known that both Eng+/− [56] and Alk1+/− [52] adult mice develop vascular lesions in various organs, but spontaneous lesions in the brain are quite modest, and only seen in older Eng+/−mice using scanning electron microscopy [44]. Our group showed that more pronounced forms of cerebral microvascular dysplasia can be induced using VEGF stimulation in Eng+/− or Alk1+/−mice [18, 19, 62], which can be enhanced by local increases in tissue perfusion rates in the Alk1+/− background [18]. Recently, we found that, for a given degree of virally-mediated VEGF overexpression, Eng+/− mice have more severe cerebrovascular dysplasia than Alk1+/− mice, which simulates the relative penetrance of brain AVM in HHT patients (HHT1>HHT2) (Figure 2C) [19]. These experiments result in enlarged, dysmorphic vascular structures at the capillary level, not the large vessels seen in the human disease.

Fig. 2
Brain AVM in Alk1 or Eng deficient mice

Oh and colleagues have developed several innovative inducible knockout systems using a novel endothelial Cre transgenic line [37, 38]. Antenatal conditional deletion of Alk1 causes severe cerebrovascular dysplasia and apparent fistula formation (Figure 2A). Interestingly, conditional Alk1 deletion in adult mice induced AV fistulas and hemorrhage in the lung and GI tracks, but not in skin or brain. Importantly, upon induction of skin wounding, Alk1 deleted mice developed vascular dysplasia and direct A–V connections, suggesting an abnormal response to injury (Figure 2B). Direct A–V connections have also been detected in the retina of Eng-deficient neonatal mice [32]. The combination of local angiogenic stimulation (Matrigel + VEGF/FGF) and Eng loss led to gross venous enlargement [32]. These results suggest that physiological or environmental factors, in addition to genetic variation, are required for Alk1 and Eng-deficient vessels to develop vascular malformations in adult mice. In support of this notion, Walker et al recently described cerebrovascular dysplasia and apparent A–V shunting after focal VEGF stimulation in mice subjected to regional conditional Alk1 deletion [58].

An additional mechanism of potential interest—especially to the phenomenon of AVM rupture—was suggested by a recent study by Lebrin et al [29]. Thalidomide reduced epistaxis and enhanced blood vessel stabilization in nasal mucosa of HHT patients. In Eng+/− mice, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects partially through upregulation of platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation.

Notch signaling appears important for the determination of arterial and venous fate, a process which seems to depend on local levels of VEGF [64]. There is empirical evidence that proteins involved in Notch signaling— including the receptor, its ligands, and downstream signals—are expressed in excised surgical specimens [34, 65]. Animal experiments support a potential link with the human disease. Using conditional endothelial expression, Murphy and colleagues used a tetracycline responsive-promoter to suppress overexpression during development and then by withdrawal of doxycycline, overexpressed the intracellular signaling portion of Notch-4 (int3) in early post-natal mice. They observed a rapidly lethal phenotype, which mimicked aspects of human AVMs, including dysplastic posterior fossa vasculature with apparent A–V shunting.

Taken together, both genetic manipulation and angiogenic stimulation appear to be important aspects of AVM model development. The angiogenic stimulus can be varied, for example via injury, exogenous growth factor delivery, or the use of young, perinatal animals that have high inherent angiogenic activity in the brain. An ideal AVM model should strive to contain the following components: (1) Anatomic, nidus of abnormal vessels of varying sizes at micro and macro-circulatory levels; (2) Physiologic, A–V shunting, hemodynamically significant, i.e., sufficient to decrease feeding artery or increase draining venous pressures; (3) Biological, alterations in angiogenic and inflammatory protein expression, involvement of or intersection with known genetic pathways; and (4) Clinical, relative quiescence, spontaneous hemorrhage into the parenchyma or CSF spaces. Currently, such an ideal animal model has not been developed in adults, which would more closely mimic the human phenotype. However, insights from the current AVM models suggest that regional conditional gene deletion plus angiogenic stimulation may promote the ideal AVM development in adult mouse brain.

Summary and synthesis of data regarding etiology and pathogenesis of AVM

Elucidating the mechanisms and factors influencing AVM lesion formation and progression to ICH offers promise for developing innovative treatments and better risk stratification for clinical management or clinical trial design. Further, study of brain AVM may be a powerful platform from which to gain insights into general vascular biologic mechanisms relevant to a wide variety of diseases affecting the vascular system.


The authors gratefully acknowledge the UCSF Brain AVM study project members <>; the other Principal Investigators (Nancy Boudreau, Tomoki Hashimoto, Charles E. McCulloch, Stephen Nishimura) of P01 NS044155 (Young), “Integrative Study of Brain Vascular Malformations”; and Voltaire Gungab for assistance in manuscript preparation. HK is supported in part by K23 NS058357. Studies are supported in part by R01 NS034949 (WLY), R01 NS027713 (WLY), and K23 NS058357 (HK).


1. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet. 2006;43:97–110. [PMC free article] [PubMed]
2. Achrol AS, Kim H, Pawlikowska L, Poon KY, Ko NU, McCulloch CE, Zaroff JG, Johnston SC, McDermott MW, Lawton MT, Kwok PY, Young WL. Association of tumor necrosis factor-alpha-238G>A and Apolipoprotein E2 polymorphisms with intracranial hemorrhage after brain arteriovenous malformation treatment. Neurosurgery. 2007;61:731–739. [PubMed]
3. Achrol AS, Pawlikowska L, McCulloch CE, Poon KY, Ha C, Zaroff JG, Johnston SC, Lee C, Lawton MT, Sidney S, Marchuk D, Kwok PY, Young WL. Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations. Stroke. 2006;37:231–234. [PubMed]
4. Al-Shahi R, Fang JS, Lewis SC, Warlow CP. Prevalence of adults with brain arteriovenous malformations: a community based study in Scotland using capture-recapture analysis. J Neurol Neurosurg Psychiatry. 2002;73:547–551. [PMC free article] [PubMed]
5. Arteriovenous Malformation Study Group. Arteriovenous malformations of the brain in adults. N Engl J Med. 1999;340:1812–1818. [PubMed]
6. Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem. 1999;274:584–594. [PubMed]
7. Berman MF, Sciacca RR, Pile-Spellman J, Stapf C, Connolly ES, Jr, Mohr JP, Young WL. The epidemiology of brain arteriovenous malformations. Neurosurgery. 2000;47:389–396. [PubMed]
8. Chen Y, Fan Y, Poon KY, Achrol AS, Lawton MT, Zhu Y, McCulloch CE, Hashimoto T, Lee C, Barbaro NM, Bollen AW, Yang GY, Young WL. MMP-9 expression is associated with leukocytic but not endothelial markers in brain arteriovenous malformations. Front Biosci. 2006;11:3121–3128. [PubMed]
9. Chen Y, Pawlikowska L, Yao JS, Shen F, Zhai W, Achrol AS, Lawton MT, Kwok PY, Yang GY, Young WL. Interleukin-6 involvement in brain arteriovenous malformations. Ann Neurol. 2006;59:72–80. [PubMed]
10. Chen Y, Zhu W, Bollen AW, Lawton MT, Barbaro NM, Dowd CF, Hashimoto T, Yang GY, Young WL. Evidence of inflammatory cell involvement in brain arteriovenous malformations. Neurosurgery. 2008;62:1340–1349. [PMC free article] [PubMed]
11. Donoso LA, Vrabec T, Kuivaniemi H. The role of complement Factor H in age-related macular degeneration: a review. Surv Ophthalmol. 2010;55:227–246. [PubMed]
12. Gabriel RA, Kim H, Sidney S, McCulloch CE, Singh V, Johnston SC, Ko NU, Achrol AS, Zaroff JG, Young WL. Ten-year detection rate of brain arteriovenous malformations in a large, multiethnic, defined population. Stroke. 2010;41:21–26. [PMC free article] [PubMed]
13. Gallione CJ, Richards JA, Letteboer TG, Rushlow D, Prigoda NL, Leedom TP, Ganguly A, Castells A, Ploos van Amstel JK, Westermann CJ, Pyeritz RE, Marchuk DA. SMAD4 Mutations found in unselected HHT patients. J Med Genet. 2006;43:793–797. [PMC free article] [PubMed]
14. Gao P, Chen Y, Lawton MT, Barbaro NM, Yang GY, Su H, Ling F, Young WL. Evidence of endothelial progenitor cells in the human brain and spinal cord arteriovenous malformations. Neurosurgery. 2010 [In press] [PMC free article] [PubMed]
15. Giusti B, Rossi L, Lapini I, Magi A, Pratesi G, Lavitrano M, Biasi GM, Pulli R, Pratesi C, Abbate R. Gene expression profiling of peripheral blood in patients with abdominal aortic aneurysm. Eur J Vasc Endovasc Surg. 2009;38:104–112. [PubMed]
16. Hao Q, Chen Y, Zhu Y, Fan Y, Palmer D, Su H, Young WL, Yang GY. Neutrophil depletion decreases VEGF-induced focal angiogenesis in the mature mouse brain. J Cereb Blood Flow Metab. 2007;27:1853–1860. [PubMed]
17. Hao Q, Liu J, Pappu R, Su H, Rola R, Gabriel RA, Lee CZ, Young WL, Yang GY. Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leucocytes and macrophages. Arterioscler Thromb Vasc Biol. 2008;28:2151–2157. [PMC free article] [PubMed]
18. Hao Q, Su H, Marchuk DA, Rola R, Wang Y, Liu W, Young WL, Yang GY. Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation. Am J Physiol Heart Circ Physiol. 2008;295:H2250–2256. [PubMed]
19. Hao Q, Zhu Y, Su H, Shen F, Yang GY, Kim H, Young WL. VEGF induces more severe cerebrovascular dysplasia in Endoglin+/− than in Alk1+/− mice. Transl Stroke Res. 2010 [In press] [PMC free article] [PubMed]
20. Hashimoto T, Lam T, Boudreau NJ, Bollen AW, Lawton MT, Young WL. Abnormal balance in the angiopoietin-tie2 system in human brain arteriovenous malformations. Circ Res. 2001;89:111–113. [PubMed]
21. Hashimoto T, Lawton MT, Wen G, Yang GY, Chaly T, Jr, Stewart CL, Dressman HK, Barbaro NM, Marchuk DA, Young WL. Gene microarray analysis of human brain arteriovenous malformations. Neurosurgery. 2004;54:410–423. [PubMed]
22. Hashimoto T, Wen G, Lawton MT, Boudreau NJ, Bollen AW, Yang GY, Barbaro NM, Higashida RT, Dowd CF, Halbach VV, Young WL. Abnormal expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in brain arteriovenous malformations. Stroke. 2003;34:925–931. [PubMed]
23. Kim H, Hysi PG, Pawlikowska L, Poon A, Burchard EG, Zaroff JG, Sidney S, Ko NU, Achrol AS, Lawton MT, McCulloch CE, Kwok PY, Young WL. Common variants in interleukin-1-beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation. Cerebrovasc Dis. 2009;27:176–182. [PubMed]
24. Kim H, Marchuk DA, Pawlikowska L, Chen Y, Su H, Yang GY, Young WL. Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations. Acta Neurochir Suppl. 2008;105:199–206. [PMC free article] [PubMed]
25. Kim H, Pawlikowska L, Weinsheimer S, Kwok PY, Zaroff JG, McCulloch CE, Young WL. Genome-wide association study of intracranial hemorrhage in brain arteriovenous malformation (BAVM) patients [Abstract] Stroke. 2010;41:e11, P37. [PubMed]
26. Kim H, Sidney S, McCulloch CE, Poon KY, Singh V, Johnston SC, Ko NU, Achrol AS, Lawton MT, Higashida RT, Young WL. Racial/ethnic differences in longitudinal risk of intracranial hemorrhage in brain arteriovenous malformation patients. Stroke. 2007;38:2430–2437. [PubMed]
27. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–389. [PMC free article] [PubMed]
28. Krebs LT, Starling C, Chervonsky AV, Gridley T. Notch 1 activation in mice causes arteriovenous malformations phenocopied by EphrinB2 and EphB4 mutants. Genesis. 2010;48:146–150. [PMC free article] [PubMed]
29. Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Breant C, Mathivet T, Larrivee B, Thomas JL, Arthur HM, Westermann CJ, Disch F, Mager JJ, Snijder RJ, Eichmann A, Mummery CL. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010;16:420–428. [PubMed]
30. Lee CZ, Xue Z, Zhu Y, Yang GY, Young WL. Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracranial hemorrhage. Stroke. 2007;38:2563–2568. [PubMed]
31. Lux A, Attisano L, Marchuk DA. Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. J Biol Chem. 1999;274:9984–9992. [PubMed]
32. Mahmoud M, Allinson KR, Zhai Z, Oakenfull R, Ghandi P, Adams RH, Fruttiger M, Arthur HM. Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res. 2010;106:1425–1433. [PubMed]
33. Marchuk DA, Srinivasan S, Squire TL, Zawistowski JS. Vascular morphogenesis: tales of two syndromes. Hum Mol Genet. 2003;12:R97–112. [PubMed]
34. Murphy PA, Lu G, Shiah S, Bollen AW, Wang RA. Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease. Lab Invest. 2009;89:971–982. [PMC free article] [PubMed]
35. Nuki Y, Matsumoto MM, Tsang E, Young WL, van Rooijen N, Kurihara C, Hashimoto T. Roles of macrophages in flow-induced outward vascular remodeling. J Cereb Blood Flow Metab. 2009;29:495–503. [PMC free article] [PubMed]
36. Ota R, Kurihara C, Tsou TL, Young WL, Yeghiazarians Y, Chang M, Mobashery S, Sakamoto A, Hashimoto T. Roles of matrix metalloproteinases in flow-induced outward vascular remodeling. J Cereb Blood Flow Metab. 2009;29:1547–1558. [PMC free article] [PubMed]
37. Park SO, Lee YJ, Seki T, Hong KH, Fliess N, Jiang Z, Park A, Wu X, Kaartinen V, Roman BL, Oh SP. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 (HHT2) Blood. 2008;111:633–642. [PubMed]
38. Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, Oh SH, Walter G, Raizada MK, Sorg BS, Oh SP. Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest. 2009;119:3487–3496. [PMC free article] [PubMed]
39. Pawlikowska L, Poon KY, Achrol AS, McCulloch CE, Ha C, Lum K, Zaroff J, Ko NU, Johnston SC, Sidney S, Marchuk DA, Lawton MT, Kwok PY, Young WL. Apoliprotein E epsilon2 is associated with new hemorrhage risk in brain arteriovenous malformation. Neurosurgery. 2006;58:838–843. [PubMed]
40. Pawlikowska L, Tran MN, Achrol AS, Ha C, Burchard EG, Choudhry S, Zaroff J, Lawton MT, Castro RA, McCulloch CE, Marchuk DA, Kwok PY, Young WL. Polymorphisms in transforming growth factor-B-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations. Stroke. 2005;36:2278–2280. [PubMed]
41. Pawlikowska L, Tran MN, Achrol AS, McCulloch CE, Ha C, Lind DL, Hashimoto T, Zaroff J, Lawton MT, Marchuk DA, Kwok PY, Young WL. Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations. Stroke. 2004;35:2294–2300. [PubMed]
42. Rogers MS, D’Amato RJ. The effect of genetic diversity on angiogenesis. Exp Cell Res. 2006;312:561–574. [PubMed]
43. Rothbart D, Awad IA, Lee J, Kim J, Harbaugh R, Criscuolo GR. Expression of angiogenic factors and stuctural proteins in central nervous system vascular malformations. Neurosurgery. 1996;38:915–924. [PubMed]
44. Satomi J, Mount RJ, Toporsian M, Paterson AD, Wallace MC, Harrison RV, Letarte M. Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic telangiectasia. Stroke. 2003;34:783–789. [PubMed]
45. Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, Lowik CW, Ten Dijke P. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci. 2007;120:964–972. [PubMed]
46. Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell. 2005;7:101–111. [PubMed]
47. Shenkar R, Elliott JP, Diener K, Gault J, Hu LJ, Cohrs RJ, Phang T, Hunter L, Breeze RE, Awad IA. Differential gene expression in human cerebrovascular malformations. Neurosurgery. 2003;52:465–478. [PMC free article] [PubMed]
48. Shenkar R, Shi C, Check IJ, Lipton HL, Awad IA. Concepts and hypotheses: inflammatory hypothesis in the pathogenesis of cerebral cavernous malformations. Neurosurgery. 2007;61:693–702. [PubMed]
49. Simon M, Franke D, Ludwig M, Aliashkevich AF, Koster G, Oldenburg J, Bostrom A, Ziegler A, Schramm J. Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. J Neurosurg. 2006;104:945–949. [PubMed]
50. Simon M, Schramm J, Ludwig M, Ziegler A. Author reply to letter by Young WL et al, “Arteriovenous malformation” J Neurosurg. 2007;106:732–733.
51. Sinnaeve PR, Donahue MP, Grass P, Seo D, Vonderscher J, Chibout SD, Kraus WE, Sketch M, Jr, Nelson C, Ginsburg GS, Goldschmidt-Clermont PJ, Granger CB. Gene expression patterns in peripheral blood correlate with the extent of coronary artery disease. PLoS One. 2009;4:e7037. [PMC free article] [PubMed]
52. Srinivasan S, Hanes MA, Dickens T, Porteous ME, Oh SP, Hale LP, Marchuk DA. A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum Mol Genet. 2003;12:473–482. [PubMed]
53. Stapf C, Mast H, Sciacca RR, Berenstein A, Nelson PK, Gobin YP, Pile-Spellman J, Mohr JP. The New York Islands AVM Study: design, study progress, and initial results. Stroke. 2003;34:e29–33. [PubMed]
54. Su H, Hao Q, Shen F, Zhu Y, Lee CZ, Young WL, Yang GY. Development of cerebral microvascular dysplasia model in rodents. Acta Neurochir Suppl. 2008;105:185–189. [PMC free article] [PubMed]
55. ten Dijke P, Goumans MJ, Pardali E. Endoglin in angiogenesis and vascular diseases. Angiogenesis. 2008;11:79–89. [PubMed]
56. Torsney E, Charlton R, Diamond AG, Burn J, Soames JV, Arthur HM. Mouse model for hereditary hemorrhagic telangiectasia has a generalized vascular abnormality. Circulation. 2003;107:1653–1657. [PubMed]
57. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet. 2000;26:328–331. [PubMed]
58. Walker E, Shen F, Halprin R, Connolly S, Nishimura SL, Young WL, Su H. Regional deletion of Smad4 plus VEGF stimulation leads to vascular dysplasia in the adult mouse brain [Abstract] Stroke. 2010;41:e20. (#68)
59. Wang Y, Barbacioru CC, Shiffman D, Balasubramanian S, Iakoubova O, Tranquilli M, Albornoz G, Blake J, Mehmet NN, Ngadimo D, Poulter K, Chan F, Samaha RR, Elefteriades JA. Gene expression signature in peripheral blood detects thoracic aortic aneurysm. PLoS One. 2007;2:e1050. [PMC free article] [PubMed]
60. Weinsheimer S, Kim H, Pawlikowska L, Chen Y, Lawton MT, Sidney S, Kwok PY, McCulloch CE, Young WL. EPHB4 gene polymorphisms and risk of intracranial hemorrhage in patients with brain arteriovenous malformations. Circ Cardiovasc Genet. 2009;2:476–482. [PMC free article] [PubMed]
61. Weinsheimer S, Kim H, Pawlikowska L, McCulloch CE, Xu H, Stamova B, Tian Y, Sharp FR, Young WL. Genome-wide expression profiling of human blood reveals biomarkers for hemorrhage in brain arteriovenous malformation patients [Abstract]. American Society of Human Genetics 59th Annual Meeting; Honolulu, HI. 2009.
62. Xu B, Wu YQ, Huey M, Arthur HM, Marchuk DA, Hashimoto T, Young WL, Yang GY. Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain. J Cereb Blood Flow Metab. 2004;24:237–244. [PubMed]
63. Xu H, Tang Y, Liu DZ, Ander BP, Liu X, Apperson M, Ran R, Gregg JP, Pancioli A, Jauch EC, Wagner KR, Verro P, Broderick JP, Sharp FR. Gene expression in peripheral blood differs following cardioembolic compared to large vessel atherosclerotic stroke: biomarkers for the etiology of ischemic stroke. J Cereb Blood Flow Metab. 2008;28:1320–1328. [PubMed]
64. Zhang G, Zhou J, Fan Q, Zheng Z, Zhang F, Liu X, Hu S. Arterial-venous endothelial cell fate is related to vascular endothelial growth factor and Notch status during human bone mesenchymal stem cell differentiation. FEBS Lett. 2008;582:2957–2964. [PubMed]
65. ZhuGe Q, Zhong M, Zheng W, Yang GY, Mao X, Xie L, Chen G, Chen Y, Lawton MT, Young WL, Greenberg DA, Jin K. Notch1 signaling is activated in brain arteriovenous malformation in humans. Brain. 2009;132:3231–3241. [PMC free article] [PubMed]