Cerebral Vascular Abnormalities in a Murine Model of Hereditary Hemorrhagic Telangiectasia

Satomi, Junichiro; Mount, Richard J.; Toporsian, Mourad; Paterson, Andrew D.; Wallace, M. Christopher; Harrison, Robert V.; Letarte, Michelle

doi:10.1161/01.str.0000056170.47815.37

Cited by 84 publications

(64 citation statements)

References 34 publications

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“…Transgenic mice confirm that the mutations cause HHT, since some mice carrying one normal and one null copy of the respective gene (i.e. endoglin +/-or ACVRL1 +/-heterozygote mice) display features of HHT 151,[153][154][155] .…”

Section: 2d) Generation Of Abnormal Vessels In Hhtmentioning

confidence: 85%

“…These models have employed classical null mice (described for Eng and Acvrl1 with embryonic homozygous lethality between E10.5-11.5 153,[158][159][160] ); heterozygous mice which developed variable but more HHT-specific features including nosebleeds, telangiectasia, dilated vessels and AVMs 151,[153][154][155] and in some ways represent the most appropriate model for human HHT 161 ; endothelial cell specific knock outs 162 ; and mice bearing conditional LoxP knockout alleles that for ALK-1 result in a model in which HHT-like vascular malformations occurred in a consistent and predictable manner 151 . As in man 90 , murine Blood Reviews _ HHT 2010_ Shovlin 14 AVMs display venous type wall structures, 28,153,158,159,160 and venous molecular signatures.…”

Section: 2d) Generation Of Abnormal Vessels In Hhtmentioning

confidence: 99%

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Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5,000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings. Blood Reviews _ HHT 2010_ Shovlin 3 Overview of HHTHHT, also known as Osler Weber Rendu syndrome [1][2][3] , is one of the most common disorders to be inherited as an autosomal dominant trait. Careful epidemiological studies reveal that it affects approximately 1 in 5,000 individuals, 4,5 with regional differences, 6 and isolated communities displaying higher prevalences due to founder effects. 7 8 HHT was first described as a familial disease characterised by severe recurrent nasal and gastrointestinal bleeding with associated anaemia, and visible dilated blood vessels (telangiectasia) on the lips and finger tips. The majority of HHT patients are also affected by larger arteriovenous malformations (AVMs) in the pulmonary, hepatic, cerebral, pancreatic, spinal and other circulations. 1,2,9 These features, presented in more detail within Table 1, are used as criteria to diagnose HHT. 2 The spectrum of disease within the HHT umbrella has extended beyond the telangiectatic/AVM HHT pathology delineated by the Curaçao criteria. 2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and poten...

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Section: 2d) Generation Of Abnormal Vessels In Hhtmentioning

confidence: 85%

Section: 2d) Generation Of Abnormal Vessels In Hhtmentioning

confidence: 99%

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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“…These newly formed microvessels showed abnormal morphology such as a mass or single enlargement, clustered, twisted, or spiral microvessels. Confocal microscopy and three-dimensional reconstruction techniques enable clear identification of the abnormal microvasculature without having to resort to scanning electron microscopy (Satomi et al, 2003). These changes are similar to small cerebral AVMs in the adult HHT patient brain and may predispose the mice to brain hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

“…The phenotype of the endoglin heterozygous mice mimics human HHT disorder, and some of them develop abnormal vascular lesions with increasing age (Bourdeau et al, 2001;Torsney et al, 2003). The endoglin heterozygous mice provide a unique tool to study the genetic role of microvascular disorders, including BAVM (Satomi et al, 2003).…”

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confidence: 99%

Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

Huey

et al. 2004

J Cereb Blood Flow Metab

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Summary:Hereditary hemorrhagic telangiectasia (HHT), associated with brain arteriovenous malformations, is caused by a loss of function mutation in either the endoglin (HHT1) or activin receptor-like kinase 1 gene (ALK-1, HHT2). Endoglin heterozygous (Eng +/− )mice have been proposed as a disease model. To better understand the role of endoglin in vascular malformation development, we examined the effect of vascular endothelial growth factor (VEGF) hyperstimulation on microvessels in adult endoglin heterozygous (Eng +/− ) mice using an adenoviral vector to deliver recombinant human VEGF 165 cDNA (AdhVEGF) into basal ganglia. VEGF expression was increased in AdhVEGF mice compared with the AdlacZ and saline group (P < 0.05) and localized to multiple cell types (neurons, astrocytes, endothelial cells, and smooth muscle cells) by double-labeled immunostaining. VEGF overexpression increased microvessel count for up to 4 weeks in both the Eng +/+ and Eng +/− groups (Eng +/+ 185 ± 14 vs. Eng +/− 201 ± 10 microvessels/mm 2 ). Confocal microscopic examination revealed grossly abnormal microvessels in eight of nine Eng +/− mouse brains compared with zero of nine in Eng +/+ mice (P < 0.05). Abnormal microvessels featured enlargement, clustering, twist, or spirals. VEGF receptor Flk-1 and TGF-␤ receptor 1 (T␤R1) expression were reduced in the Eng +/− mouse brain compared with control.Excessive VEGF stimulation may play a pivotal role in the initiation and development of brain vessel malformations in states of relative endoglin insufficiency in adulthood. These observations are relevant to our general understanding of the maintenance of vascular integrity.

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“…Common polymorphisms may subtly alter protein function or expression, resulting in phenotypes relevant to the human disease. For example, abnormal vascular development has been observed in murine models with insufficient Alk-1 [57,62] and Eng [51]. Importantly, adenoviral-mediated VEGF gene transfer in endoglin-deficient mice causes enhancement of vascular abnormalities, suggesting a synergism between TGF-β and VEGF signaling pathways in development of abnormal or "dysplastic" vessels [66].…”

Section: Candidate Gene Studies In Avm Patientsmentioning

confidence: 99%

Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

Kim

Marchuk

Pawlikowska

et al.

Acta Neurochirurgica Supplementum

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SUMMARYBrain arteriovenous malformations (AVM) cause intracranial hemorrhage (ICH), especially in young adults. Molecular characterization of lesional tissue provides evidence for involvement of both angiogenic and inflammatory pathways, but the pathogenesis remain obscure and medical therapy is lacking. Abnormal expression patterns have been observed for proteins related to angiogenesis (e.g., VEGF, Angiopoietin-2, MMP-9), and inflammation (e.g., IL-6 and MPO). Macrophage and neutrophil invasion has also been observed in the absence of prior ICH. Candidate gene association studies have identified a number of germline variants associated with clinical ICH course and AVM susceptibility. A single nucleotide polymorphism (SNP) in ALK-1 is associated with AVM susceptibility, and SNPs in IL-6, TNF-α and APOE are associated with AVM rupture. These observations suggest that even without a complete understanding of the determinants of AVM development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Further, biomarkers can now be established for assessing ICH risk. Finally, these data will generate hypotheses that can be tested mechanistically in model systems, including surrogate phenotypes, such as vascular dysplasia and/or models recapitulating the clinical syndrome of recurrent spontaneous ICH. Keywords angiogenesis; inflammation; vascular malformationsBrain arteriovenous malformations (AVM) represent a relatively infrequent but important source of neurological morbidity in relatively young adults [4]. Brain AVMs have a population prevalence of 10-18 per 100,000 adults [3,7], and a new detection rate of ~1.3 per 100,000 person-years [58]. 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

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Cerebral Vascular Abnormalities in a Murine Model of Hereditary Hemorrhagic Telangiectasia

Cited by 84 publications

References 34 publications

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

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