Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia

Park, Sung Ok; Wankhede, Mamta; Lee, Young Jae; Choi, Eun‐Jung; Fliess, Naime; Choe, Se-woon; Oh, Seh–Hoon; Walter, Glenn A.; Raizada, Mohan K.; Sorg, Brian S.; Oh, S. Paul

doi:10.1172/jci39482

Cited by 224 publications

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“…[28][29][30][31] . Attention now focuses on aberrant vascular responses to injury-induced angiogenic stimuli, when the mutated genes in HHT appear to result in the inability of a blood vessel to mature appropriately.…”

Section: Overview Of Hhtmentioning

confidence: 99%

Section: Overview Of Hhtmentioning

confidence: 99%

“…Attention now focuses on aberrant vascular responses to injury-induced angiogenic stimuli, when the mutated genes in HHT appear to result in the inability of a blood vessel to mature appropriately. 28,30,31 In man, HHT-specific pathology develops in different contexts according to the repertoire of susceptibility genes and/or environmental triggers to which each individual is exposed.Furthermore, as illustrated in Figure 1 and Table 1, the spectrum of HHT encompasses multiple organ systems and within these, numerous forms of disease. HHT therefore spans a vast range of scientific and clinical disciplines, and is an extremely challenging disorder both to understand, and to manage.…”

mentioning

confidence: 99%

“…AVMs display venous type wall structures, 28,153,158,159,160 and venous molecular signatures. 30,163,164 The latest data suggest that HHT mutations may be deleterious predominantly during some forms of angiogenesis, with specific effects on the stability of newly formed vascular sprouts.…”

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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: Overview Of Hhtmentioning

confidence: 99%

Section: Overview Of Hhtmentioning

confidence: 99%

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Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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“…Ce travail montre que la voie TGF/ALK5/TR2 ne semble pas impliquée dans cette pathologie (voir discussion plus loin). Enfin, l'année dernière, une souris dont l'invalidation de Alk1 est inductible a été générée, ce qui permit d'étudier le rôle d'ALK1 chez la souris adulte [21]. Ces travaux montrent que ces souris forment des shunt artérioveineux en réponse à une blessure.…”

Section: Modèles Animaux De Maladie De Rendu-oslerunclassified

Maladie de Rendu-Osler

2010

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Human brain arteriovenous malformations express lymphatic‐associated genes

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et al. 2014

Ann Clin Transl Neurol

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ObjectiveBrain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may have a role in AVM disease biology.MethodsWe examined 40 human brain AVMs by immunohistochemistry (IHC) and qRT-PCR for the expression of COUP-TFII as well as other genes involved in venous and lymphatic development, maintenance, and signaling. We also examined proliferation and EC tube formation with human umbilical ECs (HUVEC) following COUP-TFII overexpression.ResultsWe report that AVMs expressed COUP-TFII, SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, Podoplanin, and vascular endothelial growth factor (VEGF)-C, contained Ki67-positive cells and heterogeneously expressed genes involved in Hedgehog, Notch, Wnt, and VEGF signaling pathways. Overexpression of COUP-TFII alone in vitro resulted in increased EC proliferation and dilated tubes in an EC tube formation assay in HUVEC.InterpretationThis suggests AVM ECs are further losing their arterial/venous specificity and acquiring a partial lymphatic molecular phenotype. There was significant correlation of gene expression with presence of clinical edema and acute hemorrhage. While the precise role of these genes in the formation, stabilization, growth and risk of hemorrhage of AVMs remains unclear, these findings have potentially important implications for patient management and treatment choice, and opens new avenues for future work on AVM disease mechanisms.

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Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia

Cited by 224 publications

References 43 publications

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Maladie de Rendu-Osler

Human brain arteriovenous malformations express lymphatic‐associated genes

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