Mouse Models of Cerebral Arteriovenous Malformation

Nielsen, Corinne M.; Huang, Lawrence; Murphy, Patrick A.; Lawton, Michael T.; Wang, Rong A.

doi:10.1161/strokeaha.115.002869

Cited by 20 publications

(13 citation statements)

References 54 publications

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“… 28 , 31 Similarly, gain of constitutive Notch1 or 4 activity must be initiated during the early postnatal period to produce bAVMs. 29 Treatment of iEC-Kras G12D and control littermates with tamoxifen between 2 and 4 months of age did not affect overall survival up to 8 weeks later (Control, n=0/23; iEC-Kras G12D , n=0/19; Figure 2 A and 2 B). In a pilot cohort, no differences in viability were detected up to 36 weeks later (Control, n=0/4; iEC-Kras G12D , n=0/3; Figure 2 A and 2 B).…”

Section: Resultsmentioning

confidence: 88%

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Fish

Flores-Suarez

Boudreau

et al. 2020

Circulation Research

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Rationale: We previously identified somatic activating mutations in the KRAS gene in the endothelium of the majority of human sporadic brain arteriovenous malformations (bAVMs); a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to AVM formation, remains unknown. Objective: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish in order to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for AVMs. Methods and Results: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce bAVMs. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity, but instead appear to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent AVMs in zebrafish are refractory to inhibition of the downstream effector PI3K, but instead require active MEK signaling. Conclusions: We demonstrate that active KRAS expression in the endothelium is sufficient for bAVM formation, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for AVM patients.

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Section: Resultsmentioning

confidence: 88%

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Fish

Flores-Suarez

Boudreau

et al. 2020

Circulation Research

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“…In cerebral cavernous malformations, Notch also plays a role in the aberrant EndoMT transition and vascular malformations (Kar et al, 2016). Similarly, in arteriovenous malformations, where shunts form between arteries and veins, Notch is upregulated in human patients, and upregulation of Notch1 or Notch4 causes the disease in mouse models (Murphy et al, 2009;Nielsen et al, 2016). In vascular conditions with prominent inflammatory components, Notch ligands also determine cell fate, such as in large vessel vasculitis, vascular graft lesions, or arteriovenous graft remodeling (Guo et al, 2020;Koga et al, 2015;Wen et al, 2017).…”

Section: Box 2 Notch Mutations and Deregulation In Cardiovascular Diseasementioning

confidence: 99%

Notch in mechanotransduction – from molecular mechanosensitivity to tissue mechanostasis

Stassen

Ristori

Sahlgren

2020

Journal of Cell Science

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Tissue development and homeostasis are controlled by mechanical cues. Perturbation of the mechanical equilibrium triggers restoration of mechanostasis through changes in cell behavior, while defects in these restorative mechanisms lead to mechanopathologies, for example, osteoporosis, myopathies, fibrosis or cardiovascular disease. Therefore, sensing mechanical cues and integrating them with the biomolecular cell fate machinery is essential for the maintenance of health. The Notch signaling pathway regulates cell and tissue fate in nearly all tissues. Notch activation is directly and indirectly mechanosensitive, and regulation of Notch signaling, and consequently cell fate, is integral to the cellular response to mechanical cues. Fully understanding the dynamic relationship between molecular signaling, tissue mechanics and tissue remodeling is challenging. To address this challenge, engineered microtissues and computational models play an increasingly large role. In this Review, we propose that Notch takes on the role of a ‘mechanostat’, maintaining the mechanical equilibrium of tissues. We discuss the reciprocal role of Notch in the regulation of tissue mechanics, with an emphasis on cardiovascular tissues, and the potential of computational and engineering approaches to unravel the complex dynamic relationship between mechanics and signaling in the maintenance of cell and tissue mechanostasis.

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“…dilated vessels, an arteriovenous shunt, a highflow lesion, and formation of a nidus). 30,31 In the mouse model, the combination of the EC-specific deletion of ALK1 and administration of vascular endothelial growth factor (VEGF) in the brain causes a lesion similar to human AVM with dilated vessels and proliferation of ECs. 32 Adenovirus-mediated EC-selective ALK1 deletion and overexpression of VEGF induce lesions resembling human bAVM as well, 3 suggesting involvement of changes in EC function and angiogenesis in the pathogenesis.…”

Section: Endothelial Cellsmentioning

confidence: 99%

Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications

Ota

Komiyama

2020

Interv Neuroradiol

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Brain arteriovenous malformations have a high risk of intracranial hemorrhage, which is a substantial cause of morbidity and mortality in patients with brain arteriovenous malformations. Although a variety of genetic factors leading to hereditary brain arteriovenous malformations have been extensively investigated, their pathogenesis is still not well elucidated, especially in sporadic brain arteriovenous malformations. The authors have reviewed the updated data of not only the genetic aspects of sporadic brain arteriovenous malformations, but also the architecture of microvasculature, the roles of the angiogenic factors, and the signaling pathways. This knowledge may allow us to infer the pathogenesis of sporadic brain arteriovenous malformations and develop pre-emptive treatments for them.

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Mouse Models of Cerebral Arteriovenous Malformation

Cited by 20 publications

References 54 publications

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Notch in mechanotransduction – from molecular mechanosensitivity to tissue mechanostasis

Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications

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