Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling
| العنوان: | Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling |
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| المؤلفون: | Meng Cui, Emilie Boudreau, Alexander M. Herman, Dakota Gustafson, Ivan Radovanovic, Jason E. Fish, Karen Berman de Ruiz, Zhiqi Chen, Joshua D. Wythe, Taylor S Schexnayder, Peter V. DiStefano, Manuel Cantu Gutierrez, Carlos Perfecto Flores-Suarez, Christopher S. Ward |
| المصدر: | Circulation Research. 127:727-743 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Intracranial Arteriovenous Malformations, Male, 0301 basic medicine, Endothelium, Physiology, Angiogenesis, Somatic cell, MAP Kinase Kinase 1, Viral Oncogene, Mice, Transgenic, Biology, medicine.disease_cause, Permeability, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene, Cells, Cultured, Zebrafish, Phosphoinositide-3 Kinase Inhibitors, Vascular disease, Endothelial Cells, Zebrafish Proteins, medicine.disease, 3. Good health, Disease Models, Animal, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Gain of Function Mutation, Cancer research, Female, KRAS, Phosphatidylinositol 3-Kinase, Cardiology and Cardiovascular Medicine, Intracranial Hemorrhages, 030217 neurology & neurosurgery, Signal Transduction |
| الوصف: | Rationale: We previously identified somatic activating mutations in the KRAS ( Kirsten rat sarcoma viral oncogene homologue ) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; 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 arteriovenous malformations, remains unknown. Objective: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. 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 brain arteriovenous malformations. 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 seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. Conclusions: We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, 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 arteriovenous malformation patients. Graphical Abstract: A graphical abstract is available for this article. |
| تدمد: | 1524-4571 0009-7330 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e72fd45dea340e7725e8e56eba54c896Test https://doi.org/10.1161/circresaha.119.316500Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e72fd45dea340e7725e8e56eba54c896 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244571 00097330 |
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