Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling
| Autor: | 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 |
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| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Circulation Research. 127:727-743 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.119.316500 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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