Bone Marrow-Derived Alk1 Mutant Endothelial Cells and Clonally Expanded Somatic Alk1 Mutant Endothelial Cells Contribute to the Development of Brain Arteriovenous Malformations in Mice

被引:0
作者
Sonali S. Shaligram
Rui Zhang
Wan Zhu
Li Ma
Man Luo
Qiang Li
Miriam Weiss
Thomas Arnold
Nicolas Santander
Rich Liang
Leandro do Prado
Chaoliang Tang
Felix Pan
S. Paul Oh
Peipei Pan
Hua Su
机构
[1] University of California,Center for Cerebrovascular Research
[2] University of California,Department of Anesthesia and Perioperative Care
[3] University of California,Department of Neurosurgery
[4] University of California,Department of Pediatrics
[5] Barrow Neurological Institute,Barrow Aneurysm & AVM Research Center, Department of Neurobiology
来源
Translational Stroke Research | 2022年 / 13卷
关键词
Arteriovenous malformation; Alk1; Endothelial cells; Clonal expansion; Bone marrow derived endothelial cells;
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学科分类号
摘要
We have previously demonstrated that deletion of activin receptor-like kinase 1 (Alk1) or endoglin in a fraction of endothelial cells (ECs) induces brain arteriovenous malformations (bAVMs) in adult mice upon angiogenic stimulation. Here, we addressed three related questions: (1) could Alk1− mutant bone marrow (BM)-derived ECs (BMDECs) cause bAVMs? (2) is Alk1− ECs clonally expended during bAVM development? and (3) is the number of mutant ECs correlates to bAVM severity? For the first question, we transplanted BM from PdgfbiCreER;Alk12f/2f mice (EC-specific tamoxifen-inducible Cre with Alk1-floxed alleles) into wild-type mice, and then induced bAVMs by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor and intra-peritoneal injection of tamoxifen. For the second question, clonal expansion was analyzed using PdgfbiCreER;Alk12f/2f;confetti+/− mice. For the third question, we titrated tamoxifen to limit Alk1 deletion and compared the severity of bAVM in mice treated with low and high tamoxifen doses. We found that wild-type mice with PdgfbiCreER;Alk12f/2f BM developed bAVMs upon VEGF stimulation and Alk1 gene deletion in BMDECs. We also observed clusters of ECs expressing the same confetti color within bAVMs and significant proliferation of Alk1− ECs at early stage of bAVM development, suggesting that Alk1− ECs clonally expanded by local proliferation. Tamoxifen dose titration revealed a direct correlation between the number of Alk1− ECs and the burden of dysplastic vessels in bAVMs. These results provide novel insights for the understanding of the mechanism by which a small fraction of Alk1 or endoglin mutant ECs contribute to development of bAVMs.
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页码:494 / 504
页数:10
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