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

Shaligram, Sonali S.; Zhang, Rui; Zhu, Wan; Ma, Li; Luo, Man; Li, Qiang; Weiss, Miriam; Arnold, Thomas; Santander, Nicolas; Liang, Rich; do Prado, Leandro; Tang, Chaoliang; Pan, Felix; Oh, S. Paul; Pan, Peipei; et. al.


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;Alk1(2f/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;Alk1(2f/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;Alk1(2f/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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Título según WOS: ID WOS:000709677300001 Not found in local WOS DB
Editorial: Springer
Fecha de publicación: 2021


Notas: ISI