Abstract TMP113: Deletion of Alk1 Gene in Bone Marrow-Derived Endothelial Cells is Sufficient to Cause Brain Arteriovenous Malformation in Mice

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Abstract

Introduction: In humans, Alk1 deficiency causes arteriovenous malformations (AVMs) in multiple organs. Endothelial deletion of Alk1 in adult mice leads to AVM formation in multiple organs and the brain angiogenic region, and endoglin-deficient bone marrow (BM) transmits abnormal brain vascular phenotype to wild-type (WT) mice. We hypothesize that Alk1 deletion in BM-derived endothelial cells (BMDECs) is sufficient to induce AVM in the brain angiogenic region in adult mice.

Methods: Adult pdgfb-iCreER;Alk12f/2f mice that have Alk1 exons 4-6 flanked by loxP sites and a transgene expressing tamoxifen (TM)-inducible cre recombinase in the endothelial cells were used as BM donor. BM isolated from these mice was transplanted to lethally irradiated 8-week-old WT mice. Brain angiogenesis was induced through an intra-brain injection of an adeno-associated viral vector expressing VEGF 4 weeks after the BM transplantation. Two weeks later, Alk1 deletion was induced through an intra-peritoneal injection of TM (2.5 mg/20g body weight). Vascular morphology was analyzed using latex casting 6 weeks later.

Results: Peripheral blood cell counts fully recovered in the recipients 4 weeks after BM transplantation. Mice transplanted with pdgfb-iCreER;Alk12f/2f BM developed AVM in the brain angiogenic region. BM-derived endothelial cells were detected in brain AVM vessels. Unlike pdgfb-iCreER;Alk12f/2f mice that died 2 weeks after TM treatment due to bleeding from intestinal AVM, mice with pdgfb-iCreER;Alk12f/2f BM stayed alive within a 6-week period after TM treatment, suggesting that their intestinal AVM was less severe than in pdgfb-iCreER;Alk12f/2f mice.

Conclusion: BMDECs play a significant role in brain AVM development. Transfusion of endothelial progenitor cells or stem cell-derived endothelial cells could be a potential therapy for brain AVM patients.

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