Artikel
Selective Alk1 deficiency in bone marrow-derived endothelial cells promotes the development of cerebral arteriovenous malformation in mice
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Autoren
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Miriam Weiss
- University of California San Francisco, Center for Cerebrovascular Research, Department of Anesthesia, San Francisco, CA, Vereinigte Staaten; RWTH Aachen, Klinik für Neurochirurgie, Aachen, Deutschland
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Qiang Li
- Second Military Medical University, Department of Neurosurgery & Stroke Center, Changhai Hospital, Shanghai, China, Volksrepublik
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Man Luo
- University of California San Francisco, Center for Cerebrovascular Research, Department of Anesthesia, San Francisco, CA, Vereinigte Staaten
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Michael T. Lawton
- Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Department of Neurosurgery, Phoenix, AZ, Vereinigte Staaten
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Gerrit Alexander Schubert
- RWTH Aachen, Klinik für Neurochirurgie, Aachen, Deutschland
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Hua Su
- University of California San Francisco, Center for Cerebrovascular Research, Department of Anesthesia, San Francisco, CA, Vereinigte Staaten
| Veröffentlicht: | 18. Juni 2018 |
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Gliederung
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Objective: The pathophysiology of arteriovenous malformations (bAVM) of the brain remains incompletely understood up to date. Pan-cellular activin receptor-like kinase 1 (Alk1) mutation is a known cause of hereditary bAVM formation and has been shown to induce abnormal vessel formation when selectively knocked out in murine endothelial cells. Bone marrow-derived cells have been associated with angiogenesis in other proliferative pathologies. We investigated whether selective Alk1 knockout in bone marrow-derived endothelial cells (BMDEC) causes bAVM formation in a mouse model.
Methods: Recipient C57BL/6 wild type mice were irradiated at a lethal dose and salvaged with donor bone marrow (BM) from adult pdgfb-iCreER;Alk12f/2f mice. A control group receiving BM grafts from a GFP transgenic line was established. An adeno-associated viral vector expressing vascular endothelial growth factor (VEGF) was injected unilaterally into the basal ganglia to stimulate focal angiogenesis. Abdominal tamoxifen injection induced selective BMDEC-Alk1 deletion. The mice were terminated after intravascular latex or lectin injection for macroscopic and microscopic characterization of vessel dysplasia and density, respectively. Intestines were removed for quantification of VEGF-independent arteriovenous shunt formation.
Results: We included n=18 (n=10 latex, n=8 lectin) mice transplanted with pdgfb-iCreER;Alk12f/2f BM and n=21 (n=6 latex, n=15 lectin) control mice. Abnormal tangled vessels were observed at the injection site in mice with pdgfb-iCreER;Alk12f/2f BM only (n=2, 20%). Vessel density (225.4±27.7 vs 159.3±4.9, p<0.01) and number of dysplastic vessels (10.2±4.7 vs 3.7±1.0, p<0.01) were significantly increased with Alk1 deficient BMDEC. Mice with pdgfb-iCreER;Alk12f/2f BM exhibited higher numbers of intestinal arteriovenous shunts as compared to the control group (13.6±17.8 vs 0.7±0.8, p<0.05).
Conclusion: Our preliminary findings demonstrate that Alk1 deficient BMDEC lead to formation of abnormal vessels in angiogenic brain areas and arteriovenous shunts in mice intestines. BMDEC may play a major role in AVM pathogenesis and may represent an unrecognized target for future non-surgical treatment.
