Endoglin Deficiency in Bone Marrow is Sufficient to Cause Cerebrovascular Dysplasia in the Adult Mouse After Vascular Endothelial Growth Factor Stimulation
Background and Purpose—Bone marrow–derived cells (BMDCs) home to vascular endothelial growth factor (VEGF)–induced brain angiogenic foci, and VEGF induces cerebrovascular dysplasia in adult endoglin heterozygous (Eng+/−) mice. We hypothesized that Eng+/− BMDCs cause cerebrovascular dysplasia in the adult mouse after VEGF stimulation.
Methods—BM transplantation was performed using adult wild-type (WT) and Eng+/− mice as donors/recipients. An adeno-associated viral vector expressing VEGF was injected into the basal ganglia 4 weeks after transplantation. Vascular density, dysplasia index (vessels >15 µm/100 vessels), and BMDCs in the angiogenic foci were analyzed.
Results—The dysplasia index of WT/Eng+/− BM mice was higher than WT/WT BM mice (P<0.001) and was similar to Eng+/−/Eng+/− BM mice (P=0.2). Dysplasia in Eng+/− mice was partially rescued by WT BM (P<0.001). WT/WT BM and WT/Eng+/− BM mice had similar numbers of BMDCs in the angiogenic foci (P=0.4), most of which were CD68+. Eng+/− monocytes/macrophages expressed less matrix metalloproteinase-9 and Notch1.
Conclusions—Endoglin-deficient BMDCs are sufficient for VEGF to induce vascular dysplasia in the adult mouse brain. Our data support a previously unrecognized role of BM in the development of cerebrovascular malformations.
- Received July 23, 2012.
- Revision received October 31, 2010.
- Accepted November 19, 2012.
- © 2013 American Heart Association, Inc.