on September 18, 2008
Published online before print September 18, 2008, doi: 10.1161/ATVBAHA.108.176297
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Submitted on April 22, 2008
Accepted on September 8, 2008
Contribution of Bone Marrow–Derived Cells Associated With Brain Angiogenesis Is Primarily Through Leukocytes and Macrophages
Qi Hao ;
From the Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care (Q.H., J.L., H.S., R.A.G., C.Z.L., W.L.Y., G.-Y.Y.), Departments of Neurological Surgery (R.P., R.R., W.L.Y.), and Neurology (W.L.Y.), University of California, San Francisco; and Ruijin Hospital, School of Medicine (J.L., G.-Y.Y.), Shanghai Jiaotong University, Shanghai, China.
* To whom correspondence should be addressed. E-mail: gyyang{at}anesthesia.ucsf.edu.
Objective—We investigated the role of bone marrow–derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation.
Methods and Results—BM from GFP donor mice was isolated and transplanted into lethally irradiated recipients. Four weeks after transplantation, groups of mice received adeno-associated viral vector (AAV)-VEGF or AAV-lacZ gene (control) injection and were euthanized at 1 to 24 weeks. BMDCs were characterized by double-labeled immunostaining. The function of BMDCs was further examined through matrix metalloproteinase (MMP)-2 and -9 activity. We found that capillary density increased after 2 weeks, peaked at 4 weeks (P<0.01), and sustained up to 24 weeks after gene transfer. GFP-positive BMDCs infiltration in the angiogenic focus began at 1 week, peaked at 2 weeks, and decreased thereafter. The GFP-positive BMDCs were colocalized with CD45 (94%), CD68 (71%), 5% Vimentin (5%), CD31/von Willebrand factor (vWF) (1%), and 
-smooth muscle actin ( -SMA, 0.5%). Infiltrated BMDCs expressed MMP-9. MMP-9 KO mice confirmed the dependence of the angiogenic response on MMP-9 availability.
Conclusions—Nearly all BMDCs in the angiogenic focus showed expression for leukocytes/microglia, indicating that BMDCs minimally incorporated into the neovasculature. Colocalization of MMPs with GFP suggests that BMDCs play a critical role in VEGF-induced angiogenic response through up-regulation of MMPs.
Key words: adeno-associated virus • angiogenesis • BMDCs • MMPs • VEGF
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