Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages.
OBJECTIVE
We investigated the role of bone marrow-derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation.


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 alpha-smooth muscle actin (alpha -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/macrophages, 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.
Hao
Qi
Q
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
Liu
Jianrong
J
Pappu
Rajita
R
Su
Hua
H
Rola
Radoslaw
R
Gabriel
Rodney A
RA
Lee
Chanhung Z
CZ
Young
William L
WL
Yang
Guo-Yuan
GY
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D001921:Brain / Q000098:blood supply* / Q000166:cytology*; D000229:Dependovirus / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D011994:Recombinant Proteins / Q000235:genetics; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C090509:Icam1 protein, mouse; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C485184:enhanced green fluorescent protein; D018799:Intercellular Adhesion Molecule-1; D049452:Green Fluorescent Proteins; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
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