title: Bone marrow-derived cells contribute to vascular endothelial growth factor-induced angiogenesis in the adult mouse brain by supplying matrix metalloproteinase-9.
abstract: OBJECTIVE
  Our previous studies have shown that bone marrow-derived cells (BMDCs) home to a brain angiogenic focus. The angiogenic response to vascular endothelial growth factor (VEGF) stimulation is reduced in matrix metalloproteinase-9 (MMP-9) knockout mice. We hypothesized that BMDCs contribute to VEGF-induced angiogenesis by supplying MMP-9.
  
  
  METHODS
  Bone marrow (BM) transplantation was conducted using MMP-9 knockout (MMP-9 KO) or wild-type (WT) mice as both donors and recipients. Adeno-associated viral vectors expressing VEGF or LacZ were injected into the striatum 4 weeks after BM transplantation. Circulating white blood cells (WBCs), microvessel density, number of BMDCs, and MMP-9 activity around the injection site were analyzed.
  
  
  RESULTS
  Two weeks after vector injection, circulating WBCs increased in WT mice but not in MMP-9 KO mice. VEGF overexpression increased microvessel density by 38% in WT mice 4 weeks after vector injection (P=0.0001). After transplantation of MMP-9 KO BM to WT mice, microvessel density only increased 18% after VEGF stimulation (P=0.037), with MMP-9 activity reduced to 35% of the level of WT mice (P<0.01). There was minimal angiogenic response in MMP-9 KO mice with MMP-9 KO BM (P=0.28). Transplantation of WT BM to MMP-9 KO mice restored brain angiogenic response to 92% of the WT level, ie, a 30% increase of microvessel density with VEGF overexpression (P=0.0006); MMP-9 activity was similar to that in WT mice.
  
  
  CONCLUSIONS
  BM-derived MMP-9 plays an important role in BM cell mobilization and focal angiogenesis in the brain in response to VEGF stimulation.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94110, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hao
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: Daniel
authors.initials: D
authors.lastname: Palmer
authors.forename: Baoliang
authors.initials: B
authors.lastname: Sun
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
authors.forename: William L
authors.initials: WL
authors.lastname: Young
mesh_terms: D000367:Age Factors; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology*; D016026:Bone Marrow Transplantation / Q000379:methods; D001921:Brain / Q000098:blood supply* / Q000201:enzymology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9