Bone Marrow-Derived Cells Contribute to Vascular Endothelial Growth Factor–Induced Angiogenesis in the Adult Mouse Brain by Supplying Matrix Metalloproteinase-9

Abstract

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. 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. 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. BM-derived MMP-9 plays an important role in BM cell mobilization and focal angiogenesis in the brain in response to VEGF stimulation.