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Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages.

ABSTRACT: We investigated the role of bone marrow-derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation.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.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.

SUBMITTER: Hao Q

PROVIDER: S-EPMC2610019 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages.

Hao Qi Q 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

Arteriosclerosis, thrombosis, and vascular biology 20080918 12

<h4>Objective</h4>We investigated the role of bone marrow-derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation.<h4>Methods and results</h4>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 B ...[more]

PMID: 18802012

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Project description:Reticuloendothelial macrophages engulf ?0.2 trillion senescent erythrocytes daily in a process called erythrophagocytosis (EP). This critical mechanism preserves systemic heme-iron homeostasis by regulating red blood cell (RBC) catabolism and iron recycling. Although extensive work has demonstrated the various effects on macrophage metabolic reprogramming by stimulation with proinflammatory cytokines, little is known about the impact of EP on the macrophage metabolome and proteome. Thus, we performed mass spectrometry-based metabolomics and proteomics analyses of mouse bone marrow-derived macrophages (BMDMs) before and after EP of IgG-coated RBCs. Further, metabolomics was performed on BMDMs incubated with free IgG to ensure that changes to macrophage metabolism were due to opsonized RBCs and not to free IgG binding. Uniformly labeled tracing experiments were conducted on BMDMs in the presence and absence of IgG-coated RBCs to assess the flux of glucose through the pentose phosphate pathway (PPP). In this study, we demonstrate that EP significantly alters amino acid and fatty acid metabolism, the Krebs cycle, OXPHOS, and arachidonate-linoleate metabolism. Increases in levels of amino acids, lipids and oxylipins, heme products, and RBC-derived proteins are noted in BMDMs following EP. Tracing experiments with U-13C6 glucose indicated a slower flux through glycolysis and enhanced PPP activation. Notably, we show that it is fueled by glucose derived from the macrophages themselves or from the extracellular media prior to EP, but not from opsonized RBCs. The PPP-derived NADPH can then fuel the oxidative burst, leading to the generation of reactive oxygen species necessary to promote digestion of phagocytosed RBC proteins via radical attack. Results were confirmed by redox proteomics experiments, demonstrating the oxidation of Cys152 and Cys94 of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and hemoglobin-?, respectively. Significant increases in early Krebs cycle and C5-branched dibasic acid metabolites (?-ketoglutarate and 2-hydroxyglutarate, respectively) indicate that EP promotes the dysregulation of mitochondrial metabolism. Lastly, EP stimulated aminolevulinic acid (ALA) synthase and arginase activity as indicated by significant accumulations of ALA and ornithine after IgG-mediated RBC ingestion. Importantly, EP-mediated metabolic reprogramming of BMDMs does not occur following exposure to IgG alone. In conclusion, we show that EP reprograms macrophage metabolism and modifies macrophage polarization.

Dataset Information

Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages.

Publications

Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages.

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