Contribution of Monocytes/Macrophages to Compensatory Neovascularization: The Drilling of Metalloelastase-Positive Tunnels in Ischemic Myocardium

In a transgenic model of ischemic cardiomyopathy in which monocytes are attracted to the myocardium by the targeted overexpression of monocyte chemoattractant protein-1 (MCP-1), we have observed the presence of endothelial NO synthase and platelet endothelial cell adhesion molecule-1–negative tunnels, occasionally containing blood-derived cells, that probe the cardiac tissue. Immunohistochemical data show that monocytes/macrophages (MCs/Mphs) drill tunnels using the broad-spectrum mouse macrophage metalloelastase. 5-Bromo-2′-deoxyuridine incorporation and neo-endothelial markers present in the microvasculature of MCP-1 mouse hearts suggest an active angiogenic process. Further studies will be required to establish that the MC-/Mph-drilled tunnels evolve to become capillaries, connected to the existing vessels and colonized by circulating endothelial cell progenitors. This possibility is supported by the availability of these cells, which is demonstrated by cell tagging with &bgr;-galactosidase placed under an active endothelial Tie-2 promoter. This phenomenon might represent another mechanism, in addition to the secretion of the angiogenic factors, by which MCs/MPhs may participate in the elaboration of new blood vessels in adult tissues.

[1]  R K Jain,et al.  Openings between defective endothelial cells explain tumor vessel leakiness. , 2000, The American journal of pathology.

[2]  U. Ikeda,et al.  Expression of vascular endothelial growth factor in patients with acute myocardial infarction. , 2000, Journal of the American College of Cardiology.

[3]  R. Jain,et al.  Vasculogenic mimicry: how convincing, how novel, and how significant? , 2000, The American journal of pathology.

[4]  H. Dvorak,et al.  Different pathways of macromolecule extravasation from hyperpermeable tumor vessels. , 2000, Microvascular research.

[5]  J. Howl,et al.  Critical Evaluation of ECV304 as a Human Endothelial Cell Model Defined by Genetic Analysis and Functional Responses: A Comparison with the Human Bladder Cancer Derived Epithelial Cell Line T24/83 , 2000, Laboratory Investigation.

[6]  J. Folkman,et al.  The generation of endostatin is mediated by elastase. , 1999, Cancer research.

[7]  A. Luttun,et al.  Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure , 1999, Nature Medicine.

[8]  P. Meltzer,et al.  Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. , 1999, The American journal of pathology.

[9]  M. Chopp,et al.  Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice , 1999, Brain Research.

[10]  J. Isner,et al.  Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. , 1999, Circulation research.

[11]  S. Shapiro.  Diverse Roles of Macrophage Matrix Metalloproteinases in Tissue Destruction and Tumor Growth , 1999, Thrombosis and Haemostasis.

[12]  S. Shapiro,et al.  Enhanced expression of human metalloelastase (MMP-12) in cutaneous granulomas and macrophage migration. , 1999, The Journal of investigative dermatology.

[13]  H. Dvorak,et al.  Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. , 1999, Current topics in microbiology and immunology.

[14]  N. Ferrara.  Vascular endothelial growth factor: molecular and biological aspects. , 1999, Current topics in microbiology and immunology.

[15]  R. Pierce,et al.  Matrix metalloproteinases generate angiostatin: effects on neovascularization. , 1998, Journal of immunology.

[16]  S. Werner,et al.  Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. , 1998, Experimental cell research.

[17]  S. Shaw,et al.  Thy-1, a novel marker for angiogenesis upregulated by inflammatory cytokines. , 1998, Circulation research.

[18]  L. Sauvage,et al.  Early Flow Surface Endothelialization before Microvessel Ingrowth in Accelerated Graft Healing, with BrdU Identification of Cellular Proliferation , 1998, Annals of vascular surgery.

[19]  W. Schaper,et al.  Ischemia-induced phosphorylation and translocation of stress protein αB-crystallin to Z lines of myocardium. , 1998, American journal of physiology. Heart and circulatory physiology.

[20]  É. Allaire,et al.  Metalloproteinase blockade by local overexpression of TIMP-1 increases elastin accumulation in rat carotid artery intima. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[21]  C. Orosz,et al.  Myocarditis induced by targeted expression of the MCP-1 gene in murine cardiac muscle. , 1998, The American journal of pathology.

[22]  B. Zetter,et al.  Angiogenesis and tumor metastasis. , 1998, Annual review of medicine.

[23]  P. Carmeliet,et al.  Molecular analysis of blood vessel formation and disease. , 1997, American journal of physiology. Heart and circulatory physiology.

[24]  A. Cuvelier,et al.  Metalloelastase expression in a mouse macrophage cell line--regulation by 4beta-phorbol 12-myristate 13-acetate, lipopolysaccharide and dexamethasone. , 1997, European journal of biochemistry.

[25]  Thomas N. Sato,et al.  Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  William Arbuthnot Sir Lane,et al.  Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth , 1997, Cell.

[27]  M. O'Reilly.  Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth. , 1997, EXS.

[28]  P. Carmeliet,et al.  Molecular analysis of blood vessel formation and disease. , 1997, The American journal of physiology.

[29]  J. Folkman,et al.  Blood Vessel Formation: What Is Its Molecular Basis? , 1996, Cell.

[30]  J. Folkman.  New perspectives in clinical oncology from angiogenesis research. , 1996, European journal of cancer.

[31]  R. Kumar,et al.  Differential regulation of metalloelastase activity in murine peritoneal macrophages by granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor. , 1996, Journal of immunology.

[32]  W. Schaper,et al.  Molecular mechanisms of coronary collateral vessel growth. , 1996, Circulation research.

[33]  J. Isner.  The role of angiogenic cytokines in cardiovascular disease. , 1996, Clinical immunology and immunopathology.

[34]  S. Kano,et al.  Selective accumulation of anti-histone antibodies in glomeruli of lupus-prone lpr mice. , 1996, Clinical immunology and immunopathology.

[35]  S. Kumar,et al.  Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. , 1996, Journal of molecular and cellular cardiology.

[36]  T. Ley,et al.  Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Yasufumi Sato,et al.  [Regulators of angiogenesis]. , 1996, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.

[38]  W. Schaper.  Control of coronary angiogenesis. , 1995, European heart journal.

[39]  T. Drake,et al.  Experimental cardiac allograft vasculopathy in mice. , 1993, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[40]  P. Vaupel,et al.  Therapeutic angiogenesis. , 1993, Archives of surgery.

[41]  J. Folkman,et al.  The role of angiogenesis in tumor growth. , 1992, Seminars in cancer biology.

[42]  D. Ingber,et al.  Inhibition of angiogenesis. , 1992, Seminars in cancer biology.

[43]  M. Klagsbrun,et al.  Regulators of angiogenesis. , 1991, Annual review of physiology.

[44]  R. Montesano,et al.  Phorbol ester stimulates macrophage invasion of fibrin matrices , 1988, The Anatomical record.

[45]  Judah Folkman,et al.  Angiogenesis in vitro , 1980, Nature.

[46]  R. Jennings,et al.  ISCHEMIC INJURY OF MYOCARDIUM * , 1969, Annals of the New York Academy of Sciences.