Modulation of the vascular response to injury by autologous blood-derived outgrowth endothelial cells.

Delivery of a heterogeneous population of cells with endothelial phenotype derived from peripheral blood has been shown to improve vascular responses after balloon arterial injury in an endothelium-dependent manner. Refinement of culture techniques has enabled the generation of outgrowth endothelial cells (OECs), a homogeneous population of distinctly endothelial cells expanded from circulating progenitor cells. The present study tested the hypothesis that OEC delivery would confer vascular protection after balloon arterial injury in a rabbit model. Rabbit peripheral blood mononuclear cells (PBMCs) were cultured in endothelial growth medium for 4-5 wk, yielding proliferative OECs with distinct endothelial phenotype (morphology, incorporation of acetylated LDL, and expression of endothelial nitric oxide synthase and caveolin-1 but not CD14). Animals underwent balloon carotid injury immediately followed by local delivery of autologous OECs for 20 min. Fluorescent-labeled OECs were detected in all layers at 4 wk, with immunostaining revealing maintenance of endothelial phenotype (von Willebrand factor-positive and RAM-11-negative) by luminal and nonluminal cells. To evaluate functional effects, additional animals received autologous OECs, saline, or freshly harvested PBMCs as noncultured cell controls by local dwell after balloon injury. Local OEC delivery improved endothelium-dependent vasoreactivity (P < 0.05 vs. saline and PBMC) and similarly reduced neointimal formation (P < 0.05 vs. saline and PBMC). These data suggest that OECs can be detected in injured arterial segments at 4 wk. Moreover, delivery of OECs confers greater vascular protection than PBMCs or saline controls and may thus offer a novel, autologous strategy to limit the response to mechanical injury.

[1]  S. Dimmeler,et al.  Endothelial Progenitor Cells: Characterization and Role in Vascular Biology , 2004, Circulation research.

[2]  R. Vile,et al.  Use of blood outgrowth endothelial cells as virus-producing vectors for gene delivery to tumors. , 2004, American journal of physiology. Heart and circulatory physiology.

[3]  Hyun-Jae Kang,et al.  Characterization of Two Types of Endothelial Progenitor Cells and Their Different Contributions to Neovasculogenesis , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[4]  J. Isner,et al.  Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury , 2003, Circulation.

[5]  R. Vile,et al.  Diverse Origin and Function of Cells With Endothelial Phenotype Obtained From Adult Human Blood , 2003, Circulation research.

[6]  R. Mulligan,et al.  Isolation and Transplantation of Autologous Circulating Endothelial Cells Into Denuded Vessels and Prosthetic Grafts: Implications for Cell-Based Vascular Therapy , 2003, Circulation.

[7]  H. Matsubara,et al.  Bone Marrow Monocyte Lineage Cells Adhere on Injured Endothelium in a Monocyte Chemoattractant Protein-1–Dependent Manner and Accelerate Reendothelialization as Endothelial Progenitor Cells , 2003, Circulation research.

[8]  R. Vile,et al.  Autologous Culture-Modified Mononuclear Cells Confer Vascular Protection After Arterial Injury , 2003, Circulation.

[9]  U. Laufs,et al.  Intravenous Transfusion of Endothelial Progenitor Cells Reduces Neointima Formation After Vascular Injury , 2003, Circulation research.

[10]  S. Tamura,et al.  Contribution of von Willebrand Factor to Thrombus Formation on Neointima of Rabbit Stenotic Iliac Artery Under High Blood-Flow Velocity , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[11]  W. Edwards,et al.  Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Christie M. Orschell,et al.  Peripheral Blood “Endothelial Progenitor Cells” Are Derived From Monocyte/Macrophages and Secrete Angiogenic Growth Factors , 2003, Circulation.

[13]  Y. Yoon,et al.  Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells for Therapeutic Neovascularization of Myocardial Ischemia , 2003, Circulation.

[14]  M. Endres,et al.  Bone Marrow–Derived Progenitor Cells Modulate Vascular Reendothelialization and Neointimal Formation: Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[15]  J. Isner,et al.  Statin Therapy Accelerates Reendothelialization: A Novel Effect Involving Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells , 2002, Circulation.

[16]  M. Makuuchi,et al.  Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis , 2002, Nature Medicine.

[17]  J. Isner,et al.  Endothelial Progenitor Cell Vascular Endothelial Growth Factor Gene Transfer for Vascular Regeneration , 2002, Circulation.

[18]  Anthony Atala,et al.  Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo , 2001, Nature Medicine.

[19]  J. Isner,et al.  HMG-CoA reductase inhibitor mobilizes bone marrow--derived endothelial progenitor cells. , 2001, The Journal of clinical investigation.

[20]  A M Zeiher,et al.  HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. , 2001, The Journal of clinical investigation.

[21]  R. Hartley,et al.  CD34− Blood‐Derived Human Endothelial Cell Progenitors , 2001, Stem cells.

[22]  E. Popa,et al.  Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis. , 2001, The Journal of clinical investigation.

[23]  J. Isner,et al.  Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia , 2001, Circulation.

[24]  J. Isner,et al.  Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Rafii,et al.  Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. , 2000, Blood.

[26]  K. Pantel,et al.  In vitro differentiation of endothelial cells from AC133-positive progenitor cells. , 1999, Blood.

[27]  S. Rafii,et al.  Evidence for circulating bone marrow-derived endothelial cells. , 1998, Blood.

[28]  M. Makuuchi,et al.  Circulating smooth muscle progenitor cells contribute to atherosclerosis , 2001, Nature Medicine.

[29]  R. Hebbel,et al.  Origins of circulating endothelial cells and endothelial outgrowth from blood. , 2000, The Journal of clinical investigation.