© 2000 American Heart Association, Inc.
Reports |
Endothelial Cells of Hematopoietic Origin Make a Significant Contribution to Adult Blood Vessel Formation
From the Department of Pathology (J.R.C., W.E.K., E.W.R., R.A.S., D.F.B.-P.), University of Washington, Seattle, Wash; and Division of Clinical Research (P.J.M.), Fred Hutchinson Cancer Research Center, Seattle, Wash. Current affiliations: J.R.C., S.C. Johnson Research Center, Mayo Clinic Scottsdale, Scottsdale, Ariz; W.E.K., Department of Clinical Chemistry and Laboratory Medicine, University of Regensburg Medical School, Regensburg, Germany; and G.S., Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
Correspondence to Daniel F. Bowen-Pope, University of Washington, Department of Pathology, Box 357470, Health Sciences Center, Room D525, Seattle, WA 98195-7470. E-mail bp{at}u.washington.edu
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Abstract |
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Granulation tissue formation is an example of new tissue development in an adult. Its rich vascular network has been thought to derive via angiogenic sprouting and extension of preexisting vessels from the surrounding tissue. The possibility that circulating cells of hematopoietic origin can differentiate into vascular endothelial cells (ECs) in areas of vascular remodeling has recently gained credibility. However, no quantitative data have placed the magnitude of this contribution into a physiological perspective. We have used hematopoietic chimeras to determine that 0.2% to 1.4% of ECs in vessels in control tissues derived from hematopoietic progenitors during the 4 months after irradiation and hematopoietic recovery. By contrast, 8.3% to 11.2% of ECs in vessels that developed in sponge-induced granulation tissue during 1 month derived from circulating hematopoietic progenitors. This recruitment of circulating progenitors to newly forming vessels would be difficult to observe in standard histological studies, but it is large enough to be encouraging for attempts to manipulate this contribution for therapeutic gain.
Key Words: hematopoietic stem cell • angiogenesis • endothelial cell
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When the endothelium is removed from a segment of large artery, the denuded region is reendothelialized via migration and proliferation of endothelial cells (ECs) from the adjacent intact endothelium. Occasionally, islands of ECs are observed, possibly representing colonization of the artery wall by circulating progenitors that had attached and proliferated.1 However, these are essentially never observed after deendothelialization of the rat carotid artery,2 the most thoroughly evaluated model of reendothelialization, and their origin is uncertain. New vessels can develop in adult tissue, eg, during granulation tissue formation. In this case, it is usually believed that with the exception of leukocytes, the cells that constitute this highly vascularized tissue, including fibroblasts, smooth muscle cells, and ECs, arrive via the proliferation and migration of these cell types from the adjacent tissue. Contribution by circulating cells would be very difficult to recognize, however, unless the two possible sources of ECs could be distinguished by informative markers.
One source of circulating EC progenitors could be the hematopoietic system. During early development, hematopoiesis is closely associated with the formation of EC-lined spaces. Both angioblasts and embryonic hematopoietic progenitors express Flk-1, Tie-1, and CD34. Targeted disruption of the genes for Flk-13 and its ligand, vascular endothelial growth factor,4 specifically disrupts both hematopoietic and EC function during development. This suggested the existence of a "hemangioblast," which can give rise to both hematopoietic stem cells and ECs, and a cell with this potential has been isolated from embryoid bodies.5 Moreover, CD34+ stem cells from adult peripheral blood can reconstitute the hematopoietic system.6 If some of these circulating cells have the developmental capacity of hemangioblasts, they might, under appropriate conditions, differentiate into ECs rather than hematopoietic cells.
Marked cells of hematopoietic origin injected intravenously into host mice or rabbits have been identified as ECs in the developing collateral vessels of ischemic tissues but not in vessels in unaffected tissue.7 8 This demonstrates that circulating cells can participate in the formation of endothelium, but no quantitative data have been reported to put this contribution into a physiological perspective. We undertook the present study to determine whether circulating hematopoietic-derived EC progenitors make a biologically significant contribution to new vessels compared with other sources of ECs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation of Marked Hematopoietic Chimeras
In E16 to E17 embryos,
50% of cells in the
liver are involved in hematopoiesis. E16.5 wild-type embryos,
homozygous for the genomic globin/pBR322 marker and expressing the
Ly-5b allele, were obtained by Caesarean
section, and the livers were mechanically dissociated to provide cells
for tail vein injection into C57BL6/J Ly-5a
recipient mice that had been irradiated 24 hours before transplantation
to eliminate endogenous hematopoiesis. The chimeric mice were
used 90 days after injection, at which time the globin/pBR322-marked
cells had completely reconstituted the hematopoietic system. The Ly-5
marker was used together with markers for different hematopoietic
lineages to confirm by flow cytometry that the host hematopoietic
system had been eliminated and that donor hematopoietic cell types were
present at levels within the normal range (J.R.C., W.E.K., P.J.M.,
E.W.R., D.F.B.-P., P. Lindahl, N.L. Lin, V. Broudy, B. Swolin, R. Ross,
C. Betscholtz, unpublished data, 2000). The experimental protocol was
approved by the University of Washington Committee for Animal Care and
Use.
Evaluation of Hematopoietic Origin of
ECs
We evaluated sections from the center of the sponge.
The method for visualization of the integrated marker that identifies a
cell of hematopoietic origin has been described
elsewhere.9 10
Because the histological section does not always include the entire
nucleus, false-negatives arise when the nuclear cross section does not
include either of the two chromosomal globin marker loci. Because this
is affected by nuclear shape and orientation, we used tissue from
purebred (ie, nonchimeric) mice homozygous for the marker to determine
the false-negative rate (6%) characteristic of ECs. All data have been
corrected for this. Leukocytes associated with vessels were identified
with the panleukocyte marker CD45 using rat monoclonal anti-mouse CD45
(clone 30-F11, Pharmingen), followed by biotinylated rabbit anti-rat
IgG, then Vectastain elite ABC peroxidase (Vector), and visualized
using diaminobenzidine. Laminin was stained using rabbit anti-mouse
laminin (Collaborative Biomedical Products), followed by biotinylated
goat anti-rabbit IgG Vectastain elite ABC peroxidase (Vector), and
visualized using diaminobenzidine. ECs expressing von Willebrand factor
(vWF) were identified by treating sections with proteinase K, then
incubating with rabbit anti-human vWF (Dako), followed by biotinylated
goat anti-rabbit IgG (Vector), then Vectastain ABC alkaline phosphatase
(Vector), and visualized using Vector Red substrate (Vector). ECs
expressing platelet-endothelial cell adhesion molecule (PECAM) (CD31)
were identified by incubating with biotinylated rat anti-mouse CD31
(Pharmingen), followed by Vectastain ABC alkaline phosphatase (Vector),
and visualized using Vector Red substrate (Vector). In all cases, the
immunostained sections were counterstained with methyl green nuclear
stain. To evaluate the extent of interobserver variation in identifying
marked ECs, a series of micrographs of sections stained with each of
the three reagent sets was separately scored by three of the coauthors.
The values differed by 2% or
less.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To quantitate the contribution of circulating hematopoietic EC progenitors to new vessel formation, we prepared mouse hematopoietic chimeras in which cells derived from the hematopoietic system were marked by an integrated DNA marker detected as an unambiguous dark nuclear dot by nonisotopic in situ hybridization with a digoxigenin-labeled probe against the globin/pBR322 sequence.9 Because detection does not involve gene expression, this avoids possible effects of differentiation on marker expression.
To initiate granulation tissue formation, we implanted four small sponges under the skin on the back.10 By evaluating only tissue that developed within the sponge, we could specifically evaluate the contribution of marked cells to newly formed vessels. Four weeks later, we killed the mice and removed the sponges, along with samples of uninvolved skin, aorta, and brain. Tissues were fixed with methyl Carnoy’s fixative, embedded, sectioned, and evaluated by nonisotopic in situ hybridization to visualize the marker of hematopoietic origin and by immunohistochemical staining to identify cell type.9 10
We identified ECs in vessels of all sizes using three sets
of criteria, illustrated in the
Figure
:
(1) flattened cells on the luminal side of the basement membrane
(identified by immunostaining for laminin) that were negative for
expression of the panleukocyte marker CD45 (panel A); (2) flattened
vWF-positive cells surrounding a lumen (panel C); and (3)
PECAM-positive cells surrounding a lumen (panel E). The three methods
for identifying ECs detected somewhat different numbers of ECs per
optical field, but the percentage of these that were positive for the
globin marker of hematopoietic origin were very similar: 8.3% to
11.2% (panels B, D, and F). By contrast, the percentage of marked ECs
in normal tissues was only 0.2% to 1.4%. These results demonstrate
that circulating cells of hematopoietic origin make a significant
contribution to the endothelium of new vessels, and that these
hematopoietic-derived ECs were not different from ECs of host tissue
origin in expression of any of the EC markers
evaluated.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recruitment of circulating hematopoietic-derived EC progenitors to newly forming vessels is small enough in magnitude to explain how this source of ECs might have been overlooked in histological studies but large enough to be encouraging for attempts to manipulate this contribution for therapeutic gain. Isner’s group has demonstrated that the number of circulating progenitors can be augmented by ischemia and granulocyte/macrophage colony-stimulating factor.11 This augmentation will clearly be important for maximizing the contribution of circulating progenitors to new vessel formation. In addition, this pathway must also be regulated at the level of the destination tissue, because the contribution of hematopoietic progenitors appears to be greatly augmented at sites of new vessel formation. Consistent with earlier studies,7 8 we found that marked hematopoietic progenitors did not make significant contributions to the endothelium of blood vessels in stable adult tissue, even during 4 months, 4-fold longer than the time during which the granulation tissue formed.
In future studies, it will be important to determine the mechanisms that specifically recruit progenitors to newly forming vessels. Are specific adhesion molecules upregulated that help localize the circulating progenitors, or is the enhancement due to an increased propensity of progenitors to differentiate into ECs in new, but not mature, vessels? Do the progenitors arrive in the tissue and then coalesce into vessels as in vasculogenesis, or are they recruited by attachment to, and integration into, the growing tips or shafts of existing vessels extending via angiogenic mechanisms?
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Acknowledgments |
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This research was supported by National Institutes of Health Grants HL03174 (to D.B.-P.) and HL18645 (to E.W.R.). We thank Russell Ross (died 3/18/99) for holding us to the highest critical standards in the interpretation of these results.
Received August 14, 2000; revision received September 14, 2000; accepted September 28, 2000.
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References |
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O. M. Tepper, J. M. Capla, R. D. Galiano, D. J. Ceradini, M. J. Callaghan, M. E. Kleinman, and G. C. Gurtner Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells Blood, February 1, 2005; 105(3): 1068 - 1077. [Abstract] [Full Text] [PDF]
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D. Fliser, K. de Groot, F. H. Bahlmann, and H. Haller Cardiovascular disease in renal patients--a matter of stem cells? Nephrol. Dial. Transplant., December 1, 2004; 19(12): 2952 - 2954. [Full Text] [PDF]
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J. O. d. Buijs, M. Musters, T. Verrips, J. A. Post, B. Braam, and N. van Riel Mathematical modeling of vascular endothelial layer maintenance: the role of endothelial cell division, progenitor cell homing, and telomere shortening Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2651 - H2658. [Abstract] [Full Text] [PDF]
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 J.-H. Choi, J. Hur, C.-H. Yoon, J.-H. Kim, C.-S. Lee, S.-W. Youn, I.-Y. Oh, C. Skurk, T. Murohara, Y.-B. Park, et al. Augmentation of Therapeutic Angiogenesis Using Genetically Modified Human Endothelial Progenitor Cells with Altered Glycogen Synthase Kinase-3{beta} Activity J. Biol. Chem., November 19, 2004; 279(47): 49430 - 49438. [Abstract] [Full Text] [PDF]
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J. Chou, N. Mackman, G. Merrill-Skoloff, B. Pedersen, B. C. Furie, and B. Furie Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation Blood, November 15, 2004; 104(10): 3190 - 3197. [Abstract] [Full Text] [PDF]
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I. Rajantie, M. Ilmonen, A. Alminaite, U. Ozerdem, K. Alitalo, and P. Salven Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells Blood, October 1, 2004; 104(7): 2084 - 2086. [Abstract] [Full Text] [PDF]
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C. Fathke, L. Wilson, J. Hutter, V. Kapoor, A. Smith, A. Hocking, and F. Isik Contribution of Bone Marrow-Derived Cells to Skin: Collagen Deposition and Wound Repair Stem Cells, September 1, 2004; 22(5): 812 - 822. [Abstract] [Full Text] [PDF]
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C. Urbich and S. Dimmeler Endothelial Progenitor Cells: Characterization and Role in Vascular Biology Circ. Res., August 20, 2004; 95(4): 343 - 353. [Abstract] [Full Text] [PDF]
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T. Kinnaird, E. Stabile, M. S. Burnett, and S. E. Epstein Bone Marrow-Derived Cells for Enhancing Collateral Development: Mechanisms, Animal Data, and Initial Clinical Experiences Circ. Res., August 20, 2004; 95(4): 354 - 363. [Abstract] [Full Text] [PDF]
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 A. Weber, I. Pedrosa, A. Kawamoto, N. Himes, J. Munasinghe, T. Asahara, N. M. Rofsky, and D. W. Losordo Magnetic resonance mapping of transplanted endothelial progenitor cells for therapeutic neovascularization in ischemic heart disease Eur. J. Cardiothorac. Surg., July 1, 2004; 26(1): 137 - 143. [Abstract] [Full Text] [PDF]
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R. D. Galiano, O. M. Tepper, C. R. Pelo, K. A. Bhatt, M. Callaghan, N. Bastidas, S. Bunting, H. G. Steinmetz, and G. C. Gurtner Topical Vascular Endothelial Growth Factor Accelerates Diabetic Wound Healing through Increased Angiogenesis and by Mobilizing and Recruiting Bone Marrow-Derived Cells Am. J. Pathol., June 1, 2004; 164(6): 1935 - 1947. [Abstract] [Full Text] [PDF]
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S. Verma, M. A. Kuliszewski, S.-H. Li, P. E. Szmitko, L. Zucco, C.-H. Wang, M. V. Badiwala, D. A.G. Mickle, R. D. Weisel, P. W.M. Fedak, et al. C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function: Further Evidence of a Mechanistic Link Between C-Reactive Protein and Cardiovascular Disease Circulation, May 4, 2004; 109(17): 2058 - 2067. [Abstract] [Full Text] [PDF]
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C. Wang, C. Jiao, H. D. Hanlon, W. Zheng, R. J. Tomanek, and G. C. Schatteman Mechanical, cellular, and molecular factors interact to modulate circulating endothelial cell progenitors Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1985 - H1993. [Abstract] [Full Text] [PDF]
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V. Adams, K. Lenk, A. Linke, D. Lenz, S. Erbs, M. Sandri, A. Tarnok, S. Gielen, F. Emmrich, G. Schuler, et al. Increase of Circulating Endothelial Progenitor Cells in Patients with Coronary Artery Disease After Exercise-Induced Ischemia Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 684 - 690. [Abstract] [Full Text] [PDF]
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R. Tamarat, J.-S. Silvestre, S. Le Ricousse-Roussanne, V. Barateau, L. Lecomte-Raclet, M. Clergue, M. Duriez, G. Tobelem, and B. I. Levy Impairment in Ischemia-Induced Neovascularization in Diabetes: Bone Marrow Mononuclear Cell Dysfunction and Therapeutic Potential of Placenta Growth Factor Treatment Am. J. Pathol., February 1, 2004; 164(2): 457 - 466. [Abstract] [Full Text] [PDF]
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F. H. Bahlmann, K. de Groot, J.-M. Spandau, A. L. Landry, B. Hertel, T. Duckert, S. M. Boehm, J. Menne, H. Haller, and D. Fliser Erythropoietin regulates endothelial progenitor cells Blood, February 1, 2004; 103(3): 921 - 926. [Abstract] [Full Text] [PDF]
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U. Laufs, N. Werner, A. Link, M. Endres, S. Wassmann, K. Jurgens, E. Miche, M. Bohm, and G. Nickenig Physical Training Increases Endothelial Progenitor Cells, Inhibits Neointima Formation, and Enhances Angiogenesis Circulation, January 20, 2004; 109(2): 220 - 226. [Abstract] [Full Text] [PDF]
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 C. J.M. Loomans, E. J.P. de Koning, F. J.T. Staal, M. B. Rookmaaker, C. Verseyden, H. C. de Boer, M. C. Verhaar, B. Braam, T. J. Rabelink, and A.-J. van Zonneveld Endothelial Progenitor Cell Dysfunction: A Novel Concept in the Pathogenesis of Vascular Complications of Type 1 Diabetes Diabetes, January 1, 2004; 53(1): 195 - 199. [Abstract] [Full Text] [PDF]
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M. Tomita, H. Yamada, Y. Adachi, Y. Cui, E. Yamada, A. Higuchi, K. Minamino, Y. Suzuki, M. Matsumura, and S. Ikehara Choroidal Neovascularization Is Provided by Bone Marrow Cells Stem Cells, January 1, 2004; 22(1): 21 - 26. [Abstract] [Full Text] [PDF]
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Q. Xu, Z. Zhang, F. Davison, and Y. Hu Circulating Progenitor Cells Regenerate Endothelium of Vein Graft Atherosclerosis, Which Is Diminished in ApoE-Deficient Mice Circ. Res., October 17, 2003; 93 (8): e76 - e86. [Abstract] [Full Text] [PDF]
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B. R. Stoll, C. Migliorini, A. Kadambi, L. L. Munn, and R. K. Jain A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy Blood, October 1, 2003; 102(7): 2555 - 2561. [Abstract] [Full Text] [PDF]
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 V. Chhokar and A. L. Tucker Angiogenesis: Basic Mechanisms and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 253 - 280. [Abstract] [PDF]
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B. S. Buetow, K. A. Tappan, J. R. Crosby, R. A. Seifert, and D. F. Bowen-Pope Chimera Analysis Supports a Predominant Role of PDGFR{beta} in Promoting Smooth-Muscle Cell Chemotaxis after Arterial Injury Am. J. Pathol., September 1, 2003; 163(3): 979 - 984. [Abstract] [Full Text] [PDF]
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M. B. Rookmaaker, A. M. Smits, H. Tolboom, K. van 't Wout, A. C. Martens, R. Goldschmeding, J. A. Joles, A. J. van Zonneveld, H.-J. Grone, T. J. Rabelink, et al. Bone-Marrow-Derived Cells Contribute to Glomerular Endothelial Repair in Experimental Glomerulonephritis Am. J. Pathol., August 1, 2003; 163(2): 553 - 562. [Abstract] [Full Text] [PDF]
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B. Assmus, C. Urbich, A. Aicher, W. K. Hofmann, J. Haendeler, L. Rossig, I. Spyridopoulos, A. M. Zeiher, and S. Dimmeler HMG-CoA Reductase Inhibitors Reduce Senescence and Increase Proliferation of Endothelial Progenitor Cells via Regulation of Cell Cycle Regulatory Genes Circ. Res., May 16, 2003; 92(9): 1049 - 1055. [Abstract] [Full Text] [PDF]
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H. Masuda and T. Asahara Post-natal endothelial progenitor cells for neovascularization in tissue regeneration Cardiovasc Res, May 1, 2003; 58(2): 390 - 398. [Abstract] [Full Text] [PDF]
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A. Solowiej, P. Biswas, D. Graesser, and J. A. Madri Lack of Platelet Endothelial Cell Adhesion Molecule-1 Attenuates Foreign Body Inflammation because of Decreased Angiogenesis Am. J. Pathol., March 1, 2003; 162(3): 953 - 962. [Abstract] [Full Text] [PDF]
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N. Werner, J. Priller, U. Laufs, M. Endres, M. Bohm, U. Dirnagl, and G. Nickenig Bone Marrow-Derived Progenitor Cells Modulate Vascular Reendothelialization and Neointimal Formation: Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1567 - 1572. [Abstract] [Full Text] [PDF]
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M. G. Frid, V. A. Kale, and K. R. Stenmark Mature Vascular Endothelium Can Give Rise to Smooth Muscle Cells via Endothelial-Mesenchymal Transdifferentiation: In Vitro Analysis Circ. Res., June 14, 2002; 90(11): 1189 - 1196. [Abstract] [Full Text] [PDF]
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 D. C. Hess, W. D. Hill, A. Martin-Studdard, J. Carroll, J. Brailer, and J. Carothers Bone Marrow as a Source of Endothelial Cells and NeuN-Expressing Cells After Stroke Stroke, May 1, 2002; 33(5): 1362 - 1368. [Abstract] [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF]
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B. S. Buetow, J. R. Crosby, W. E. Kaminski, R. K. Ramachandran, P. Lindahl, P. Martin, C. Betsholtz, R. A. Seifert, E. W. Raines, and D. F. Bowen-Pope Platelet-Derived Growth Factor B-Chain of Hematopoietic Origin Is Not Necessary for Granulation Tissue Formation and Its Absence Enhances Vascularization Am. J. Pathol., November 1, 2001; 159(5): 1869 - 1876. [Abstract] [Full Text] [PDF]
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M. Harraz, C. Jiao, H. D. Hanlon, R. S. Hartley, and G. C. Schatteman CD34- Blood-Derived Human Endothelial Cell Progenitors Stem Cells, July 1, 2001; 19(4): 304 - 312. [Abstract] [Full Text] [PDF]
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Editorial Policy Changes at Circulation Research Circ. Res., January 19, 2001; 88(1): 1 - 1. [Full Text] [PDF]
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S. V. Brodsky, T. Yamamoto, T. Tada, B. Kim, J. Chen, F. Kajiya, and M. S. Goligorsky Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells Am J Physiol Renal Physiol, June 1, 2002; 282(6): F1140 - F1149. [Abstract] [Full Text] [PDF]
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H. Iwaguro, J.-i. Yamaguchi, C. Kalka, S. Murasawa, H. Masuda, S.-i. Hayashi, M. Silver, T. Li, J. M. Isner, and T. Asahara Endothelial Progenitor Cell Vascular Endothelial Growth Factor Gene Transfer for Vascular Regeneration Circulation, February 12, 2002; 105(6): 732 - 738. [Abstract] [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF]
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