This Article Full Text Full Text (PDF) Correction (v110,p3741) All Versions of this Article: 110/24/3699    most recent 01.CIR.0000143626.16576.51v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nowak, G. Articles by Sumitran-Holgersson, S. Search for Related Content PubMed PubMed Citation Articles by Nowak, G. Articles by Sumitran-Holgersson, S. Related Collections Peripheral vascular disease Restenosis Restenosis Endothelium/vascular type/nitric oxide Other Vascular biology Smooth muscle proliferation and differentiation

(Circulation. 2004;110:3699-3707.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Expression of Vascular Endothelial Growth Factor Receptor-2 or Tie-2 on Peripheral Blood Cells Defines Functionally Competent Cell Populations Capable of Reendothelialization

Grzegorz Nowak, MD, PhD; Azza Karrar, MSc; Carolina Holmén, BSc; Silvia Nava, BSc; Mehmet Uzunel, PhD; Kjell Hultenby, PhD; Suchitra Sumitran-Holgersson, PhD

From the Divisions of Transplantation Surgery (G.N., A.K., S.N., S.S.-H.), Clinical Immunology (C.H., M.U.), and Pathology (K.H.), Karolinska University Hospital-Huddinge, Karolinska Institute, Stockholm. Sweden.

Correspondence to Dr Suchitra Sumitran-Holgersson, Department of Transplantation Surgery B56, Huddinge University Hospital, S-141 86 Stockholm, Sweden. E-mail suchitra.holgersson{at}cfss.ki.se

Received June 24, 2004; accepted July 22, 2004.

Background— Receptor tyrosine kinases that include vascular endothelial growth factor (VEGFR)-1, VEGFR-2, and Tie-2 regulate cardiovascular development and physiological and pathological angiogenesis. We were interested in the phenotypic and functional characterization of peripheral blood cells expressing these receptors and their therapeutic potential in vascular injury.

Methods and Results— VEGFR-1⁺, VEGFR-2⁺, and Tie-2⁺ cells constituted 3.0±0.2%, 0.8±0.5%, and 2.0±0.3%, respectively, of the total population of mononuclear cells in blood. Phenotypic analysis demonstrated that all 3 cell populations mainly expressed markers of monocytic/macrophage lineage. Only VEGFR-2⁺ and Tie-2⁺ cells phenotypically, morphologically, and functionally differentiated to endothelial cells after culture, whereas VEGFR-1⁺ cells did not. None of the cell types proliferated in vitro. Only freshly isolated VEGFR-2⁺ or Tie-2⁺ cells but not VEGFR-2^– or Tie-2^– cell populations significantly contributed to efficient endothelialization of balloon-injured femoral arteries of nude mice. Furthermore, these cells also differentiated into -actin–positive smooth muscle cells. Administration of bromodeoxyuridine to animals transplanted with human endothelial progenitor cells showed that VEGFR-2⁺ and Tie-2⁺ cells proliferated in vivo.

Conclusions— These data demonstrate that expression of VEGFR-2 and/or Tie-2 on peripheral blood cells defines functionally competent cell populations that proliferate in vivo and that contribute to reendothelialization. These findings may have implications for a cell-based approach in vascular diseases.

Key Words: endothelium-derived factors • cells • revascularization

This article has been cited by other articles:

				S. Nogueras, A. Merino, R. Ojeda, J. Carracedo, M. Rodriguez, A. Martin-Malo, R. Ramirez, and P. Aljama Coupling of endothelial injury and repair: an analysis using an in vivo experimental model Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H708 - H713. [Abstract] [Full Text] [PDF]

				G. Grenier, A. Scime, F. Le Grand, A. Asakura, C. Perez-Iratxeta, M. A. Andrade-Navarro, P. A. Labosky, and M. A. Rudnicki Resident Endothelial Precursors in Muscle, Adipose, and Dermis Contribute to Postnatal Vasculogenesis Stem Cells, December 1, 2007; 25(12): 3101 - 3110. [Abstract] [Full Text] [PDF]

				A. D. Hauer, G. H.M. van Puijvelde, N. Peterse, P. de Vos, V. van Weel, E. J.A. van Wanrooij, E. A.L. Biessen, P. H.A. Quax, A. G. Niethammer, R. A. Reisfeld, et al. Vaccination Against VEGFR2 Attenuates Initiation and Progression of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 2050 - 2057. [Abstract] [Full Text] [PDF]

				R. Riccioni, D. Diverio, G. Mariani, S. Buffolino, V. Riti, E. Saulle, E. Petrucci, M. Cedrone, F. Lo-Coco, R. Foa, et al. Expression of Tie-2 and Other Receptors for Endothelial Growth Factors in Acute Myeloid Leukemias Is Associated with Monocytic Features of Leukemic Blasts Stem Cells, August 1, 2007; 25(8): 1862 - 1871. [Abstract] [Full Text] [PDF]

				C. Murdoch, S. Tazzyman, S. Webster, and C. E. Lewis Expression of Tie-2 by Human Monocytes and Their Responses to Angiopoietin-2 J. Immunol., June 1, 2007; 178(11): 7405 - 7411. [Abstract] [Full Text] [PDF]

				Q. Xiao, L. Zeng, Z. Zhang, A. Margariti, Z. A Ali, K. M. Channon, Q. Xu, and Y. Hu Sca-1+ Progenitors Derived From Embryonic Stem Cells Differentiate Into Endothelial Cells Capable of Vascular Repair After Arterial Injury Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2244 - 2251. [Abstract] [Full Text] [PDF]

				B. G. Sharifi, Z. Zeng, L. Wang, L. Song, H. Chen, M. Qin, M. R. Sierra-Honigmann, S. Wachsmann-Hogiu, and P. K. Shah Pleiotrophin Induces Transdifferentiation of Monocytes Into Functional Endothelial Cells Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1273 - 1280. [Abstract] [Full Text] [PDF]

				M. Anghelina, P. Krishnan, L. Moldovan, and N. I. Moldovan Monocytes/Macrophages Cooperate with Progenitor Cells during Neovascularization and Tissue Repair: Conversion of Cell Columns into Fibrovascular Bundles Am. J. Pathol., February 1, 2006; 168(2): 529 - 541. [Abstract] [Full Text] [PDF]

				K Herbrig, S Haensel, U Oelschlaegel, F Pistrosch, S Foerster, and J Passauer Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells Ann Rheum Dis, February 1, 2006; 65(2): 157 - 163. [Abstract] [Full Text] [PDF]

				C. Holmen, E. Elsheikh, P. Stenvinkel, A. R. Qureshi, E. Pettersson, S. Jalkanen, and S. Sumitran-Holgersson Circulating Inflammatory Endothelial Cells Contribute to Endothelial Progenitor Cell Dysfunction in Patients with Vasculitis and Kidney Involvement J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3110 - 3120. [Abstract] [Full Text] [PDF]

				E. Elsheikh, M. Uzunel, Z. He, J. Holgersson, G. Nowak, and S. Sumitran-Holgersson Only a specific subset of human peripheral-blood monocytes has endothelial-like functional capacity Blood, October 1, 2005; 106(7): 2347 - 2355. [Abstract] [Full Text] [PDF]

				N. Werner, S. Kosiol, T. Schiegl, P. Ahlers, K. Walenta, A. Link, M. Bohm, and G. Nickenig Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes N. Engl. J. Med., September 8, 2005; 353(10): 999 - 1007. [Abstract] [Full Text] [PDF]

				P. Romagnani, F. Annunziato, F. Liotta, E. Lazzeri, B. Mazzinghi, F. Frosali, L. Cosmi, L. Maggi, L. Lasagni, A. Scheffold, et al. CD14+CD34low Cells With Stem Cell Phenotypic and Functional Features Are the Major Source of Circulating Endothelial Progenitors Circ. Res., August 19, 2005; 97(4): 314 - 322. [Abstract] [Full Text] [PDF]

				V. J. Dzau, M. Gnecchi, A. S. Pachori, F. Morello, and L. G. Melo Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases Hypertension, July 1, 2005; 46(1): 7 - 18. [Abstract] [Full Text] [PDF]