This Article Full Text Full Text (PDF) All Versions of this Article: 109/11/1392    most recent 01.CIR.0000123231.49594.21v1 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 Wang, C.-H. Articles by Verma, S. Search for Related Content PubMed PubMed Citation Articles by Wang, C.-H. Articles by Verma, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Animal models of human disease Pathophysiology Other Vascular biology

(Circulation. 2004;109:1392-1400.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage

A New Paradigm in Glitazone Pleiotropy

Chao-Hung Wang, MD; Nadia Ciliberti, BSc; Shu-Hong Li, MSc; Paul E. Szmitko, BSc; Richard D. Weisel, MD; Paul W.M. Fedak, MD; Mohammed Al-Omran, MD, MSc; Wen-Jin Cherng, MD; Ren-Ke Li, MD, PhD; William L. Stanford, PhD; Subodh Verma, MD, PhD

From the Division of Cardiovascular Surgery, Toronto General Hospital, Toronto, Ontario, Canada (C.W., S.L., P.E.S., R.D.W., P.W.M.F., M.A.-O., R.L., S.V.); Institute of Biomaterials and Biomedical Engineering, University of Toronto, and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (N.C., W.L.S.); Cardiology Section, Department of Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan (C.W., W.C.); and Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada (S.V.).

Correspondence to Subodh Verma, MD, PhD, Division of Cardiac Surgery, 14EN-215, 200 Elizabeth St, Toronto General Hospital, Toronto, Ontario, Canada M5G 2C4. E-mail Subodh.Verma{at}sympatico.ca

Received September 18, 2003; de novo received December 8, 2003; revision received January 22, 2004; accepted January 30, 2004.

Background— Peroxisome proliferator–activated receptor- (PPAR-) agonists inhibit vascular smooth muscle proliferation and migration and improve endothelial function. It is unknown whether PPAR- agonists favorably modulate bone marrow (BM)–derived angiogenic progenitor cells (APCs) to promote endothelial lineage differentiation and early reendothelialization after vascular intervention.

Methods and Results— C57/BL6 mice, treated with or without rosiglitazone (8 mg/kg per day), a PPAR- agonist, underwent femoral angioplasty. Rosiglitazone treatment attenuated neointimal formation (intima/media ratio: 0.98±0.12 [rosiglitazone] versus 3.1±0.5 [control]; P<0.001; n=10 per group). Using a BM transplantation model, we identified that 58±12% of the cells within the neointima at 4 weeks were derived from the BM. Pure endothelial marker–positive, pure -smooth muscle actin (SMA)–positive, or double-positive APCs could be found both in mouse BM and in human peripheral blood after culture in conditional medium enriched with vascular endothelial growth factor. Rosiglitazone caused a 6-fold (P<0.001) increase in colony formation by human endothelial progenitor cells, promoted the differentiation of APCs toward the endothelial lineage in mouse BM in vivo (0.66±0.06% [control] to 0.95±0.08% [rosiglitazone]; P<0.05) and in human peripheral blood in vitro (13.2±1.5% [control] to 28.4±3.3% [rosiglitazone]; P<0.05), and inhibited the differentiation toward the smooth muscle cell lineage. Within the neointima, rosiglitazone also stimulated APCs to differentiate into mature endothelial cells and caused earlier reendothelialization compared with controls (31±5 versus 8±2 CD31-positive cells per millimeter of neointimal surface on day 14; P<0.01).

Conclusions— Similar to embryonic stem cell–derived progenitors, the adult BM and peripheral blood harbor APCs that are at least bipotential and able to differentiate into endothelial and smooth muscle lineages. The PPAR- agonist rosiglitazone promotes the differentiation of these APCs toward the endothelial lineage and attenuates restenosis after angioplasty.

Key Words: cells • endothelium, vascular • vessels • receptors, cytoplasmic and nuclear • thiazolidinediones

This article has been cited by other articles:

				W. Zhao, S. G. Thacker, J. B. Hodgin, H. Zhang, J. H. Wang, J. L. Park, A. Randolph, E. C. Somers, S. Pennathur, M. Kretzler, et al. The Peroxisome Proliferator-Activated Receptor {gamma} Agonist Pioglitazone Improves Cardiometabolic Risk and Renal Inflammation in Murine Lupus J. Immunol., August 15, 2009; 183(4): 2729 - 2740. [Abstract] [Full Text] [PDF]

				J. Grisar, C. W. Steiner, M. Bonelli, T. Karonitsch, I. Schwarzinger, G. Weigel, G. Steiner, and J. S. Smolen Systemic lupus erythematosus patients exhibit functional deficiencies of endothelial progenitor cells Rheumatology, October 1, 2008; 47(10): 1476 - 1483. [Abstract] [Full Text] [PDF]

				F. Biscetti and R. Pola Endothelial Progenitor Cells and Angiogenesis Join the PPARty Circ. Res., July 3, 2008; 103(1): 7 - 9. [Full Text] [PDF]

				C.-H. Wang, W.-J. Cherng, N.-I Yang, C.-M. Hsu, C.-H. Yeh, Y.-J. Lan, J.-S. Wang, and S. Verma Cyclosporine increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R811 - R818. [Abstract] [Full Text] [PDF]

				P. E. Westerweel, K. den Ouden, T. Q. Nguyen, R. Goldschmeding, J. A. Joles, and M. C. Verhaar Amelioration of anti-Thy1-glomerulonephritis by PPAR-{gamma} agonism without increase of endothelial progenitor cell homing Am J Physiol Renal Physiol, February 1, 2008; 294(2): F379 - F384. [Abstract] [Full Text] [PDF]

				C.-H. Wang, W.-J. Cherng, N.-I Yang, L.-T. Kuo, C.-M. Hsu, H.-I Yeh, Y.-J. Lan, C.-H. Yeh, and W. L. Stanford Late-Outgrowth Endothelial Cells Attenuate Intimal Hyperplasia Contributed by Mesenchymal Stem Cells After Vascular Injury Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 54 - 60. [Abstract] [Full Text] [PDF]

				C.-C. Fang, Yeun Tarl Fresner Ng Jao, Yi-Chen, C.-L. Yu, C.-L. Chen, and S.-P. Wang Angiographic and Clinical Outcomes of Rosiglitazone in Patients With Type 2 Diabetes Mellitus After Percutaneous Coronary Interventions: A Single Center Experience Angiology, November 1, 2007; 58(5): 523 - 534. [Abstract] [PDF]

				C. Werner, C. H. Kamani, C. Gensch, M. Bohm, and U. Laufs The Peroxisome Proliferator Activated Receptor-{gamma} Agonist Pioglitazone Increases Number and Function of Endothelial Progenitor Cells in Patients With Coronary Artery Disease and Normal Glucose Tolerance Diabetes, October 1, 2007; 56(10): 2609 - 2615. [Abstract] [Full Text] [PDF]

				J. Grisar, D. Aletaha, C. W Steiner, T. Kapral, S. Steiner, M. Saemann, I. Schwarzinger, B. Buranyi, G. Steiner, and J. S Smolen Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy Ann Rheum Dis, October 1, 2007; 66(10): 1284 - 1288. [Abstract] [Full Text] [PDF]

				S. A. Sorrentino, F. H. Bahlmann, C. Besler, M. Muller, S. Schulz, N. Kirchhoff, C. Doerries, T. Horvath, A. Limbourg, F. Limbourg, et al. Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus: Restoration by the Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Rosiglitazone Circulation, July 10, 2007; 116(2): 163 - 173. [Abstract] [Full Text] [PDF]

				R. M Cubbon, A. Rajwani, and S. B Wheatcroft The impact of insulin resistance on endothelial function, progenitor cells and repair Diabetes and Vascular Disease Research, June 1, 2007; 4(2): 103 - 111. [Abstract] [PDF]

				G. P. Fadini, S. Sartore, C. Agostini, and A. Avogaro Significance of Endothelial Progenitor Cells in Subjects With Diabetes Diabetes Care, May 1, 2007; 30(5): 1305 - 1313. [Full Text] [PDF]

				C.-H. Wang, N. Anderson, S.-H. Li, P. E. Szmitko, W.-J. Cherng, P. W.M. Fedak, S. Fazel, R.-K. Li, T. M. Yau, R. D. Weisel, et al. Stem Cell Factor Deficiency Is Vasculoprotective: Unraveling a New Therapeutic Potential of Imatinib Mesylate Circ. Res., September 15, 2006; 99(6): 617 - 625. [Abstract] [Full Text] [PDF]

				P. Roy-Chaudhury, V. P. Sukhatme, and A. K. Cheung Hemodialysis Vascular Access Dysfunction: A Cellular and Molecular Viewpoint J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1112 - 1127. [Abstract] [Full Text] [PDF]

				N. Marx, J. Wohrle, T. Nusser, D. Walcher, A. Rinker, V. Hombach, W. Koenig, and M. Hoher Pioglitazone Reduces Neointima Volume After Coronary Stent Implantation: A Randomized, Placebo-Controlled, Double-Blind Trial in Nondiabetic Patients Circulation, November 1, 2005; 112(18): 2792 - 2798. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin Peroxisome proliferator-activated receptors and cardiovascular remodeling Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1037 - H1043. [Abstract] [Full Text] [PDF]

				A. Aicher, A. M. Zeiher, and S. Dimmeler Mobilizing Endothelial Progenitor Cells Hypertension, March 1, 2005; 45(3): 321 - 325. [Abstract] [Full Text] [PDF]

				V. A. Fonseca, J. Diez, and D. B. McNamara Decreasing Restenosis Following Angioplasty: The potential of peroxisome proliferator-activated receptor {gamma} agonists Diabetes Care, November 1, 2004; 27(11): 2764 - 2766. [Full Text] [PDF]