Published Online
on March 15, 2004

A more recent version of this article appeared on April 6, 2004

This Article Full Text (PDF) All Versions of this Article: 109/13/1647    most recent 01.CIR.0000124066.35200.18v1 Alert me when this article is cited Alert me if a correction is posted 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 van Royen, N. Articles by Pals, S. T. Search for Related Content PubMed PubMed Citation Articles by van Royen, N. Articles by Pals, S. T. Pubmed/NCBI databases Domain Gene GEO Profiles HomoloGene OMIM UniGene Substance via MeSH Related Collections Angiogenesis Animal models of human disease Smooth muscle proliferation and differentiation Endothelium/vascular type/nitric oxide Other Vascular biology Other Research

Submitted on August 22, 2003
Revised on November 21, 2003
Accepted on December 5, 2003

CD44 Regulates Arteriogenesis in Mice and Is Differentially Expressed in Patients With Poor and Good Collateralization

N. van Royen MD, PhD^*, M. Voskuil MD, PhD, I. Hoefer MD, M. Jost PhD, S. de Graaf MD, F. Hedwig , J. -P. Andert , T. A.M. Wormhoudt BS, J. Hua MD, S. Hartmann BS, C. Bode MD, I. Buschmann MD, W. Schaper MD, PhD, R. van der Neut PhD, J. J. Piek MD, PhD, and S. T. Pals MD, PhD

From the Departments of Cardiology (N.v.R., M.V., S.d.G., J.J.P.) and Pathology (T.A.M.W., R.v.d.N., S.T.P.), Academic Medical Center, University of Amsterdam, the Netherlands; and the Department of Cardiology, University of Freiburg, Freiburg (N.v.R., I.H., M.J., F.H., J.-P.A., J.H., S.H., C.B., I.B.), and Department of Physiology and Experimental Cardiology, Max Planck Institute, Bad Nauheim (W.S.), Germany.

^* To whom correspondence should be addressed. E-mail: n.vanroyen{at}amc.uva.nl.

Background--Arteriogenesis refers to the development of collateral conductance arteries and is orchestrated by circulating monocytes, which invade growing collateral arteries and act as suppliers of cytokines and growth factors. CD44 glycoproteins are involved in leukocyte extravasation but also in the regulation of growth factor activation, stability, and signaling. Here, we explored the role of CD44 during arteriogenesis.

Methods and Results--CD44 expression increases strongly during collateral artery growth in a murine hind-limb model of arteriogenesis. This CD44 expression is of great functional importance, because arteriogenesis is severely impaired in CD44^-/- mice (wild-type, 54.5±14.9% versus CD44^-/-, 24.1±9.2%, P<0.001). The defective arteriogenesis is accompanied by reduced leukocyte trafficking to sites of collateral artery growth (wild-type, 29±12% versus CD44^-/-, 18±7% CD11b-positive cells/square, P<0.01) and reduced expression of fibroblast growth factor-2 and platelet-derived growth factor-B protein. Finally, in patients with single-vessel coronary artery disease, the maximal expression of CD44 on activated monocytes is reduced in case of impaired collateral artery formation (poor collateralization, 1764±572 versus good collateralization, 2817±1029 AU, P<0.05).

Conclusions--For the first time, the pivotal role of CD44 during arteriogenesis is shown. The expression of CD44 increases during arteriogenesis, and the deficiency of CD44 severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is decreased in patients with a poor collateralization compared with patients with a good collateralization.

Key words: angiogenesis • collateral circulation • glycoproteins • monocytes • growth substances

This article has been cited by other articles:

				J. Waltenberger Limits to Growth of Native Collateral Vessels: Just One Mouse CLIC Away From Unlimited Collateral Perfusion? Circ. Res., July 2, 2009; 105(1): 9 - 11. [Full Text] [PDF]

				P Meier, J Antonov, R Zbinden, A Kuhn, S Zbinden, S Gloekler, M Delorenzi, R Jaggi, and C Seiler Non-invasive gene-expression-based detection of well-developed collateral function in individuals with and without coronary artery disease Heart, June 1, 2009; 95(11): 900 - 908. [Abstract] [Full Text] [PDF]

				S H Schirmer, F C van Nooijen, J J Piek, and N van Royen Stimulation of collateral artery growth: travelling further down the road to clinical application Heart, February 1, 2009; 95(3): 191 - 197. [Abstract] [Full Text] [PDF]

				S. H. Schirmer, J. O. Fledderus, P. T.G. Bot, P. D. Moerland, I. E. Hoefer, J. Baan Jr, J. P.S. Henriques, R. J. van der Schaaf, M. M. Vis, A. J.G. Horrevoets, et al. Interferon-{beta} Signaling Is Enhanced in Patients With Insufficient Coronary Collateral Artery Development and Inhibits Arteriogenesis in Mice Circ. Res., May 23, 2008; 102(10): 1286 - 1294. [Abstract] [Full Text] [PDF]

				C Kalka and I. Baumgartner Gene and stem cell therapy in peripheral arterial occlusive disease Vascular Medicine, May 1, 2008; 13(2): 157 - 172. [Abstract] [PDF]

				N. van Royen, S. H. Schirmer, B. Atasever, C. Y.H. Behrens, D. Ubbink, E. E. Buschmann, M. Voskuil, P. Bot, I. Hoefer, R. O. Schlingemann, et al. START Trial: A Pilot Study on STimulation of ARTeriogenesis Using Subcutaneous Application of Granulocyte-Macrophage Colony-Stimulating Factor as a New Treatment for Peripheral Vascular Disease Circulation, August 16, 2005; 112(7): 1040 - 1046. [Abstract] [Full Text] [PDF]

				G. Gruionu, J. B. Hoying, A. R. Pries, and T. W. Secomb Structural remodeling of mouse gracilis artery after chronic alteration in blood supply Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2047 - H2054. [Abstract] [Full Text] [PDF]

				M. Simons Angiogenesis: Where Do We Stand Now? Circulation, March 29, 2005; 111(12): 1556 - 1566. [Full Text] [PDF]

				H. M. Nathoe, E. Buskens, E. W.L. Jansen, W. J.L. Suyker, P. R. Stella, J. R. Lahpor, W.-J. van Boven, D. van Dijk, J. C. Diephuis, C. Borst, et al. Role of Coronary Collaterals in Off-Pump and On-Pump Coronary Bypass Surgery Circulation, September 28, 2004; 110(13): 1738 - 1742. [Abstract] [Full Text] [PDF]