This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: j.jacc.2005.08.076v1 47/5/1067    most recent 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Cheema, A. N. Articles by Strauss, B. H. Search for Related Content PubMed PubMed Citation Articles by Cheema, A. N. Articles by Strauss, B. H.

PRECLINICAL STUDY

Adventitial Microvessel Formation After Coronary Stenting and the Effects of SU11218, a Tyrosine Kinase Inhibitor

Asim N. Cheema, MD, PhD, FACC^_*, Tony Hong^_*, Nafiseh Nili, PhD^_*, Amit Segev, MD^_*, John G. Moffat, PhD, Kenneth E. Lipson, PhD, Anthony R. Howlett, PhD, David W. Holdsworth, PhD, Michael J. Cole, MESc, Beiping Qiang, MD^_*, Frank Kolodgie, PhD, Renu Virmani, MD, FACC, Duncan J. Stewart, MD, FACC^_* and Bradley H. Strauss, MD, PhD, FACC^_*,_*

^_* Roy and Ann Foss Cardiovascular Research Program, Terrence Donnelly Heart Center, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
SUGEN, Inc., South San Francisco, California
Robarts Research Institute, London, Ontario, Canada
Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC

Manuscript received June 10, 2005; revised manuscript received August 11, 2005, accepted August 15, 2005.

^_* Reprint requests and correspondence: Dr. Bradley H. Strauss, Division of Cardiology, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. (Email: straussb{at}smh.toronto.on.ca).

OBJECTIVES: The aim of this study was to delineate the temporal profile of adventitial microvessel (Ad-MV) formation after stenting, its relationship to arterial wall hypoxia, and the effects of a tyrosine kinase inhibitor (TKI), SU11218, on Ad-MV and in-stent intimal hyperplasia (IH).

BACKGROUND: Adventitial microvessels have been reported after arterial injury; however, the underlying stimulus for this response and its relationship to IH is unknown.

METHODS: Coronary stenting was performed in 40 pigs randomized to SU11218 (n = 20) or placebo (n = 20). Vessel wall hypoxia was assessed by pimonidazole adducts and hypoxia-inducible factor (HIF)-1 alpha expression. Adventitial microvessels were quantified by three-dimensional microscopic computed tomography (3D micro CT). Intimal hyperplasia was measured by intravascular ultrasound (IVUS), 3D micro CT, and morphometry. The effects of SU11218 were assessed in vitro on smooth muscle cell (SMC) and endothelial cell (EC) functions and in vivo on Ad-MV and IH.

RESULTS: Hypoxia was evident in the vessel wall at 48 h and persisted for four weeks. Adventitial microvessels increased significantly at one week (24 ± 7 microvessels/segment) and four weeks (23 ± 7 microvessels/segment) compared with uninjured arteries (16 ± 2 microvessels/segment; p < 0.001) and correlated with IH (r = 0.77, p < 0.001). The TKI SU11218 inhibited platelet-derived growth factor receptor–beta phosphorylation, EC and SMC DNA synthesis, and migration in a dose-dependent manner in vitro and significantly inhibited Ad-MV (16 ± 5 vs. 23 ± 7 microvessels/segment in placebo, p < 0.001) and produced approximately 80% reduction in IH (0.52 ± 0.51 mm² vs. 2.47 ± 1.66 mm² in placebo, p < 0.001) at four weeks in vivo.

CONCLUSIONS: Arterial stenting causes arterial wall hypoxia followed by Ad-MV formation. The TKI SU11218 inhibits both Ad-MV formation and IH and represents a promising therapeutic agent to prevent in-stent restenosis.

Abbreviations and Acronyms   3D micro CT = three-dimensional microscopic computed tomography   Ad-MV = adventitial microvessels   BrdU = bromo-dexoyuridine   CA-EC = coronary artery endothelial cells   CA-SMC = coronary artery smooth muscle cells   CSA = cross-sectional area   EC = endothelial cells   HIF = hypoxia-inducible factor   IH = in-stent intimal hyperplasia   IVUS = intravascular ultrasound   PDGF = platelet-derived growth factor   SMC = smooth muscle cells   TKI = tyrosine kinase inhibitor   VEGF = vascular endothelial growth factor

This article has been cited by other articles:

				M. Ohta, Chuan He, T. Nakayama, A. Takahashi, and D. A. Rufenacht Three-Dimensional Reconstruction of a Cerebral Stent using Micro-CT for Computational Simulation Journal of Intelligent Material Systems and Structures, March 1, 2008; 19(3): 313 - 318. [Abstract] [PDF]

				E. L. Ritman and A. Lerman The dynamic vasa vasorum Cardiovasc Res, September 1, 2007; 75(4): 649 - 658. [Abstract] [Full Text] [PDF]

				J.-B. Michel, O. Thaunat, X. Houard, O. Meilhac, G. Caligiuri, and A. Nicoletti Topological Determinants and Consequences of Adventitial Responses to Arterial Wall Injury Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1259 - 1268. [Abstract] [Full Text] [PDF]