Adventitial microvessel formation after coronary stenting and the effects of SU11218, a tyrosine kinase inhibitor.
OBJECTIVE
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.
Cheema
Asim N
AN
Roy and Ann Foss Cardiovascular Research Program, Terrence Donnelly Heart Center, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Hong
Tony
T
Nili
Nafiseh
N
Segev
Amit
A
Moffat
John G
JG
Lipson
Kenneth E
KE
Howlett
Anthony R
AR
Holdsworth
David W
DW
Cole
Michael J
MJ
Qiang
Beiping
B
Kolodgie
Frank
F
Virmani
Renu
R
Stewart
Duncan J
DJ
Strauss
Bradley H
BH
D000818:Animals; D015687:Cell Hypoxia; D003238:Connective Tissue / Q000098:blood supply*; D003331:Coronary Vessels; D006965:Hyperplasia; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015607:Stents; D013552:Swine; D017539:Tunica Intima / Q000473:pathology
D011505:Protein-Tyrosine Kinases