Molecular magnetic resonance imaging of myocardial angiogenesis after acute myocardial infarction.
BACKGROUND
Angiogenesis is a natural mechanism to restore perfusion to the ischemic myocardium after acute myocardial infarction (MI). Therapeutic angiogenesis is being explored as a novel treatment for MI patients; however, sensitive, noninvasive in vivo measures of therapeutic efficacy are lacking and need to be developed. Here, a molecular magnetic resonance imaging method is presented to noninvasively image angiogenic activity in vivo in a murine model of MI with cyclic Asn-Gly-Arg (cNGR)-labeled paramagnetic quantum dots (pQDs). The tripeptide cNGR homes specifically to CD13, an aminopeptidase that is strongly upregulated during myocardial angiogenesis.


RESULTS
Acute MI was induced in male Swiss mice via permanent ligation of the left anterior descending coronary artery. Molecular magnetic resonance imaging was performed 7 days after surgery and up to 2 hours after intravenous contrast agent administration. Injection of cNGR-pQDs resulted in a strong negative contrast that was located mainly in the infarcted myocardium. This negative contrast was significantly less in MI mice injected with unlabeled pQDs and in sham-operated mice injected with cNGR-pQDs. Validation with ex vivo 2-photon laser scanning microscopy revealed a strong colocalization of cNGR-pQDs with vascular endothelial cells, whereas unlabeled pQDs were mostly extravasated and diffused through the tissue. Additionally, 2-photon laser scanning microscopy demonstrated significant microvascular remodeling in the infarct/border zones compared with remote myocardium.


CONCLUSIONS
cNGR-pQDs allow selective, noninvasive detection of angiogenic activity in the infarcted heart with the use of in vivo molecular magnetic resonance imaging and ex vivo 2-photon laser scanning microscopy.
Oostendorp
Marlies
M
Department of Radiology, Maastricht University Medical Centre, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
Douma
Kim
K
Wagenaar
Allard
A
Slenter
Jos M G M
JM
Hackeng
Tilman M
TM
van Zandvoort
Marc A M J
MA
Post
Mark J
MJ
Backes
Walter H
WH
D000818:Animals; D018826:CD13 Antigens / Q000378:metabolism; D003287:Contrast Media; D003331:Coronary Vessels / Q000502:physiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D008026:Ligation / Q000009:adverse effects; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009842:Oligopeptides; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D003287:Contrast Media; C526428:NGR peptide; D009842:Oligopeptides; D018826:CD13 Antigens