Reactive hyperemia and BOLD MRI demonstrate that VEGF inhibition, age, and atherosclerosis adversely affect functional recovery in a murine model of peripheral artery disease.
OBJECTIVE
To develop magnetic resonace imaging (MRI) methods for functional assessment of arteriogenesis in a murine model of peripheral artery disease to quantify the influences of vascular endothelial growth factor (VEGF), age, and atherosclerosis.


METHODS
Reactive hyperemia (RH), which was induced using a device designed for remote and transient occlusion of the aorta and vena cava, was measured by blood-oxygen-level-dependent MRI. Twenty-eight days after femoral artery ligation, peak height (PH) and time to peak (TTP) of the RH response was compared with sham-operated animals in 10-week-old C57Bl6, 9-month-old C57Bl6, and 9-month-old Ldlr(-/-)Apobec(-/-) mice. The contribution of VEGF to functional recovery was assessed in young mice. Angiogenesis was quantified using an anti-PECAM1 radioimmunoassay.


RESULTS
In young animals, angiogenesis was maximal 7 days after ligation, whereas functional recovery took 28 days. Inhibition of VEGF eliminated the angiogenesis seen at 7 days and reduced RH (PH, P < 0.05). At day 28, RH was altered in old (TTP, P < 0.05) and atherosclerotic (PH, P < 0.05; TTP, P < 0.05) animals. RH was different in young, old, and atherosclerotic sham animals. Old and atherosclerotic mice showed reduced angiogenesis.


CONCLUSIONS
The method presented herein can provide a sensitive assay for the functional assessment of arteriogenesis and highlights the contribution of VEGF, age, and atherosclerosis to this process.
Greve
Joan M
JM
Department of Biomedical Imaging, Genentech, Inc., South San Franscisco, California 94080, USA. jgreve@gene.com
Williams
Simon P
SP
Bernstein
Lisa J
LJ
Goldman
Hope
H
Peale
Franklin V
FV
Bunting
Stuart
S
van Bruggen
Nicholas
N
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D006614:Hindlimb; D006940:Hyperemia / Q000378:metabolism / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D016491:Peripheral Vascular Diseases / Q000378:metabolism / Q000503:physiopathology*; D011863:Radioimmunoassay; D020127:Recovery of Function; D012307:Risk Factors; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D042461:Vascular Endothelial Growth Factor A