Cellular and molecular mechanism regulating blood flow recovery in acute versus gradual femoral artery occlusion are distinct in the mouse

Background Most current animal models of hindlimb ischemia use acute arterial occlusion that does not accurately reflect the pathogenesis of gradual arterial occlusion in humans. We, therefore, developed the first mouse model of gradual arterial occlusion and tested the hypothesis that the mechanism...

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Bibliographic Details
Published in:Journal of vascular surgery 2008-12, Vol.48 (6), p.1546-1558
Main Authors: Yang, Yagai, PhD, Tang, Gale, MD, Yan, Jinglian, PhD, Park, Brian, MD, Hoffman, Ari, MD, Tie, Guodong, PhD, Wang, Rong, PhD, Messina, Louis M., MD
Format: Article
Language:English
Subjects:
Acute Disease
Animals
Arterial Occlusive Diseases - genetics
Arterial Occlusive Diseases - metabolism
Arterial Occlusive Diseases - physiopathology
Biological and medical sciences
Blood Flow Velocity - physiology
Chemokine CXCL12 - biosynthesis
Chemokine CXCL12 - genetics
Chronic Disease
Disease Models, Animal
Disease Progression
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Femoral Artery - physiology
Gene Expression
Hormones. Endocrine system
Immunohistochemistry
Laser-Doppler Flowmetry
Medical sciences
Mice
Mice, Inbred C57BL
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Pharmacology. Drug treatments
Polymerase Chain Reaction
Recovery of Function - physiology
RNA, Messenger - genetics
Surgery
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels
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Summary:Background Most current animal models of hindlimb ischemia use acute arterial occlusion that does not accurately reflect the pathogenesis of gradual arterial occlusion in humans. We, therefore, developed the first mouse model of gradual arterial occlusion and tested the hypothesis that the mechanisms regulating blood flow recovery are critically dependent on the rate of arterial occlusion. Methods Gradual arterial occlusion was induced by placing ameroid constrictors on the proximal and distal left femoral artery, and ligating the femoral arterial branches (n = 36). Acute arterial occlusion was accomplished by excising the left femoral artery (n = 36). The blood flow recovery was studied by laser Doppler imaging. Differential gene expression between these two models was assessed by quantitative real-time polymerase chain reactions (PCR). Inflammatory and progenitor cells recruitment were determined by immunohistochemistry. Results We found that hypoxia-related genes increased significantly in the calf, but not in the thigh, after gradual and acute femoral arterial occlusion ( P < .05). Shear-stress dependent genes and inflammatory genes were upregulated immediately in the thigh only after acute femoral arterial occlusion ( P < .05). These differences in gene expression were consistent with increased SDF-1α expression, recruitment of macrophages and hemangiocytes, and higher blood flow recovery after acute arterial occlusion than after gradual arterial occlusion ( P < .05). Conclusion This is the first study to show the mechanisms that regulate blood flow recovery are critically dependent on the rate of arterial occlusion. This novel model of gradual arterial occlusion may more closely resemble the human diseases, and may provide more accurate mechanistic insights for creating novel molecular therapies.
ISSN:0741-5214
1097-6809
DOI:10.1016/j.jvs.2008.07.063