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 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-1alpha expression, recruitment of macrophages and hemangiocytes, and higher blood flow recovery after acute arterial occlusion than after gradual arterial occlusion (P < .05).


CONCLUSIONS
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.
Yang
Yagai
Y
Department of Medicine, Division of Cardiology, University of California, San Francisco, California, USA.
Tang
Gale
G
Yan
Jinglian
J
Park
Brian
B
Hoffman
Ari
A
Tie
Guodong
G
Wang
Rong
R
Messina
Louis M
LM
D000208:Acute Disease; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D001783:Blood Flow Velocity / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics*; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005263:Femoral Artery / Q000502:physiology*; D015870:Gene Expression; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D020127:Recovery of Function / Q000502:physiology*
D054377:Chemokine CXCL12; D012333:RNA, Messenger