Endothelial nitric oxide synthase affects both early and late collateral arterial adaptation and blood flow recovery after induction of hind limb ischemia in mice

Objective The goals of this study were to determine if endothelial nitric oxide synthase (eNOS) affects both early and late collateral arterial adaptation and blood flow recovery after severe limb ischemia in a mouse model and to determine if eNOS-derived NO is necessary for recruitment of chemokine...

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Published in:Journal of vascular surgery 2010, Vol.51 (1), p.165-173
Main Authors: Park, Brian, MD, Hoffman, Ari, MD, Yang, Yagai, PhD, Yan, Jinglian, PhD, Tie, Guodong, PhD, Bagshahi, Hossein, MD, Nowicki, Philip T., MD, Messina, Louis M., MD
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Chemotaxis
Collateral Circulation - drug effects
Disease Models, Animal
Enzyme Inhibitors - pharmacology
Gangrene
Hindlimb
Hormones. Endocrine system
Ischemia - enzymology
Ischemia - pathology
Ischemia - physiopathology
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal - blood supply
NG-Nitroarginine Methyl Ester - pharmacology
Nitric Oxide - metabolism
Nitric Oxide Synthase Type III - antagonists & inhibitors
Nitric Oxide Synthase Type III - deficiency
Nitric Oxide Synthase Type III - genetics
Nitric Oxide Synthase Type III - metabolism
Pharmacology. Drug treatments
Receptors, CXCR4 - metabolism
Recovery of Function
Regional Blood Flow - drug effects
Stem Cells - metabolism
Surgery
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
Time Factors
Toes - pathology
Vascular Endothelial Growth Factor Receptor-1 - metabolism
Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels
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Summary:Objective The goals of this study were to determine if endothelial nitric oxide synthase (eNOS) affects both early and late collateral arterial adaptation and blood flow recovery after severe limb ischemia in a mouse model and to determine if eNOS-derived NO is necessary for recruitment of chemokine (C-X-C motif) receptor 4 (CXCR4)+ vascular endothelial growth factor receptor-1 (VEGFR1)+ hemangiocytes to the site of ischemia. Methods Two studies were completed. In the first, hind limb ischemia was induced by unilateral femoral artery excision in three groups: C57Bl6 (wild-type), eNOS−/− , and C57Bl/6 mice treated with NG -nitro- l -arginine methyl ester (L-NAME) from 1 day before excision through day 3 after excision (early L-NAME group). These groups were studied on day 3 after induction of ischemia. In the second study, hind limb ischemia was induced in C57Bl/6 mice (wild-type) and C57Bl/6 mice treated with L-NAME from days 3 through 28 after induction of ischemia. These groups were studied day 28 after ischemia induction. Dependent variables included hind limb perfusion, collateral artery diameter, and the number and location of hemangiocytes within the ischemic hind limb. Results In the first study, toe gangrene developed in the eNOS−/− and early L-NAME treatment groups by day 2. These groups demonstrated less blood flow recovery and smaller collateral artery diameter than the wild-type group. Hemangiocytes were present within the adventitia of collateral arteries in the wild-type group but were only sparsely present, in a random pattern, in the eNOS−/− and early L-NAME treatment groups. In the second study, the late L-NAME group showed less blood flow recovery and smaller collateral artery diameter on day 28 of ischemia than the wild-type group. Hemangiocytes were present in a pericapillary distribution in the wild-type group, but were present only sparsely in the late L-NAME treatment group. Conclusion Early (day 3) and late (day 28) adaptive responses to hind limb ischemia both require eNOS–derived NO. NO is necessary for normal hemangiocyte recruitment to the ischemic tissue.
ISSN:0741-5214
1097-6809
DOI:10.1016/j.jvs.2009.08.045