Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.
OBJECTIVE
In preclinical models of peripheral arterial disease the angiogenic response is typically robust, though it can be impaired in conditions such as hypercholesterolemia and diabetes where the endothelium is dysfunctional. Myoglobin (Mb) is expressed exclusively in striated muscle cells. We hypothesized that myocyte specific overexpression of myoglobin attenuates ischemia-induced angiogenesis even in the presence of normal endothelium.


RESULTS
Mb overexpressing transgenic (MbTg, n=59) and wild-type (WT, n=56) C57Bl/6 mice underwent unilateral femoral artery ligation/excision. Perfusion recovery was monitored using Laser Doppler. Ischemia-induced changes in muscle were assessed by protein and immunohistochemistry assays. Nitrite/nitrate and protein-bound NO, and vasoreactivity was measured. Vasoreactivity was similar between MbTg and WT. In ischemic muscle, at d14 postligation, MbTg increased VEGF-A, and activated eNOS the same as WT mice but nitrate/nitrite were reduced whereas protein-bound NO was higher. MbTg had attenuated perfusion recovery at d21 (0.37+/-0.03 versus 0.47+/-0.02, P<0.05), d28 (0.40+/-0.03 versus 0.50+/-0.04, P<0.05), greater limb necrosis (65.2% versus 15%, P<0.001), a lower capillary density, and greater apoptosis versus WT.


CONCLUSIONS
Increased Mb expression in myocytes attenuates angiogenesis after hind-limb ischemia by binding NO and reducing its bioavailability. Myoglobin can modulate the angiogenic response to ischemia even in the setting of normal endothelium.
Hazarika
Surovi
S
Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Angelo
Michael
M
Li
Yongjun
Y
Aldrich
Amy J
AJ
Odronic
Shelley I
SI
Yan
Zhen
Z
Stamler
Jonathan S
JS
Annex
Brian H
BH
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009211:Myoglobin / Q000235:genetics*; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000235:genetics; D009569:Nitric Oxide / Q000502:physiology
D009211:Myoglobin; D009569:Nitric Oxide