||Hazarika S, Angelo M, Li Y, Aldrich AJ, Odronic SI, Yan Z, Stamler JS, Annex BH
||Thomas Coffman on 2/8/2009
||Arteriosclerosis, thrombosis, and vascular biology
|Volume : Pages
||28(12) : 2144 - 2150
||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.
METHODS AND 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.