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Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.

ABSTRACT: 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.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.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.

SUBMITTER: Hazarika S

PROVIDER: S-EPMC3152376 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.

Hazarika Surovi S 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

Arteriosclerosis, thrombosis, and vascular biology 20080925 12

<h4>Objective</h4>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.<h4>Methods and results</h4>Mb overexpressing ...[more]

PMID: 18818418

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Project description:Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

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Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.

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Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.

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