Impaired exercise capacity in patients with chronic disease, such as chronic obstructive pulmonary disease (COPD), is likely due in part to skeletal muscle dysfunction. One possible contributing factor is altered regulation of angiogenesis leading to reduced skeletal muscle capillarity. Capillaries are a critical component of oxygen transport to mitochondria, and sufficient capillarity is thus important to endurance exercise. Expression of vascular endothelial growth factor (VEGF), an important regulator of skeletal muscle angiogenesis, is reduced in skeletal muscle in COPD. Recently, we showed that reduction in VEGF across all skeletal muscle cell types in adult mice causes extensive (∼60%) and permanent capillary loss. We also showed that capillary loss of this magnitude was associated with severe exercise limitation. Furthermore, VEGF is cytoprotective, and apoptosis from lack of VEGF could lead to muscle inflammation and/or atrophy that could compromise muscle integrity and result in contractile dysfunction. By far the most VEGF expressed in muscle comes from the myocytes themselves. Accordingly, this thesis tests the hypothesis that myocyte-specific VEGF (as opposed to VEGF from other cells in muscle tissue, such as satellite and endothelial cells) is critical for maintaining skeletal muscle capillarity, muscle function, and exercise capacity in adult cage-confined mice. To test this hypothesis, we developed a novel, inducible skeletal myocyte-specific VEGF knockout mouse. We found that these mice exhibit >90% reduction in whole muscle VEGF protein levels (similar to our prior models), yet only a modest impairment of exercise capacity and no reduction in capillarity or impairment of contractile function. This suggests that in adult mice, VEGF from other cells within muscle must be more important for capillary maintenance and muscle contraction.
|Advisor:||Hogan, Michael C., Wagner, Peter D.|
|Commitee:||Johnson, Randall R., Lieber, Richard L., Webster, Nicholas J.|
|School:||University of California, San Diego|
|School Location:||United States -- California|
|Source:||DAI-B 70/06, Dissertation Abstracts International|
|Keywords:||Capillarity, Contractile function, Exercise capacity, Myocytes, Skeletal muscle, VEGF|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be