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Skeletal muscle structure and function in mice lacking VEGF

Institution: University of California, San Diego
Investigator(s): Ivan Olfert, Ph.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14KT-0091H Award: $284,491
Subject Area: Pulmonary Disease
Award Type: New Investigator Awards

Initial Award Abstract
Exercise limitation is a hallmark of chronic obstructive pulmonary disease (COPD). Historically, central factors, like lung and heart limitations, which can reduce oxygen transport have been touted as the principal determinant of exercise intolerance. However, there is a growing realization that in chronic conditions, like COPD, are also responsible for other organ dysfunction or disease. In particular, skeletal muscle function has been found to be abnormal in patients with COPD. Since skeletal muscle abnormalities may also limit exercise capacity, it is perhaps not surprising that exercise capacity remains significantly reduced in many COPD patients after lung transplant, even when pulmonary function has been fully, or near fully, restored. The importance of angiogenesis, i.e. new blood vessel formation, is becoming widely recognized in both health and disease, and is increasingly recognized as a determinant in the pathophysiology of many chronic diseases, like COPD. However, the underlying mechanisms and factors regulating skeletal muscle angiogenesis still remain poorly understood.

The purpose of this study is to investigate the importance of vascular endothelial growth factor (VEGF), a potent angiogenic stimulator, in the making and maintenance of blood vessels in adult skeletal muscle. We know that VEGF is important in the growth and development of blood vessels during the early stages of life, e.g. embryogenesis, because if the VEGF gene is abnormal or missing blood vessels do not form and/or organize properly, which ultimately results in death. But whether or not VEGF is as important in skeletal muscle during adult life is not known. In this study, we will selectively remove VEGF from the skeletal muscle of mice, thus creating a muscle-specific VEGF deficient (or knockout) mouse. This will allow us to determine whether or not life-long absence of VEGF in skeletal muscle will alter the number blood vessels in the muscle and its effect on physical activity, e.g. exercise. Understanding these basic mechanisms may someday lead to therapies which may benefit patients suffering from skeletal muscle dysfunction associated with COPD by advancing our understanding of the factors and mechanisms regulating skeletal muscle angiogenesis.

Muscle-targeted deletion of VEGF and exercise capacity in mice.
Periodical: Respiratory Physiological Neurobiological Index Medicus:
Authors: Wagner PD, Olfert IM, Tang K, Breen EC ART
Yr: 2006 Vol: 151 Nbr: Abs: Pg: 159-166

Skeleton muscle capillarity during hypoxia VEGF and its activation.
Periodical: High Altitude Medicine & Biology Index Medicus:
Authors: Breen EC, Tang K, Olfert IM, Knapp A, Wagner PD ART
Yr: 2008 Vol: Nbr: Abs: Pg:

Arteriolar and venular capillary distribution in skeletal muscle of old rats.
Periodical: Journals of Gerontology Series A: Biological Sciences and Medical Sciences Index Medicus:
Authors: Cui L, Ju Y, Ding L, Trejo-Morales M, Olfert IM ART
Yr: 2008 Vol: Nbr: Abs: Pg:

Muscle-specific VEGF deficiency greatly reduces exercise endurance in mice.
Periodical: Journal of Physiology Index Medicus:
Authors: Olfert IM, Howlett RA, Tang K, Dalton ND, Gu Y, Peterson KL, Wagner PD, Breen EC ART
Yr: 2009 Vol: 587 Nbr: 8 Abs: Pg: 1755-1767

Global deletion of thrombospondin-1 increases cardiac and skeletal muscle capillarity and exercise capacity.
Periodical: Experimental Physiology_x000D_ Index Medicus:
Authors: Malek MH, Olfert IM ART
Yr: 2009 Vol: 94 Nbr: 6 Abs: Pg: 749-760

Skeletal muscle VEGF deficiency: Tthe impact mitochondrial respiration.
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Merlone JP, Olfert IM, Richardson RS ART
Yr: 2005 Vol: 37 Nbr: 5 Abs: Pg: S455

Skeletal muscle capillary and exercise capacity is increased thrombospondin-1 knock-out mice.
Periodical: Physiologist Index Medicus:
Authors: Olfert IM, Malek M ART
Yr: 2008 Vol: 51 Nbr: 6 Abs: Pg: 66