[Frontiers in Bioscience 6, d75-89, January 1, 2001]


Thomas Gustafsson 1,2 William E. Kraus 3

1 Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden. 2 Department of Medical Laboratory Sciences and Technology, Huddinge University Hospital, Karolinska institutet, Huddinge, Sweden 3Division of Cardiology, Departments of Medicine and Cell Biology, Duke University Medical Center, Durham, N.C, USA


1. Abstract
2. Introduction
3. Capillarization: its importance and change in response to increased muscle activity
3.1. Oxygen uptake and metabolic exchange
3.2. Changes in capillary formation in response to physical activity
4. Angiogenesis and angiogenic growth factors
4.1. Angiogenesis
4.2. Angiogenic factors
4.2.1. Vascular endothelial growth factor (VEGF)
4.2.2. Fibroblast growth factors (FGF)
4.2.3. Angiopoietins
4.2.4. Transforming Growth Factors (TGF-b ) and Platelet Derived Growth Factors (PDGF-BB)
4.2.5. Integrins
5. The response of angiogenic factors and related transcription factors to exercise and proposed exercise induced angiogenic stimuli
5.1. Expression of angiogenic factors in response to increased muscle activity or endurance type of exercise
5.2. Angiogenesis and angiogenic factors response in skeletal muscle to local hypoxia/ischemia and related metabolic alteration
5.3. Angiogenesis and angiogenic factors response in skeletal muscle to changes in blood flow and muscle stretching
6. Angiogenesis and angiogenic factors in muscle pathophysiology
6.1. Metabolic disorders and diabetes mellitus
6.2. Peripheral vascular disease
6.3. Chronic congestive heart failure
7. Summary and perspective
8. Acknowledgement
9. References


Angiogenesis is the process of formation of new blood vessels; it is generally a rare occurrence in the adult, although it is a common adaptive response to exercise training in skeletal muscle. Current thinking is that angiogenesis is mediated by diffusible angiogenic factors and that the angiogenic activity is regulated through the balance between stimulatory and inhibitory factors. Recent studies have shown that up-regulation of angiogenic factors occurs in response to increased muscle activity in skeletal muscle. The major putative angiogenic factor, vascular endothelial growth factor (VEGF), seems to increase to a greater extent and more consistently than other measured angiogenic factors, such as fibroblast growth factor-2 (FGF-2) and transforming growth factor-b1 (TGF-b1). While the regulating mechanisms in this response are not clear, present data indicate reduced oxygen tension and/or related metabolic alterations in the skeletal muscle as possible stimuli. Data on other angiogenic growth factors are limited, but an increase in endothelial cell-stimulating angiogenic growth factor (ESAF) has been observed in response to increased blood flow and muscle stretching. Therefore, different exercise associated stimuli may all contribute to exercise-induced angiogenesis in skeletal muscle, but possibly through differing angiogenic factors and mechanisms. Understanding these processes is important for the elucidation of mechanisms mediating exercise responsiveness in skeletal muscle, but also for the potential that such understanding might bring to the treatment and prevention of human diseases such as intermittent claudication.