Angiogenesis is important in health and disease. In particular, exercise training is known to increase skeletal muscle capillarity, providing there is sufficient training intensity. The stimulus for this may be intracellular hypoxia activating angiogenic growth factor gene expression. Acute hypoxia alone has been shown to increase the gene expression of several key angiogenic regulators, e.g. vascular endothelial growth factor (VEGF) and to a lesser degree transforming growth factor-β1 (TGF-β1), basic fibroblast growth factor (bFGF), and thrombospondin-1 (TSP-1), an endogenous negative angiogenic regulator. Paradoxically, however, chronic hypoxia is generally not found to increase mammalian skeletal muscle capillarity. Accordingly, we hypothesized that chronic hypoxia might alter the gene expression of angiogenic regulators in a manner different from that which has been demonstrated following acute hypoxia and that this might affect the angiogenic response to exercise. We examined the skeletal muscle gene expression of several putative angiogenic regulators following 1) normoxia, 2) chronic hypoxia, 3) normoxic exercise training, and 4) chronic hypoxic exercise training. We report that 8-weeks of continuous hypoxia (FIO2 = 0.12) did not increase rat gastrocnemius muscle capillarity and that basal, i.e. resting, gene expression of VEGF and its receptors, flt-1 and flk-1, as well as TSP-1 mRNA levels were decreased in the gastrocnemius. Neither TGF-βl nor bFGF mRNA’s were significantly altered. In addition, using a single exercise bout to measure the acute angiogenic response to exercise, we report that chronic hypoxia attenuated the VEGF mRNA response to exercise, but did not significantly alter the TSP-1 exercise-induced response. Neither TGF-βl nor bFGF responded significantly to the single bout of exercise. Exercise training, whether in chronic hypoxia or normoxia (room air), did not significantly alter either basal or exercise-induced mRNA levels of VEGF,flk-1, or TSP-1. In contrast, the flt-1 mRNA response to exercise was blunted following normoxic training and was abolished after hypoxic training. Normoxic training increased both basal and exercise-induced bFGF mRNA levels, but did not significantly alter TGF-βl mRNA. Surprisingly, hypoxic training significantly decreased both basal and exercise-induced bFGF and TGF-β1 mRNA’s. We conclude that training in hypoxia, compared to the same absolute training intensity in normoxia, results in a greater aerobic adaptation to exercise (i.e. increased muscle capillarity). This is likely due to a greater relative exercise intensity and thus a greater level of tissue hypoxia experienced during exercise. Based on the observation that both VEGF and TSP-1 mRNA levels increased following a single acute exercise bout, these data suggest that exercise-induced skeletal muscle angiogenesis is likely regulated by both angiogenic stimulators (i.e. VEGF, and perhaps TGF-β1) and inhibitors (i.e. TSP-1). Moreover, the lack of an increase in muscle capillarity observed in sedentary animals following chronic hypoxia, may be explained, at least partially, by the decreases in gene expression of VEGF and its receptors (flt-1 and flk-1), as well as the attenuated VEGF mRNA response to the stimulus of exercise. Taken together with the preservation of the TSP-1 gene response to exercise, it is speculated that chronic hypoxia alters the gene expression of positive angiogenic regulators in a manner which is unlikely to favor new capillary growth.

LLU Discipline





Graduate School

First Advisor

Peter D. Wagner

Second Advisor

Gordon G. Power

Third Advisor

Ellen C. Breen

Fourth Advisor

Marino De León

Fifth Advisor

Odile Mathieu-Costello

Degree Name

Doctor of Philosophy (PhD)

Degree Level


Year Degree Awarded


Date (Title Page)




Library of Congress/MESH Subject Headings

Exertion -- physiology; Capillaries -- physiology; Anoxia -- physiology; Gene Expression -- physiology Chronic Disease; Endothelial growth factors -- genetics; Body Mass Index; Muscle, Skeletal -- blood supply; Extracellular Matrix Proteins -- genetics; Neovascularization, Physiologic -- physiology; Lymphokines -- genetics Blotting, Northern; Oxygen -- blood; RNA, Messenger -- analysis; Receptors, Growth Factor -- genetics



Page Count

viii; 156

Digital Format


Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.


Loma Linda University Electronic Theses and Dissertations

Collection Website



Loma Linda University. Del E. Webb Memorial Library. University Archives