DNA SEQUENCE VARIATION IN THE PROMOTER REGION OF THE VEGF GENE: IMPACTS ON VEGF GENE EXPRESSION AND MAXIMAL OXYGEN CONSUMPTION

Abstract

Maximal oxygen consumption (Vo_2max) is inversely associated with cardiovascular and all-cause mortality and is responsive to aerobic exercise training. A portion of the increase in Vo_2max with aerobic exercise training can be attributed to an increase in skeletal muscle capillarity (i.e., angiogenesis), which contributes to increased blood flow and oxygen extraction in working skeletal muscle. One contributing factor to exercise-induced angiogenesis is vascular endothelial growth factor (VEGF), as it is an endothelial cell proliferation and migration factor that is upregulated by acute aerobic exercise. Significant variability has been observed in VEGF protein levels, <i>VEGF</i> gene expression, skeletal muscle capillarity, and Vo_2max before and after aerobic exercise training. Additionally, variability is found in the DNA sequence of the gene encoding VEGF. Variation in the <i>VEGF</i> gene has the ability to impact <i>VEGF</i> gene expression and VEGF protein level and because of the relationship between VEGF, angiogenesis, and Vo_2max, we hypothesized that variation in the <i>VEGF</i> gene is related to <i>VEGF</i> gene expression in human myoblasts, plasma VEGF level, and Vo_2max before and after aerobic exercise training.

The present report shows that <i>VEGF</i> promoter region haplotype impacts <i>VEGF</i> gene expression in human myoblasts <i>in vitro</i>. It was also found that <i>VEGF</i> promoter region haplotype was associated with Vo_2max in older men and women before and after exercise training in a manner that is consistent with the results of the <i>VEGF</i> gene expression experiments. Additionally, we found that plasma VEGF level was not associated with <i>VEGF</i> promoter region haplotype, nor did plasma VEGF level correlate with baseline Vo_2max or the change in Vo_2max with aerobic exercise training. To date, we are the first to report that <i>VEGF</i> promoter region haplotype impacts <i>VEGF</i> gene expression in human myoblasts and is associated with Vo_2max. These results have potential implications for aerobic exercise training and may also contribute to the understanding of the function of the <i>VEGF</i> promoter region in different cell types. Furthermore, these results may prove relevant in the study of pathological conditions which can be affected by angiogenesis, namely obesity, cancer, coronary artery disease, and peripheral artery disease.