Human VEGF gene expression in skeletal muscle: effect of acute normoxic and hypoxic exercise

Abstract

Vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation, both of which are precursors to new capillary growth. Angiogenesis is a vital adaptation to exercise training, and the exercise-induced reduction in intracellular PO2 has been proposed as a stimulus for this process. Thus we studied muscle cell PO2 [myoglobin PO2 (MbPO2)] during exercise in normoxia and in hypoxia (12% O2) and studied the mRNA levels of VEGF in six untrained subjects after a single bout of exercise by quantitative Northern analysis. Single-leg knee extension provided the acute exercise stimulus: a maximal test followed by 30 min at 50% of the peak work rate achieved in this graded test. Because peak work rate was not affected by hypoxia, the absolute and relative work rates were identical in hypoxia and normoxia. Three pericutaneous needle biopsies were collected from the vastus lateralis muscle, one at rest and then the others at 1 h after exercise in normoxia or hypoxia. At rest (control), VEGF mRNA levels were very low (0.38 +/- 0.04 VEGF/18S). After exercise in normoxia or hypoxia, VEGF mRNA levels were much greater (16.9 +/- 6.7 or 7.1 +/- 1.8 VEGF/18S, respectively). In contrast, there was no measurable basic fibroblast growth factor mRNA response to exercise at this 1-h postexercise time point. Magnetic resonance spectroscopy of myoglobin confirmed a reduction in MbPO2 in hypoxia (3.8 +/- 0.3 mmHg) compared with normoxia (7.2 +/- 0.6 mmHg) but failed to reveal a relationship between MbPO2 during exercise and VEGF expression. This VEGF mRNA increase in response to acute exercise supports the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis but questions the importance of a reduced cellular PO2 as a stimulus for this response.

Passive leg movement enhances interstitial VEGF protein, endothelial cell proliferation, and eNOS mRNA content in human skeletal muscle

“…Studies on the regulation of capillarization in response to exercise and training have shown that acute exercise enhances the protein and mRNA levels of several angiogenic factors such as vascular endothelial growth factor (VEGF) (21,31), matrix metalloproteinase-2 (MMP-2) (6,15), and endothelial nitric oxide synthase (eNOS) (11,34). In addition, acute exercise has been shown to cause an increase in the muscle interstitial concentration of VEGF (18,21), which, at least in part, appears to reflect a release of VEGF from skeletal muscle cells as demonstrated in cultured muscle cells (22).…”

Capillary regression in vascular endothelial growth factor-deficient skeletal muscle

“…Multiple signals generated during exercise, including mechanical events associated with muscle contraction and reduced muscle intracellular oxygen tension, have the potential to regulate vascular endothelial growth factor (VEGF) gene expression (6,28,29). VEGF is a well-known, potent angiogenic factor, which also functions as a vascular permeability and endothelial cell survival factor (13).…”

Acclimatization to 4100 m does not change capillary density or mRNA expression of potential angiogenesis regulatory factors in human skeletal muscle

“…VEGF mRNA levels have been reported to increase with hypoxia in mouse brain (Chávez et al, 2000;Kuo et al, 1999) but also to decrease in rat muscle (Olfert et al, 2001b). In human muscle, VEGF is increased with acute exercise (Gustafsson et al, 2002;Richardson et al, 1999). However, it has not previously been studied whether VEGF expression is increased in human muscle in response to hypoxia, and simultaneous determination of these signalling factors and morphological characterization of capillary density in human skeletal muscle has not previously been performed in lowlanders acclimatizing to altitude or in high-altitude natives.…”