VEGF gradients, receptor activation, and sprout guidance in resting and exercising skeletal muscle
VEGF gradients, receptor activation, and sprout guidance in resting and exercising skeletal muscle
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DOI：
10.1152/japplphysiol.00800.2006
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发表时间：
2007-02-01
影响因子：
3.3
通讯作者：
Popel, Aleksander S.
中科院分区：
文献类型：
--
作者：
Mac Gabhann, Feilim;Ji, James W.;Popel, Aleksander S.
在休息和锻炼骨骼肌中VEGF梯度，受体激活和发芽指导。中国生物医学工程学报，2009,31(2):559 - 564。首次发表于2006年10月12日；doi: 10.1152 / japplphysiol.00800.2006。-广泛的实验研究已经确定血管内皮生长因子（VEGF）浓度和浓度梯度是血管生成的主要因素；然而，这些参数的局部体内测量是不可能的。我们开发了骨骼肌纤维、血管和间隙的三维计算模型。这里应用于大鼠指长伸肌。VEGF异构体由肌细胞分泌，通过细胞外基质和基底膜扩散，并结合血管内皮细胞表面受体。此外，一种异构体VEGF（164）在间隙中与蛋白聚糖结合。VEGF的分泌速率是通过其对缺氧诱导因子-1 α转录因子的影响来预测组织氧水平。我们估计血管内皮生长因子的分泌及其浓度和梯度在休息肌肉和不同水平的运动。还研究了低水平吸入氧的影响。我们预测，低氧组织中肌纤维VEGF分泌的高度空间异质性导致VEGF浓度和VEGF受体激活的显著梯度。预计在静息肌和运动肌中VEGF浓度梯度均显著（10 μ m内VEGF变化分别为4%和6-8%），足以对50 μ m长的芽尖细胞进行趋化引导。VEGF梯度也导致了VEGF受体激活的异质性，这可能解释了发芽位置的随机性。在没有间隙流的情况下，横向（即垂直于肌纤维）的梯度比纵向陡峭10倍。这可以解释在骨骼肌中观察到的垂直吻合。
VEGF gradients, receptor activation, and sprout guidance in resting and exercising skeletal muscle. J Appl Physiol 102: 722-734, 2007. First published October 12, 2006; doi:10.1152/japplphysiol.00800.2006.-Extensive experimental studies have identified vascular endothelial growth factor (VEGF) concentrations and concentration gradients as major factors in angiogenesis; however, localized in vivo measurements of these parameters have not been possible. We developed a three-dimensional computational model of skeletal muscle fibers, blood vessels, and interstitial space. Here it is applied to rat extensor digitorum longus. VEGF isoforms are secreted by myocytes, diffuse through extracellular matrix and basement membranes, and bind endothelial cell surface receptors on blood vessels. In addition, one isoform, VEGF(164), binds to proteoglycans in the interstitial space. VEGF secretion rate is determined from the predicted tissue oxygen level through its effect on the hypoxia inducible factor-1 alpha transcription factor. We estimate VEGF secretion and its concentrations and gradients in resting muscle and for different levels of exercise. The effects of low levels of inspired oxygen are also studied. We predict that the high spatial heterogeneity of muscle fiber VEGF secretion in hypoxic tissue leads to significant gradients of VEGF concentration and VEGF receptor activation. VEGF concentration gradients are predicted to be significant in both resting and exercising muscle (4% and 6-8% change in VEGF over 10 mu m, respectively), sufficient for chemotactic guidance of 50-mu m-long sprout tip cells. VEGF gradients also result in heterogeneity in VEGF receptor activation - a possible explanation for the stochasticity of sprout location. In the absence of interstitial flow, gradients are 10-fold steeper in the transverse direction (i.e., perpendicular to the muscle fibers) than in the longitudinal direction. This may explain observed perpendicular anastomoses in skeletal muscle.