Astrocytes spatially restrict VEGF signaling by polarized secretion and incorporation of VEGF into the actively assembling extracellular matrix.
Astrocytes spatially restrict VEGF signaling by polarized secretion and incorporation of VEGF into the actively assembling extracellular matrix.
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作者：
Egervari K;Potter G;Guzman-Hernandez ML;Salmon P;Soto-Ribeiro M;Kastberger B;Balla T;Wehrle-Haller B;Kiss JZ
血管内皮生长因子（VEGF）信号传导的空间组织是发育和组织修复过程中血管模式形成的关键决定因素。VEGF信号如何在空间上受到限制，以及VEGF分泌星形胶质细胞在这一过程中的作用仍然知之甚少。使用VEGF-GFP融合蛋白和共聚焦延时显微镜，我们观察了划痕激活的活星形胶质细胞中VEGF的细胞内路由，分泌和固定。我们发现VEGF被直接运输到细胞-细胞外基质附件，在那里它被并入纤连蛋白原纤维。VEGF在含有β1整联蛋白的纤维状粘连处积聚，并在内化和降解之前沿细胞表面沿着移位。我们还发现，只有星形胶质细胞来源的、基质结合的且不可溶的VEGF降低纤维粘连中的β1整合素转换。我们认为，VEGF分泌细胞的极化VEGF释放和ECM重塑是控制局部VEGF浓度和信号传导的关键。我们的研究结果强调了星形胶质细胞在指导VEGF功能中的重要性，并将这些机制确定为血管生成方法的有前途的靶点。
The spatial organization of vascular endothelial growth factor (VEGF) signaling is a key determinant of vascular patterning during development and tissue repair. How VEGF signaling becomes spatially restricted and the role of VEGF secreting astrocytes in this process remains poorly understood. Using a VEGF-GFP fusion protein and confocal time-lapse microscopy, we observed the intracellular routing, secretion and immobilization of VEGF in scratch-activated living astrocytes. We found VEGF to be directly transported to cell-extracellular matrix attachments where it is incorporated into fibronectin fibrils. VEGF accumulated at β1 integrin containing fibrillar adhesions and was translocated along the cell surface prior to internalization and degradation. We also found that only the astrocyte-derived, matrix-bound, and not soluble VEGF decreases β1 integrin turnover in fibrillar adhesions. We suggest that polarized VEGF release and ECM remodeling by VEGF secreting cells is key to control the local concentration and signaling of VEGF. Our findings highlight the importance of astrocytes in directing VEGF functions and identify these mechanisms as promising target for angiogenic approaches.
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