Endothelial cell traction and ECM density influence both capillary morphogenesis and maintenance in 3-D
Endothelial cell traction and ECM density influence both capillary morphogenesis and maintenance in 3-D
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DOI：
10.1152/ajpcell.00018.2009
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发表时间：
2009-07-01
影响因子：
5.5
通讯作者：
Putnam, Andrew J.
中科院分区：
文献类型：
--
作者：
Kniazeva, Ekaterina;Putnam, Andrew J.
Kniazeva E，Putnam AJ.内皮细胞牵引力和细胞外基质密度影响3-D中毛细血管的形态和维持。AM J Physiol Cell Physiol 297：C179-C187,2009。2009年5月13日首次出版；doi：10.1152/ajpcell.00018.2009。-确定癌症和心脏病等病理性疾病中血管生成的调控机制对于开发成功的治疗方法至关重要。血管生成对这些条件的特征特性的依赖，例如由于细胞外基质(ECM)组成的变化而导致的组织硬度的变化，可能有助于揭示潜在的治疗策略。先前的研究表明，ECM顺应性调节毛细血管形态发生，但机制尚不清楚。在这项研究中，我们假设影响底物力学的ECM密度可能通过涉及肌动蛋白介导的细胞生成力的机制来调节血管生成。为了研究这一假说，我们利用了血管生成的体外模型，在该模型中，包裹在微载体珠子上的内皮细胞分布在三维(3-D)纤维蛋白ECM中。一层单层的成纤维细胞，提供促血管生成因子，培养在凝胶的顶部。纤维蛋白凝胶密度的变化，以及抑制肌动蛋白细胞骨架产生的力量的药理药剂库，被用来证明细胞产生的牵引力在血管形成中的必要性。我们的数据表明，细胞生成力不仅在毛细血管形态发生的早期萌发阶段发挥关键作用，而且在后期维持阶段也是必需的，从而表明组织僵硬、细胞收缩力和血管生成之间存在更广泛的相互依赖。
Kniazeva E, Putnam AJ. Endothelial cell traction and ECM density influence both capillary morphogenesis and maintenance in 3-D. Am J Physiol Cell Physiol 297: C179-C187, 2009. First published May 13, 2009; doi:10.1152/ajpcell.00018.2009.-Identifying the mechanisms regulating angiogenesis in pathological conditions such as cancer and heart disease is crucial to develop successful therapies. The dependence of angiogenesis on characteristic properties of these conditions, such as alterations in tissue stiffness due to changes in the composition of the extracellular matrix (ECM), may shed light on potential therapeutic strategies. Prior studies have suggested that ECM compliance regulates capillary morphogenesis, but the mechanisms remain unclear. In this study, we hypothesized that ECM density, which influences substrate mechanics, may regulate angiogenesis via a mechanism involving actin-mediated cell-generated forces. To investigate this hypothesis, we utilized an in vitro model of angiogenesis in which endothelial cells coated on microcarrier beads are distributed within a three-dimensional (3-D) fibrin ECM. A monolayer of fibroblasts, which provides pro-angiogenic factors, is cultured on top of the gel. Variations in fibrin gel density, along with a library of pharmacological agents that inhibit forces generated by the actin cytoskeleton, were used to prove the necessity of cell-generated tractional forces in blood vessel formation. Our data demonstrate that cell-generated forces not only play a crucial role in the early sprouting stages of capillary morphogenesis but are also required in the later maintenance stages, and thereby suggest a broader interdependence among tissue stiffness, cell contractile forces, and angiogenesis.