Mechanisms controlling human endothelial lumen formation and tube assembly in three-dimensional extracellular matrices
Mechanisms controlling human endothelial lumen formation and tube assembly in three-dimensional extracellular matrices
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DOI：
10.1002/bdrc.20107
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发表时间：
2007-12-01
影响因子：
2.1
通讯作者：
Stratman, Amber N.
中科院分区：
文献类型：
--
作者：
Davis, George E.;Koh, Wonshill;Stratman, Amber N.
最近的数据揭示了在发育、伤口修复和其他疾病状态中的血管形态发生事件期间内皮细胞（EC）管腔形成的新机制。很明显，EC与细胞外基质（ECM）的相互作用在整合素连接的下游建立了信号级联，导致Rho GTP酶Cdc 42和Rac 1的激活，这是管腔形成所需的。在很大程度上，这一过程是由细胞内空泡形成和聚结驱动的，这迅速导致产生充满流体的无基质空间，然后通过EC-EC相互作用相互连接以产生多细胞管结构。EC空泡以极化的方式显著地聚集在中心体附近的区域中，该区域强烈地聚集Cdc 42蛋白，如由绿色荧光蛋白（GFP）-Cdc 42在管腔形成过程期间所指示的。在Cdc 42介导的信号传导的下游，已经鉴定为EC管腔形成所需的关键分子包括Pak 2、Pak 4、Par 3、Par 6和蛋白激酶C（PKC）亚型zeta和zeta。这些分子共同协调调节三维（3D）胶原基质中关键的EC管腔形成过程。这些事件还需要通过膜1型基质金属蛋白酶（MT 1-MMP）介导的细胞表面蛋白水解，这是在3D基质环境中创建血管引导通道所必需的。这些通道代表ECM内的物理空间，其对于调节血管形态发生事件是必要的，包括建立互连的血管管网络以及周细胞的募集以启动血管管成熟（通过基底膜基质组装）和稳定化。目前的研究继续分析特定分子如何整合信号信息，以催化EC管腔形成，周细胞募集和稳定过程，以控制3D细胞外基质中的血管形态发生。
Recent data have revealed new mechanisms that underlie endothelial cell (EC) lumen formation during vascular morphogenic events in development, wound repair, and other disease states. It is apparent that EC interactions with extracellular matrices (ECMs) establish signaling cascades downstream of integrin ligation leading to activation of the Rho GTPases, Cdc42 and Rac1, which are required for lumen formation. In large part, this process is driven by intracellular vacuole formation and coalescence, which rapidly leads to the creation of fluid-filled matrix-free spaces that are then interconnected via EC-EC interactions to create multicellular tube structures. EC vacuoles markedly accumulate in a polarized fashion directly adjacent to the centrosome in a region that strongly accumulates Cdc42 protein as indicated by green fluorescent protein (GFP)-Cdc42 during the lumen formation process. Downstream of Cdc42-mediated signaling, key molecules that have been identified to be required for EC lumen formation include Pak2, Pak4, Par3, Par6, and the protein kinase C (PKC) isoforms zeta and epsilon. Together, these molecules coordinately regulate the critical EC lumen formation process in three-dimensional (3D) collagen matrices. These events also require cell surface proteolysis mediated through membrane type 1 matrix metalloproteinase (MT1-MMP), which is necessary to create vascular guidance tunnels within the 3D matrix environment. These tunnels represent physical spaces within the ECM that are necessary to regulate vascular morphogenic events, including the establishment of interconnected vascular tube networks as well as the recruitment of pericytes to initiate vascular tube maturation (via basement membrane matrix assembly) and stabilization. Current research continues to analyze how specific molecules integrate signaling information in concert to catalyze EC lumen formation, pericyte recruitment, and stabilization processes to control vascular morphogenesis in 3D extracellular matrices.