The role of adherens junctions and VE-cadherin in the control of vascular permeability
The role of adherens junctions and VE-cadherin in the control of vascular permeability
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DOI：
10.1242/jcs.017897
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发表时间：
2008-07-01
影响因子：
4
通讯作者：
Lampugnani, Maria Grazia
中科院分区：
文献类型：
--
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
内皮细胞控制血浆成分和循环细胞从血液到下层组织的通道。这种特殊的功能在几种病理条件下丧失或受损-包括炎症，败血症，缺血和糖尿病-这导致严重的，有时是致命的，器官功能障碍。内皮细胞的通透性在一定程度上受细胞-细胞粘附连接（AJs）的动态开放和关闭的调节。在内皮细胞中，AJs主要由血管内皮钙粘蛋白（VE-钙粘蛋白）组成，VE-钙粘蛋白是粘附蛋白钙粘蛋白家族的内皮特异性成员，通过其胞质结构域与几种蛋白质伴侣结合，包括p120、β-连环蛋白和斑珠蛋白。增加血管通透性的内源性途径以多种方式影响AJs中VE-钙粘蛋白和其他蛋白质的功能和组织。例如，包括血管内皮生长因子（VEGF）在内的几种因子诱导VE-钙粘蛋白的酪氨酸磷酸化，这伴随着血管通透性和白细胞渗出的增加;此外，VE-钙粘蛋白的内化和切割可导致AJs被拆除。从AJ组织如何被调制的知识，有可能制定几种药理学策略来控制内皮的屏障功能。我们讨论了SRC和其他激酶的抑制剂，增加cAMP水平的药物，和溶解酶的抑制剂作为降低内皮通透性的药理学工具的可能用途。
Endothelial cells control the passage of plasma constituents and circulating cells from blood to the underlying tissues. This specialized function is lost or impaired in several pathological conditions - including inflammation, sepsis, ischemia and diabetes - which leads to severe, and sometimes fatal, organ dysfunction. Endothelial permeability is regulated in part by the dynamic opening and closure of cell-cell adherens junctions (AJs). In endothelial cells, AJs are largely composed of vascular endothelial cadherin (VE-cadherin), an endothelium-specific member of the cadherin family of adhesion proteins that binds, via its cytoplasmic domain, to several protein partners, including p120, beta-catenin and plakoglobin. Endogenous pathways that increase vascular permeability affect the function and organization of VE-cadherin and other proteins at AJs in diverse ways. For instance, several factors, including vascular endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability.