Antagonism of VEGF-A-induced increase in vascular permeability by an integrin α3β1-Shp-1-cAMP/PKA pathway
Antagonism of VEGF-A-induced increase in vascular permeability by an integrin α3β1-Shp-1-cAMP/PKA pathway
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DOI：
10.1182/blood-2012-05-428243
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发表时间：
2012-12-06
期刊：
影响因子：
20.3
通讯作者：
Seo, Dong-Wan
中科院分区：
文献类型：
--
作者：
Kim, Soo Hyeon;Cho, Young-Rak;Seo, Dong-Wan
在癌症中，VEGF 诱导的血管通透性增加导致间质压力增加、灌注减少和缺氧增加，从而减少化疗药物的输送并增加对电离辐射的抵抗力。在这里，我们表明，TIMP-2 和 Ala + TIMP-2（一种不具有基质金属蛋白酶抑制活性的 TIMP-2 突变体）在体外和体内均可拮抗 VEGF-A 诱导的血管通透性增加。与其他已知可保护内皮屏障功能的药物一样，TIMP-2 可以提高人微血管内皮细胞中 cAMP 的胞质水平并增加细胞骨架相关的血管内皮钙粘蛋白。通过选择性敲低整合素 α 3 β 1 表达、显性失活蛋白酪氨酸磷酸酶 Shp-1 突变体的表达、施用蛋白酪氨酸磷酸酶抑制剂原钒酸盐或腺苷酸环化酶抑制剂 SQ22536，可以完全消除所有这些影响。这种 TIMP-2 介导的血管通透性抑制涉及整合素 α 3 β 1-Shp-1-cAMP/蛋白激酶 A 依赖性血管内皮钙粘蛋白细胞骨架关联，如使用 siRNA 整合 α 3 β 1 和 Shp-1，或用 Shp-1 抑制剂 NSC87877 和蛋白激酶 A 抑制剂 H89 治疗所证明的那样。我们的结果证明了 TIMP-2 除了先前描述的抗血管生成作用之外，还通过血管通透性“正常化”在癌症治疗中的潜在用途。 （血。2012；120(24):4892-4902）
In cancer, VEGF-induced increase in vascular permeability results in increased interstitial pressure, reducing perfusion and increasing hypoxia, which reduce delivery of chemotherapeutic agents and increase resistance to ionizing radiation. Here, we show that both TIMP-2 and Ala + TIMP-2, a TIMP-2 mutant without matrix metalloproteinase inhibitory activity, antagonize the VEGF-A-induced increase in vascular permeability, both in vitro and in vivo. Like other agents known to preserve endothelial barrier function, TIMP-2 elevates cytosolic levels of cAMP and increases cytoskeletal-associated vascular endothelial cadherin in human microvascular endothelial cells. All of these effects are completely ablated by selective knockdown of integrin alpha 3 beta 1 expression, expression of a dominant negative protein tyrosine phosphatase Shp-1 mutant, administration of the protein tyrosine phosphatase inhibitor orthovanadate, or the adenylate cyclase inhibitor SQ22536. This TIMP-2-mediated inhibition of vascular permeability involves an integrin alpha 3 beta 1-Shp-1-cAMP/protein kinase A-dependent vascular endothelial cadherin cytoskeletal association, as evidenced by using siRNAs to integrin alpha 3 beta 1 and Shp-1, or treatment with Shp-1 inhibitor NSC87877 and protein kinase A inhibitor H89. Our results demonstrate the potential utility for TIMP-2 in cancer therapy through "normalization" of vascular permeability in addition to previously described antiangiogenic effects. (Blood. 2012;120(24):4892-4902)