Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells.
Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells.
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发表时间：
1991
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通讯作者：
Tommy A. Brock;Harold F. Dvorak;Donald R. Sengert
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作者：
Tommy A. Brock;Harold F. Dvorak;Donald R. Sengert
血管通透性因子（VPF）是一种肿瘤分泌的肝素结合蛋白（Mr约38，000），负责增加与肿瘤生长相关的血管通透性和液体蓄积。血管通透性因子还能促进人脐静脉内皮细胞和牛肺内皮细胞的生长。首次表明豚鼠VPF（半最大和最大剂量分别约为0.4和22 pmol/l（皮摩尔））以及人VPF是人EC的有效刺激物，导致[Ca 2 +]i增加（最大3 - 4倍）和三磷酸肌醇（IP 3）形成。与对凝血酶和组胺的最大反应不同，对最大VPF剂量的[Ca 2 +]i反应之前有一个特征性的10- 15秒延迟。豚鼠VPF也选择性地增加培养的主动脉和肺动脉EC中的[Ca 2 +]i，但不增加主动脉平滑肌细胞、人成纤维细胞或中性粒细胞中的[Ca 2 +] i。亲和纯化的兔抗体（产生代表VPF N-末端氨基酸1至24的合成肽）吸附所有血管通透性增加活性、EC生长促进活性，特别是负责增加EC [Ca 2 +]i的所有活性。类似于其他介质，增加[Ca 2 +]i在培养的EC，VPF也诱导了200%的增加血管性血友病因子的释放。总之，这些数据表明，VPF直接作用于EC，其体内/体外作用中的快速细胞事件可能涉及磷脂酶C激活、[Ca 2 +]i增加和血管性血友病因子释放。
Vascular permeability factor (VPF), a tumor-secreted heparin-binding protein (Mr approximately 38,000), is responsible for increased vessel permeability and fluid accumulation associated with tumor growth. Vascular permeability factor also promotes the growth of human umbilical vein endothelial cells (EC) and bovine pulmonary ECs in vitro. It is shown for the first time that guinea pig VPF (half-maximal and maximal dose approximately 0.4 and 22 pmol/l (picomolar), respectively), as well as human VPF, are potent stimuli for human ECs resulting in [Ca2+]i increases (maximal three- to fourfold) and inositol triphosphate (IP3) formation. Unlike the maximal responses to thrombin and histamine, the [Ca2+]i response to a maximal VPF dose was preceded by a characteristic 10- to 15-second delay. Guinea pig VPF also selectively increased [Ca2+]i in cultured aortic and pulmonary artery ECs, but not aortic smooth muscle cells, human fibroblasts, or neutrophils. Affinity-purified rabbit antibody (raised to a synthetic peptide representing VPF N-terminal amino acids 1 to 24) adsorbed all vessel permeability-increasing activity, EC growth-promoting activity, and specifically all activity responsible for increasing EC [Ca2+]i. Similar to other mediators that increase [Ca2+]i in cultured ECs, VPF also induced a 200% increase in von Willebrand factor release. Together these data indicate that VPF acts directly on ECs and that rapid cellular events in its in vivo/in vitro actions are likely to involve phospholipase C activation, [Ca2+]i increase, and von Willebrand factor release.