HYPOXIA-INDUCED INCREASED PERMEABILITY OF ENDOTHELIAL MONOLAYERS OCCURS THROUGH LOWERING OF CELLULAR CAMP LEVELS
HYPOXIA-INDUCED INCREASED PERMEABILITY OF ENDOTHELIAL MONOLAYERS OCCURS THROUGH LOWERING OF CELLULAR CAMP LEVELS
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DOI：
10.1152/ajpcell.1992.262.3.c546
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发表时间：
1992-03-01
影响因子：
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通讯作者：
STERN, D
中科院分区：
文献类型：
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作者：
OGAWA, S;KOGA, S;STERN, D
长期暴露在低氧环境中，就像在高海拔地区一样，会导致血管通透性增加，而糖皮质激素的使用可能会改善这种情况。为了了解这些观察的机制，我们对体外培养的牛主动脉和肺动脉内皮细胞(ECs)进行了低氧处理，并检测了单层通透性和3‘，5’-环磷酸腺苷(CAMP)水平的变化。两种类型的培养内皮细胞暴露于低氧(PO2约为14Torr)时，单层通透性随时间和剂量的增加而增加，通过放射性标记的溶质扩散来测量，这与EC cAMP水平从60 pmol/mg蛋白质逐渐降低到15 pmol/mg蛋白质以及EC腺苷环化酶活性降低有关。加入cAMP类似物可阻止内皮屏障功能的改变。百日咳毒素保护EC单层免受缺氧引起的通透性增加，同时保持cAMP水平和腺苷环化酶活性。在低氧条件下孵育EC单层之前或同时加入地塞米松可阻断低氧引起的单层通透性增加。地塞米松的预处理也阻止了缺氧培养中cAMP和腺苷环化酶水平的下降。这些数据表明，低氧通过降低腺苷环化酶活性和细胞内cAMP水平来降低EC屏障功能。提示地塞米松可能通过阻止低氧引起的腺苷环化酶活性下降，导致细胞内cAMP升高，维持EC屏障功能，从而发挥其保护作用。
Prolonged exposure to hypoxia, as at high altitude, results in increased vascular permeability that may be ameliorated by administration of glucocorticoids. To understand mechanisms underlying these observations, cultured bovine aortic and pulmonary artery endothelial cells (ECs) were subjected to hypoxia, and changes in monolayer permeability and adenosine 3',5'-cyclic monophosphate (cAMP) levels were assessed. Exposure of both types of cultured ECs to hypoxia (Po2 approximately 14 Torr) led to a time- and dose-dependent increase in monolayer permeability, as measured by diffusion of radiolabeled solutes, which was associated with a progressive decrease in EC cAMP levels from 60 to 15 pmol/mg protein, and a decrease in EC adenylate cyclase activity. The change in endothelial barrier function was prevented by addition of cAMP analogues. Pertussis toxin protected EC monolayers from hypoxia-mediated increase in permeability while maintaining cAMP levels and adenylate cyclase activity. Addition of dexamethasone to EC monolayers before or simultaneously with their incubation under hypoxic conditions blocked the hypoxia-mediated increase in monolayer permeability. Dexamethasone pretreatment also prevented the decline in cAMP and adenylate cyclase levels in oxygen-deprived cultures. These data indicate that hypoxia decreases EC barrier function by lowering adenylate cyclase activity and cellular cAMP levels. They suggest that dexamethasone may exert its protective effect, in part, by preventing the hypoxia-induced decline in adenylate cyclase activity, leading to an increase in cellular cAMP and maintenance of EC barrier function.