Prostaglandin D2-DP Signaling Promotes Endothelial Barrier Function via the cAMP/PKA/Tiam1/Rac1 Pathway
Prostaglandin D2-DP Signaling Promotes Endothelial Barrier Function via the cAMP/PKA/Tiam1/Rac1 Pathway
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DOI：
10.1161/atvbaha.112.300993
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发表时间：
2013-03-01
影响因子：
8.7
通讯作者：
Murata, Takahisa
中科院分区：
文献类型：
--
作者：
Kobayashi, Koji;Tsubosaka, Yoshiki;Murata, Takahisa
目的：前列腺素D-2(PGD(2))是炎症过程中产生的一种前列腺素。方法与结果：前列腺素D(2)(0.1~3mU/L)或DP受体激动剂BW245C(0.1~3mU/L)可剂量依赖性地增加人脐静脉内皮细胞的跨内皮电阻，降低FITC-葡聚糖的通透性。两者均显示内皮细胞通透性降低。伴随这些现象的是Tiam1/rac1依赖的细胞骨架重排。BW245C(0.3ae摩尔/L)可增加细胞内cAMP水平及随后的蛋白激酶A活性。预先给予PKA抑制肽，但不去除cAMP 1直接激活的交换蛋白(Epac1)基因，可减弱BW245C诱导的rac1激活和跨内皮细胞电阻的增加。在体内，应用2.5%巴豆油或组胺(100mUg)导致血管渗漏，以染料渗出为指标。预先给予BW245C(1 mg/kg)可减轻染料渗出。结论pGD(2)-dp信号转导通路在体内和体外均可降低血管通透性。这一现象是由cAMP/PKA/Tiam1依赖的Epac1非依赖的rac1激活和随后内皮细胞黏附连接的增强所介导的。(动脉血栓血管生物)2013；33：565-571。)
Objective-Prostaglandin D-2 (PGD(2)) is one of the prostanoids produced during inflammation. Although PGD(2) is known to decrease endothelial permeability through D prostanoid (DP) receptor stimulation, the detailed mechanism is unknown.Methods and Results-Treatment with PGD(2) (0.1-3 mu mol/L) or the DP receptor agonist, BW245C (0.1-3 mu mol/L), dose-dependently increased transendothelial electrical resistance and decreased the FITC-dextran permeability of human umbilical vein endothelial cells. Both indicated decreased endothelial permeability. These phenomena were accompanied by Tiam1/Rac1-dependent cytoskeletal rearrangement. BW245C (0.3 ae mol/L) increased the intracellular cAMP level and subsequent protein kinase A (PKA) activity. Pretreatment with PKA inhibitory peptide, but not gene depletion of exchange protein directly activated by cAMP 1 (Epac1), attenuated BW245C-induced Rac1 activation and transendothelial electric resistance increase. In vivo, application of 2.5% croton oil or histamine (100 mu g) caused vascular leakage indexed by dye extravasation. Pretreatment with BW245C (1 mg/kg) attenuated the dye extravasation. Gene deficiency of DP abolished, or inhibition of PKA significantly reduced, the DP-mediated barrier enhancement.Conclusion-PGD(2)-DP signaling reduces vascular permeability both in vivo and in vitro. This phenomenon is mediated by cAMP/PKA/Tiam1-dependent Epac1-independent Rac1 activation and subsequent enhancement of adherens junction in endothelial cell. (Arterioscler Thromb Vasc Biol. 2013;33:565-571.)