Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Arterioscler Thromb Vasc Biol. 2013 Mar;33(3):565-71. doi: 10.1161/ATVBAHA.112.300993. Epub 2013 Jan 10.
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.
Treatment with PGD(2) (0.1-3 μmol/L) or the DP receptor agonist, BW245C (0.1-3 μmol/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 μmol/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 μg) 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.
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.
前列腺素 D(2) (PGD(2)) 是炎症过程中产生的一种前列腺素。尽管已知 PGD(2) 通过 D 型前列腺素 (DP) 受体刺激降低内皮通透性，但详细机制尚不清楚。
用 PGD(2) (0.1-3 μmol/L) 或 DP 受体激动剂 BW245C (0.1-3 μmol/L) 处理，剂量依赖性地增加了人脐静脉内皮细胞的跨内皮电阻，降低了 FITC-葡聚糖的通透性。两者均表明内皮通透性降低。这些现象伴随着 Tiam1/Rac1 依赖性细胞骨架重排。BW245C (0.3 μmol/L) 增加了细胞内 cAMP 水平和随后的蛋白激酶 A (PKA) 活性。用 PKA 抑制肽预处理，但不是 cAMP 直接激活交换蛋白 1 (Epac1) 的基因缺失，减弱了 BW245C 诱导的 Rac1 激活和跨内皮电阻增加。在体内，应用 2.5%巴豆油或组胺 (100 μg) 导致染料渗出指数的血管渗漏。用 BW245C (1 mg/kg) 预处理可减轻染料渗出。DP 的基因缺失或 PKA 的抑制显著降低了 DP 介导的屏障增强作用。
PGD(2)-DP 信号在体内和体外均降低血管通透性。这种现象是由 cAMP/PKA/Tiam1 依赖性、Epac1 非依赖性 Rac1 激活介导的，随后增强了内皮细胞中黏附连接。
