在高血压妊娠的转基因模型中，早期妊娠时子宫动脉的血管紧张素 II 收缩增加，通过抑制内源性大麻素水解得到减少。
Increased angiotensin II contraction of the uterine artery at early gestation in a transgenic model of hypertensive pregnancy is reduced by inhibition of endocannabinoid hydrolysis.
机构信息
From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
出版信息
Hypertension. 2014 Sep;64(3):619-25. doi: 10.1161/HYPERTENSIONAHA.114.03633. Epub 2014 Jun 16.
Increased vascular sensitivity to angiotensin II (Ang II) is a marker of a hypertensive human pregnancy. Recent evidence of interactions between the renin-angiotensin system and the endocannabinoid system suggests that anandamide and 2-arachidonoylglycerol may modulate Ang II contraction. We hypothesized that these interactions may contribute to the enhanced vascular responses in hypertensive pregnancy. We studied Ang II contraction in isolated uterine artery (UA) at early gestation in a rat model that mimics many features of preeclampsia, the transgenic human angiotensinogen×human renin (TgA), and control Sprague-Dawley rats. We determined the role of the cannabinoid receptor 1 by blockade with SR171416A, and the contribution of anandamide and 2-arachidonoylglycerol degradation to Ang II contraction by inhibiting their hydrolyzing enzyme fatty acid amide hydrolase (with URB597) or monoacylglycerol lipase (with JZL184), respectively. TgA UA showed increased maximal contraction and sensitivity to Ang II that was inhibited by indomethacin. Fatty acid amide hydrolase blockade decreased Ang IIMAX in Sprague-Dawley UA, and decreased both Ang IIMAX and sensitivity in TgA UA. Monoacylglycerol lipase blockade had no effect on Sprague-Dawley UA and decreased Ang IIMAX and sensitivity in TgA UA. Blockade of the cannabinoid receptor 1 in TgA UA had no effect. Immunolocalization of fatty acid amide hydrolase and monoacylglycerol lipase showed a similar pattern between groups; fatty acid amide hydrolase predominantly localized in endothelium and monoacylglycerol lipase in smooth muscle cells. We demonstrated an increased Ang II contraction in TgA UA before initiation of the hypertensive phenotype. Anandamide and 2-arachidonoylglycerol reduced Ang II contraction in a cannabinoid receptor 1-independent manner. These renin-angiotensin system-endocannabinoid system interactions may contribute to the enhanced vascular reactivity in early stages of hypertensive pregnancy.
血管对血管紧张素 II（Ang II）的敏感性增加是人类高血压妊娠的标志。最近有证据表明，肾素-血管紧张素系统和内源性大麻素系统之间存在相互作用，表明大麻素和 2-花生四烯酸甘油可能调节 Ang II 的收缩。我们假设这些相互作用可能导致高血压妊娠中血管反应增强。我们在一种模拟子痫前期许多特征的大鼠模型中研究了早期妊娠时分离的子宫动脉（UA）中 Ang II 的收缩，该模型是转基因人血管紧张素原×人肾素（TgA）和对照 Sprague-Dawley 大鼠。我们通过 SR171416A 阻断大麻素受体 1，通过抑制其水解酶脂肪酸酰胺水解酶（用 URB597）或单酰基甘油脂肪酶（用 JZL184）分别抑制大麻素和 2-花生四烯酸甘油降解对 Ang II 收缩的作用，来确定其作用。TgA UA 显示出对 Ang II 的最大收缩和敏感性增加，这种增加被吲哚美辛抑制。脂肪酸酰胺水解酶阻断降低了 Sprague-Dawley UA 中的 Ang II MAX，并降低了 TgA UA 中的 Ang II MAX 和敏感性。单酰基甘油脂肪酶阻断对 Sprague-Dawley UA 没有影响，并降低了 TgA UA 中的 Ang II MAX 和敏感性。在 TgA UA 中阻断大麻素受体 1 没有影响。脂肪酸酰胺水解酶和单酰基甘油脂肪酶的免疫定位显示出各组之间相似的模式；脂肪酸酰胺水解酶主要定位于内皮细胞，单酰基甘油脂肪酶定位于平滑肌细胞。我们在 TgA UA 发生高血压表型之前就证明了 Ang II 收缩的增加。大麻素和 2-花生四烯酸甘油以不依赖于大麻素受体 1 的方式降低 Ang II 的收缩。这些肾素-血管紧张素系统-内源性大麻素系统相互作用可能导致高血压妊娠早期血管反应性增强。
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