BACKGROUND Prostaglandin I2 synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I2 production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I2 synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown. METHODS Experiments were performed with wild-type, Pgis knockout (Pgis-/-) and Pgis/thromboxane-prostanoid receptor gene (Tp) double knockout (Pgis-/-Tp-/-) mice and Pgis-/- mice transplanted with unfractionated wild-type or Cox-1-/- bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored. RESULTS PGF2α, PGE2, and a trace amount of PGD2, but not thromboxane A2 (TxA2), were produced in response to acetylcholine in Pgis-/- or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in Pgis-/- aortas. Pgis-/- mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA2 receptor) not only restrained EDC and the downregulation of NO signaling in Pgis-/- mice but also ameliorated the cardiovascular abnormalities. Stimulation of Pgis-/- vessels with acetylcholine in the presence of platelets led to increased TxA2 generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in Pgis-/- mice though it largely suppressed the increase of plasma TxB2 (TxA2 metabolite) level. CONCLUSIONS Our study demonstrates that the non-TxA2 prostanoids/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.

中文翻译：

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前列环素合酶缺乏症导致内皮依赖性收缩加重或发生，并主要通过非 TxA2 前列腺素/TP 轴引起心血管疾病。


背景 由内皮 COX（环氧合酶）合成的前列腺素 I2 在某些血管中引起有效的血管舒张，但自相矛盾的是，它会导致其他血管的内皮依赖性收缩 （EDC）。前列腺素 I2 的产生和 EDC 可能在高血压等疾病中增强。然而，PGIS（前列腺素 I2 合酶）缺乏症如何影响 EDC 以及这与随之而来的心血管病变有何关系在很大程度上仍然未知。方法 以野生型 Pgis 敲除 （Pgis-/-） 和 Pgis/血栓素-前列腺素受体基因 （Tp） 双重敲除 （Pgis-/-Tp-/-） 小鼠和 Pgis-/- 小鼠为实验对象，移植未分级野生型或 Cox-1-/-骨髓细胞，以及人脐动脉。通过高效液相色谱-质谱法测量 COX 衍生的前列腺素。通过等长力测量评估不同类型动脉的血管舒缩反应。监测不同年龄小鼠的高血压、血管重塑和心脏肥大等参数。结果 PGF2α 、 PGE2 和微量的 PGD2 ，但不是血栓素 A2 （TxA2），是在 Pgis-/- 或 PGIS 抑制的动脉中响应乙酰胆碱产生的。PGIS 缺陷导致离体和体内 EDC 恶化或发生。内皮依赖性超极化保持不变，但 eNOS （内皮一氧化氮合酶） 在 Ser1177 和 Thr495 位点的磷酸化水平发生改变，并且 NO 产生和乙酰胆碱诱导的 NO 依赖性松弛在 Pgis-/- 主动脉中显着降低。Pgis-/-小鼠在 16 至 17 周时出现高血压和血管重塑，随后在 24 至 26 周出现心脏肥大。 同时，血压和心脏参数在 8 至 10 周时保持正常。TP （TxA2 receptor） 的额外消融不仅抑制了 Pgis-/- 小鼠的 EDC 和 NO 信号的下调，而且还改善了心血管异常。在血小板存在下，用乙酰胆碱刺激 Pgis-/- 血管导致 TxA2 生成增加。骨髓来源细胞中的 COX-1 破坏未能影响 Pgis-/- 小鼠高血压的发生和血管重塑，尽管它在很大程度上抑制了血浆 TxB2 （TxA2 代谢物） 水平的增加。结论 我们的研究表明，当 PGIS 缺乏时，非 TxA2 前列腺素类/TP 轴在介导 EDC 和心血管疾病的增加中起着至关重要的作用，这表明 TP 是与 PGIS 功能不全相关的疾病的一个有前途的治疗靶点。