Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
Bio-Analytical Laboratory (H. Li, Yongyin Zhou, H. Luo, W.L.), Shantou University Medical College, China.
Circ Res. 2024 Aug 30;135(6):e133-e149. doi: 10.1161/CIRCRESAHA.124.324924. Epub 2024 Jul 31.
Prostaglandin I synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.
Experiments were performed with wild-type, knockout () and /thromboxane-prostanoid receptor gene () double knockout () mice and mice transplanted with unfractionated wild-type or 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.
PGF, PGE, and a trace amount of PGD, but not thromboxane A (TxA), were produced in response to acetylcholine in 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 aortas. 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 (TxA receptor) not only restrained EDC and the downregulation of NO signaling in mice but also ameliorated the cardiovascular abnormalities. Stimulation of vessels with acetylcholine in the presence of platelets led to increased TxA generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in mice though it largely suppressed the increase of plasma TxB (TxA metabolite) level.
Our study demonstrates that the non-TxA 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.
内皮细胞合成的前列腺素 I 通过环氧化酶（COX）引起某些血管强烈舒张，但在其他血管中却引起内皮依赖性收缩（EDC），这种现象令人费解。PGIS 缺乏如何影响 EDC，以及由此导致的心血管病变，目前尚不完全清楚。
本研究使用野生型、PGIS 基因敲除（）和血栓素 A（TxA）-前列腺素受体基因双敲除（）小鼠以及骨髓细胞未分离的野生型或 PGIS 基因敲除（）骨髓细胞移植小鼠和人脐动脉进行实验。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。监测不同年龄的小鼠高血压、血管重塑和心脏肥大的参数。
PGF2、PGE2 和痕量的 PGD2，但不是 TxA2，在乙酰胆碱刺激下在或 PGIS 抑制的动脉中产生。PGIS 缺乏导致体外和体内 EDC 的加重或发生。内皮依赖性超极化没有改变，但 eNOS（内皮型一氧化氮合酶）Ser1177 和 Thr495 的磷酸化水平发生改变，乙酰胆碱诱导的 NO 产生和 NO 依赖性舒张明显减少。PGIS 缺乏的主动脉。16-17 周时，小鼠发生高血压和血管重塑，24-26 周时发生心脏肥大。同时，8-10 周时血压和心脏参数仍正常。TP（TxA 受体）的额外消融不仅抑制了的 EDC 和 NO 信号转导的下调，还改善了心血管异常。在血小板存在的情况下，用乙酰胆碱刺激的血管生成增加了 TxA 的产生。骨髓细胞中 COX-1 的破坏虽然大大抑制了血浆 TxB（TxA 代谢物）水平的升高，但并未影响 PGIS 缺乏小鼠高血压和血管重塑的发展。
我们的研究表明，当 PGIS 缺乏时，非 TxA 前列腺素/TP 轴在介导 EDC 增强和心血管疾病中起重要作用，提示 TP 可能是与 PGIS 不足相关疾病的有希望的治疗靶点。
