By activating prostacyclin receptors (IP receptors), prostacyclin (PGI₂) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI₂ produces detrimental effects that are opposite to its physiological protective effects via thromboxane‐prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI₂ action. Methods: The effects of PGI₂ and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR‐Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IP^R212C. Results: PGI₂/iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI₂/iloprost promotes VSMC phenotypic transformation in IP‐deficient cells. The effect of PGI₂/iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI₂ is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane. Conclusion: PGI₂ induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI₂ medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases.

中文翻译：

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当 IP 受体缺乏时，前列环素通过激活 TP 受体促进血管平滑肌细胞表型转化。

通过激活前列环素受体 (IP 受体)，前列环素 (PGI ₂ ) 发挥心血管保护作用，例如血管舒张和抑制血管平滑肌细胞 (VSMC) 增殖。然而，IP 受体在病理条件下功能失调，PGI ₂通过血栓素-前列腺素 (TP) 受体产生与其生理保护作用相反的有害作用。这试图研究 IP 受体功能障碍是否促进 PGI ₂作用的转变。方法：PGI ₂的影响在沉默 IP 受体的 A10 细胞、通过 CRISPR-Cas9 敲低 IP 受体的人主动脉 VSMC (HAVSMC) 或转染了 IP 受体 IP ^R212C功能失调突变的 HAVSMC 中，研究了伊洛前列素及其稳定的类似物伊洛前列素对 VSMC 表型转化和增殖的^影响。结果：PGI ₂ /伊洛前列素处理刺激细胞增殖，上调合成蛋白和下调收缩蛋白，表明 PGI ₂ /伊洛前列素促进 IP 缺陷细胞中的 VSMC 表型转化。PGI ₂ /伊洛前列素的作用被TP拮抗剂S18886或TP敲低阻止，表明PGI ₂的VSMC有害作用依赖于 TP 受体。RNA 测序和蛋白质印迹结果表明 RhoA/ROCKs、MEK1/2 和 JNK 信号级联反应参与其中。此外，IP 缺乏增加了 TP 受体在细胞膜上的分布。结论：当 IP 受体受损时，PGI ₂诱导 VSMC 表型转化。这归因于 TP 受体及其下游信号级联的激活，以及 TP 受体的膜分布增加。由 IP 功能障碍和 TP 激活引起的 PGI ₂对 VSMC 的不利影响可能会加剧血管重塑，加速心血管疾病。