AT2R activation increases in vitro angiogenesis in pregnant human uterine artery endothelial cells.
AT2R activation increases in vitro angiogenesis in pregnant human uterine artery endothelial cells.
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DOI：
10.1371/journal.pone.0267826
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发表时间：
2022
期刊：
影响因子：
3.7
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中科院分区：
文献类型：
--
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血管生成在妊娠期间对于重塑和增强母体子宫动脉的血管舒张以及增加子宫血流是至关重要的。异常血管生成与子宫胎盘血流减少和妊娠疾病的发展相关，如妊娠期高血压、先兆子痫、胎儿生长受限、早产、死产和流产。促进正常血管生成的机制仍然不清楚。我们以前的研究表明，血管紧张素2型受体（AT 2 R）的表达增加，而血管紧张素1型受体（AT 1 R）是不变的子宫动脉内皮细胞，AT 2 R介导的妊娠适应促进增强血管舒张和子宫动脉血流。然而，AT 2 R在妊娠期间调节血管生成中的作用从未被研究过。本研究探讨是否AT 2 R激活诱导血管生成，如果是这样，涉及的机制是什么。为此，我们使用原代人子宫动脉内皮细胞（hUAEC）分离的孕妇和非孕妇接受子宫切除术。本研究表明，化合物21，一种选择性AT 2 R激动剂，以浓度依赖性方式诱导妊娠hUAEC的增殖，但不诱导非妊娠hUAEC的增殖，并且这种C21诱导的促有丝分裂作用被PD 123319阻断，PD 123319是一种选择性AT 2 R拮抗剂。C21诱导的促有丝分裂作用可通过阻断JNK信号通路而非ERK、PI 3 K和p38信号通路来抑制。此外，C21浓度依赖性地增加妊娠hUAEC中的细胞迁移和毛细血管样管形成。基于膜的抗体阵列显示，C21增加多种血管生成蛋白的表达，包括EGF、bFGF、瘦素、PLGF、IGF-1和血管生成素。我们的qPCR分析表明，C21诱导的这些血管生成蛋白表达的增加与mRNA表达的成比例增加相关，表明AT 2 R在转录水平上激活血管生成蛋白。总之，本研究表明，AT 2 R激活诱导血管生成的hUAEC在妊娠特异性的方式通过JNK介导的途径与相关的转录上调多种促血管生成蛋白。
Angiogenesis is vital during pregnancy for remodeling and enhancing vasodilation of maternal uterine arteries, and increasing uterine blood flow. Abnormal angiogenesis is associated with decreased uteroplacental blood flow and development of pregnancy disorders such as gestational hypertension, preeclampsia, fetal growth restriction, preterm delivery, stillbirth, and miscarriage. The mechanisms that contribute to normal angiogenesis remain obscure. Our previous studies demonstrated that expression of the angiotensin type 2 receptor (AT2R) is increased while the angiotensin type 1 receptor (AT1R) is unchanged in the endothelium of uterine arteries, and that AT2R-mediated pregnancy adaptation facilitates enhanced vasodilation and uterine arterial blood flow. However, the role of AT2R in regulating angiogenesis during pregnancy has never been studied. This study examines whether or not AT2R activation induces angiogenesis and, if so, what mechanisms are involved. To this end, we used primary human uterine artery endothelial cells (hUAECs) isolated from pregnant and nonpregnant women undergoing hysterectomy. The present study shows that Compound 21, a selective AT2R agonist, induced proliferation of pregnant-hUAECs, but not nonpregnant-hUAECs, in a concentration-dependent manner, and that this C21-induced mitogenic effect was blocked by PD123319, a selective AT2R antagonist. The mitogenic effects induced by C21 were inhibited by blocking JNK—but not ERK, PI3K, and p38—signaling pathways. In addition, C21 concentration dependently increased cell migration and capillary-like tube formation in pregnant-hUAECs. The membrane-based antibody array showed that C21 increased expression of multiple angiogenic proteins, including EGF, bFGF, leptin, PLGF, IGF-1, and angiopoietins. Our qPCR analysis demonstrates that C21-induced increase in expression of these angiogenic proteins correlates with a proportional increase in mRNA expression, indicating that AT2R activates angiogenic proteins at the transcriptional level. In summary, the present study shows that AT2R activation induces angiogenesis of hUAECs in a pregnancy-specific manner through JNK-mediated pathways with associated transcriptional upregulation of multiple proangiogenic proteins.
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影响因子：
3.7
作者：
Du H;Liang Z;Zhang Y;Jie F;Li J;Fei Y;Huang Z;Pei N;Wang S;Li A;Chen B;Zhang Y;Sumners C;Li M;Li H
通讯作者：
Li H
影响因子：
4.8
作者：
Bird, IM;Sullivan, JA;Magness, RR
通讯作者：
Magness, RR
影响因子：
8.3
作者：
Mirabito, Katrina M.;Hilliard, Lucinda M.;Denton, Kate M.
通讯作者：
Denton, Kate M.
影响因子：
82.9
作者：
Carmeliet, P;Moons, L;Persico, MG
通讯作者：
Persico, MG
影响因子：
4.1
作者：
Grummer, Mary A.;Sullivan, Jeremy A.;Bird, Ian M.
通讯作者：
Bird, Ian M.