Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs.
Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs.
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DOI：
10.3390/antiox13010078
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发表时间：
2024-01-08
期刊：
影响因子：
7
通讯作者：
Liu, Jiankang
中科院分区：
文献类型：
--
作者：
Thapa, Shyam;Shankar, Nithyapriya;Shrestha, Amrit Kumar;Civunigunta, Monish;Gaikwad, Amos S.;Shivanna, Binoy;Liu, Jiankang
中断的肺血管生成是支气管肺发育不良（BPD）的标志;然而，可以挽救这种表型的药物靶点仍然难以捉摸。因此，我们的研究集中在双调蛋白（Areg），一种介导细胞增殖，分化，迁移，存活和修复的生长因子。虽然Areg促进肺分支形态发生，但其对发育中肺的内皮细胞（EC）稳态的影响尚未得到充分研究。因此，我们假设Areg促进了暴露于高氧的小鼠肺发育中EC的促血管生成能力。从暴露于常氧或高氧的新生小鼠收获肺组织以确定Areg表达。接下来，我们在常氧和高氧暴露的胎鼠肺EC中进行了遗传功能丧失和药理学功能获得的研究。高氧可增加全肺Areg mRNA水平和Areg+细胞。当暴露于高氧的肺EC中Areg表达增加时，其信号受体表皮生长因子受体的表达降低，表明高氧降低肺EC中Areg信号传导。Areg缺乏增强高氧介导的抗血管生成作用。与此相反，Areg治疗增加细胞外信号调节激酶激活，并发挥促血管生成作用。总之，Areg促进了暴露于高氧的小鼠肺发育中EC小管的形成。
Interrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, survival, and repair. While Areg promotes lung branching morphogenesis, its effect on endothelial cell (EC) homeostasis in developing lungs is understudied. Therefore, we hypothesized that Areg promotes the proangiogenic ability of the ECs in developing murine lungs exposed to hyperoxia. Lung tissues were harvested from neonatal mice exposed to normoxia or hyperoxia to determine Areg expression. Next, we performed genetic loss-of-function and pharmacological gain-of-function studies in normoxia- and hyperoxia-exposed fetal murine lung ECs. Hyperoxia increased Areg mRNA levels and Areg+ cells in whole lungs. While Areg expression was increased in lung ECs exposed to hyperoxia, the expression of its signaling receptor, epidermal growth factor receptor, was decreased, indicating that hyperoxia reduces Areg signaling in lung ECs. Areg deficiency potentiated hyperoxia-mediated anti-angiogenic effects. In contrast, Areg treatment increased extracellular signal-regulated kinase activation and exerted proangiogenic effects. In conclusion, Areg promotes EC tubule formation in developing murine lungs exposed to hyperoxia.
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