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ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia.
Am J Physiol Cell Physiol 2019; 316(4):C481-C491AJ

Abstract

The inadequate trophoblast invasion is associated with the development of preeclampsia (PE). Considering that annexin A4 (ANXA4) enhances tumor invasion, we aimed to explore the functional role of ANXA4 in trophoblast cells and to examine the underlying mechanism. ANXA4 expression in PE placentas was analyzed using immunohistochemistry and Western blotting. Cell proliferation, invasion, and apoptosis were determined using a MTT assay, Transwell assay, and flow cytometry, respectively. The expression levels of matrix metalloproteinase (MMP)-2, MMP-9, phosphoinositide 3-kinase (PI3K), Akt, phosphorylated (p)-Akt, and phosphorylated endothelial nitric oxide synthase (p-eNOS) were detected by Western blotting. Placentas were prepared for pathological examination using hematoxylin and eosin staining and apoptosis determination using the TUNEL method. Expression of ANXA4, PI3K, p-Akt and p-eNOS was downregulated in human PE placentas and PE placenta-derived extravillous cytotrophoblasts (EVCTs). Furthermore, ANXA4 overexpression promoted cell proliferation and invasion, inhibited cell apoptosis, and upregulated protein expression of PI3K, p-Akt, and p-eNOS in human trophoblast cells HTR-8/SVneo and JEG-3. By contrast, ANXA4 knockdown exerted the opposite effects. Furthermore, inhibition of the PI3K/Akt pathway by LY294002 abrogated the ANXA4 overexpression-mediated effects on trophoblast behavior. Furthermore, eNOS knockdown abrogated the ANXA4 overexpression-induced promotion of cell invasion and MMP2/9 expression. Additionally, in N-nitro-l-arginine methyl ester (l-NAME)-induced PE rats, ANXA4 overexpression alleviated PE progression, accompanied by an increase in expression of PI3K, p-Akt, and p-eNOS in rat placentas. Our findings demonstrate that ANXA4 expression is downregulated in PE. ANXA4 may promote trophoblast invasion via the PI3K/Akt/eNOS pathway.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, Peking University People's Hospital , Beijing , China.Department of Obstetrics and Gynecology, China-Japan Friendship Hospital , Beijing , China.Central Laboratory, Peking Union Medical College Hospital , Beijing , China.Department of Obstetrics and Gynecology, Peking University People's Hospital , Beijing , China.Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.Department of Obstetrics and Gynecology, Peking University People's Hospital , Beijing , China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30673304

Citation

Xu, Yalan, et al. "ANXA4 Promotes Trophoblast Invasion Via the PI3K/Akt/eNOS Pathway in Preeclampsia." American Journal of Physiology. Cell Physiology, vol. 316, no. 4, 2019, pp. C481-C491.
Xu Y, Sui L, Qiu B, et al. ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia. Am J Physiol, Cell Physiol. 2019;316(4):C481-C491.
Xu, Y., Sui, L., Qiu, B., Yin, X., Liu, J., & Zhang, X. (2019). ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia. American Journal of Physiology. Cell Physiology, 316(4), pp. C481-C491. doi:10.1152/ajpcell.00404.2018.
Xu Y, et al. ANXA4 Promotes Trophoblast Invasion Via the PI3K/Akt/eNOS Pathway in Preeclampsia. Am J Physiol, Cell Physiol. 2019 04 1;316(4):C481-C491. PubMed PMID: 30673304.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia. AU - Xu,Yalan, AU - Sui,Lili, AU - Qiu,Bintao, AU - Yin,Xiuju, AU - Liu,Juntao, AU - Zhang,Xiaohong, Y1 - 2019/01/23/ PY - 2019/1/24/pubmed PY - 2019/12/25/medline PY - 2019/1/24/entrez KW - PI3K/Akt/eNOS pathway KW - annexin A4 KW - invasion KW - preeclampsia KW - trophoblast SP - C481 EP - C491 JF - American journal of physiology. Cell physiology JO - Am. J. Physiol., Cell Physiol. VL - 316 IS - 4 N2 - The inadequate trophoblast invasion is associated with the development of preeclampsia (PE). Considering that annexin A4 (ANXA4) enhances tumor invasion, we aimed to explore the functional role of ANXA4 in trophoblast cells and to examine the underlying mechanism. ANXA4 expression in PE placentas was analyzed using immunohistochemistry and Western blotting. Cell proliferation, invasion, and apoptosis were determined using a MTT assay, Transwell assay, and flow cytometry, respectively. The expression levels of matrix metalloproteinase (MMP)-2, MMP-9, phosphoinositide 3-kinase (PI3K), Akt, phosphorylated (p)-Akt, and phosphorylated endothelial nitric oxide synthase (p-eNOS) were detected by Western blotting. Placentas were prepared for pathological examination using hematoxylin and eosin staining and apoptosis determination using the TUNEL method. Expression of ANXA4, PI3K, p-Akt and p-eNOS was downregulated in human PE placentas and PE placenta-derived extravillous cytotrophoblasts (EVCTs). Furthermore, ANXA4 overexpression promoted cell proliferation and invasion, inhibited cell apoptosis, and upregulated protein expression of PI3K, p-Akt, and p-eNOS in human trophoblast cells HTR-8/SVneo and JEG-3. By contrast, ANXA4 knockdown exerted the opposite effects. Furthermore, inhibition of the PI3K/Akt pathway by LY294002 abrogated the ANXA4 overexpression-mediated effects on trophoblast behavior. Furthermore, eNOS knockdown abrogated the ANXA4 overexpression-induced promotion of cell invasion and MMP2/9 expression. Additionally, in N-nitro-l-arginine methyl ester (l-NAME)-induced PE rats, ANXA4 overexpression alleviated PE progression, accompanied by an increase in expression of PI3K, p-Akt, and p-eNOS in rat placentas. Our findings demonstrate that ANXA4 expression is downregulated in PE. ANXA4 may promote trophoblast invasion via the PI3K/Akt/eNOS pathway. SN - 1522-1563 UR - https://www.unboundmedicine.com/medline/citation/30673304/ANXA4_promotes_trophoblast_invasion_via_the_PI3K/Akt/eNOS_pathway_in_preeclampsia_ L2 - http://www.physiology.org/doi/full/10.1152/ajpcell.00404.2018?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -