Essential role of prostaglandin E2 and the EP3 receptor in lymphatic vessel development during zebrafish embryogenesis
Essential role of prostaglandin E2 and the EP3 receptor in lymphatic vessel development during zebrafish embryogenesis
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DOI：
10.1038/s41598-019-44095-5
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发表时间：
2019-05
影响因子：
4.6
通讯作者：
R. Iwasaki;Kyoshiro Tsuge;Koichiro Kishimoto;Y. Hayashi;Takuya Iwaana;H. Hohjoh;Tomoaki Inazumi
中科院分区：
文献类型：
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作者：
R. Iwasaki;Kyoshiro Tsuge;Koichiro Kishimoto;Y. Hayashi;Takuya Iwaana;H. Hohjoh;Tomoaki Inazumi
淋巴管内皮细胞起源于胚胎淋巴管发育中的静脉内皮细胞。然而，其分子机制仍有待阐明。本文报道了前列腺素E_2（PGE_2）受体之一的EP_3受体在胚胎淋巴管发育中的重要作用。敲低EP 3受体或抑制环氧合酶（考克斯; PG合成的限速酶）通过扰乱斑马鱼发育过程中的淋巴特异性而损害淋巴发育。这些由考克斯抑制引起的损害可通过磺前列酮（EP 1/3激动剂）治疗恢复。EP 3受体的敲除进一步证明了其对性别决定区Y-box 18（sox 18）和核受体亚家族2、F组成员2（nr 2f 2）（淋巴特异性的必需因子）的表达的需要。EP 3受体表达于后主静脉（胚胎淋巴发育区域）和邻近的中间细胞团（ICM）在淋巴规范。COX 1表达在相对于EP 3受体的后主静脉更上游的区域，COX 1选择性抑制剂损害了淋巴特异性。另一方面，两种COX 2亚型在EP 3受体表达区域周围没有显示出不同的表达位点。最后，我们产生了EP 3缺陷的斑马鱼，这也表现出缺陷的淋巴规范和发展。因此，我们证明了COX 1衍生的PGE 2-EP 3通路是胚胎淋巴发育所必需的，通过上调淋巴特异性关键因子的表达。
Lymphatic endothelial cells arise from the venous endothelial cells in embryonic lymphatic development. However, the molecular mechanisms remain to be elucidated. We here report that prostaglandin (PG) E2plays essential roles in the embryonic lymphatic development through the EP3 receptor, one of the PGE2receptors. Knockdown of the EP3 receptor or inhibition of cyclooxygenases (COX; rate-limiting enzymes for PG synthesis) impaired lymphatic development by perturbing lymphatic specification during zebrafish development. These impairments by COX inhibition were recovered by treatment with sulprostone (EP1/3 agonist). Knockdown of the EP3 receptor further demonstrated its requirement in the expression of sex determining region Y-box 18 (sox18) and nuclear receptor subfamily 2, group F, member 2 (nr2f2), essential factors of the lymphatic specification. The EP3 receptor was expressed in the posterior cardinal vein (region of embryonic lymphatic development) and the adjacent intermediate cell mass (ICM) during the lymphatic specification. COX1 was expressed in the region more upstream of the posterior cardinal vein relative to the EP3 receptor, and the COX1-selective inhibitor impaired the lymphatic specification. On the other hand, two COX2 subtypes did not show distinct sites of expression around the region of expression of the EP3 receptor. Finally, we generated EP3-deficient zebrafish, which also showed defect in lymphatic specification and development. Thus, we demonstrated that COX1-derived PGE2-EP3 pathway is required for embryonic lymphatic development by upregulating the expression of key factors for the lymphatic specification.