Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
Department of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, China.
Reprod Sci. 2019 Dec;26(12):1590-1602. doi: 10.1177/1933719119831775. Epub 2019 Feb 26.
The transfer of long noncoding RNAs (lncRNAs) via exosomes to modulate recipient cells represents an important mechanism for disease progression. Antisense hypoxia-inducible factor (aHIF) is a well-known angiogenesis-related lncRNA. Here, we aimed to investigate the clinical implications of aHIF and exosomal aHIF in endometriosis and the involvement of exosome-shuttled aHIF in endometriosis angiogenesis.
The distribution and expression of aHIF in ectopic, eutopic, and normal endometria was evaluated. Serum exosomal aHIF levels in patients with endometriosis were tested. The correlation between serum exosomal aHIF and aHIF expression in ectopic endometria was analyzed. Endometriotic cyst stromal cells (ECSCs)-derived exosomes were characterized. The internalization of exosomes by human umbilical vein endothelial cells (HUVECs) was observed. A series of in vitro assays were conducted to investigate the roles and mechanisms of exosomal aHIF in endometriosis angiogenesis.
Clinically, aHIF was highly expressed in ectopic endometria and serum exosomes in patients with endometriosis. Serum exosomal aHIF was significantly correlated to aHIF expression in matched ectopic endometria. In vitro, PKH67-labeled exosomes derived from aHIF high expression ECSCs were effectively internalized by recipient HUVECs. Notably, exosome-shuttled aHIF was transferred from ECSCs to HUVECs, which in turn elicited proangiogenic behavior in HUVECs by activating vascular endothelial growth factor (VEGF)-A, VEGF-D, and basic fibroblast growth factor, thereby facilitating endometriosis angiogenesis.
Our study illustrates a potential cell-cell communication between ECSCs and HUVECs in an ectopic environment, provides a novel mechanistic model explaining how ECSCs induce angiogenesis from the perspective of the "exosomal transfer of aHIF," and highlights the clinical value of circulating exosomal aHIF in endometriosis.
长链非编码 RNA（lncRNA）通过外泌体转移来调节受体细胞，这是疾病进展的一个重要机制。反义低氧诱导因子（aHIF）是一种众所周知的血管生成相关 lncRNA。在这里，我们旨在研究 aHIF 和外泌体 aHIF 在子宫内膜异位症中的临床意义，以及外泌体穿梭 aHIF 在子宫内膜异位症血管生成中的作用。
评估 aHIF 在异位、在位和正常子宫内膜中的分布和表达。检测子宫内膜异位症患者血清外泌体 aHIF 水平。分析血清外泌体 aHIF 与异位子宫内膜中 aHIF 表达的相关性。对子宫内膜异位症囊肿基质细胞（ECSCs）衍生的外泌体进行特征分析。观察人脐静脉内皮细胞（HUVEC）对 exosomes 的内化。进行一系列体外实验，以研究外泌体 aHIF 在子宫内膜异位症血管生成中的作用和机制。
临床上，aHIF 在子宫内膜异位症患者的异位子宫内膜和血清外泌体中高表达。血清外泌体 aHIF 与配对异位子宫内膜中 aHIF 表达显著相关。在体外，来自 aHIF 高表达 ECSCs 的 PKH67 标记的 exosomes 被受体 HUVECs 有效内化。值得注意的是，外泌体转运的 aHIF 从 ECSCs 转移到 HUVECs，从而通过激活血管内皮生长因子（VEGF）-A、VEGF-D 和碱性成纤维细胞生长因子，使 HUVECs 产生促血管生成行为，从而促进子宫内膜异位症的血管生成。
本研究说明了在异位环境中 ECSCs 和 HUVECs 之间存在一种潜在的细胞间通讯，提供了一种新的机制模型，从“外泌体转移 aHIF”的角度解释了 ECSCs 如何诱导血管生成，并强调了循环外泌体 aHIF 在子宫内膜异位症中的临床价值。
