The Exosomal Long Noncoding RNA aHIF is Upregulated in Serum From Patients With Endometriosis and Promotes Angiogenesis
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The Exosomal Long Noncoding RNA aHIF is Upregulated in Serum From Patients With Endometriosis and Promotes Angiogenesis in Endometriosis
Reproductive Sciences 1-13 ª The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1933719119831775 journals.sagepub.com/home/rsx
Jun-Jun Qiu, PhD1,2,3, Xiao-Jing Lin, MD1,2,3, Ting-Ting Zheng, PhD1,2,3, Xiao-Yan Tang, PhD1,2,3, Ying Zhang, PhD1,2,3, and Ke-Qin Hua, PhD1,2,3
Abstract Objective: 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. Study Design: 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. Results: 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. Conclusion: 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. Keywords exosome, circulating exosomal aHIF, intercellular communication, angiogenesis, endometriosis
Introduction Endometriosis, which is characterized by the ectopic presence of endometrial tissue and glands outside the uterine cavity, is a prevalent gynecological disease with high incidence and recurrence rates.1 It affects approximately 10% of reproductive-aged women, and up to 50% of affected patients suffer from endometriosis-related pain and/or infertility, resulting in a dramatic reduction in quality of life.2 Although various theories have been put forward to explain the etiology of endometriosis, its exact causative mechanism
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