Epas1, also known as HIF2A, is a transcription factor that belongs to the hypoxia-inducible factor (HIF) family. HIFs are key regulators of the adaptive response to hypoxia, with Epas1 having both unique and overlapping functions in the regulation of diverse cellular processes [2]. It is involved in various pathways, such as those related to oxygen homeostasis, fatty acid metabolism, and cell proliferation, and is of great biological importance in processes like angiogenesis, cell survival, and response to hypoxic stress. Genetic models, especially KO/CKO mouse models, can be valuable in studying its functions.

In atherosclerosis, endothelial Epas1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Epas1 protects arteries by maintaining endothelial proliferation through positive regulation of fatty acid-handling molecules to increase fatty acid beta-oxidation [1]. In chronic mountain sickness, EPAS1 expression in bone marrow erythroblasts of patients was higher than that of controls. Over-expressing EPAS1 in K562 cells accelerated the erythroid cell cycle and promoted proliferation, suggesting EPAS1 might be involved in the pathogenesis of excessive erythrocytosis [3]. In papillary thyroid carcinoma, higher EPAS1/HIF-2α mRNA expression was associated with lower N and M stages, better progression-free and disease-free time. It was mainly involved in the PI3K-Akt signaling pathway, promoted CD8+ T cell infiltration, and inhibited PD-L1 expression, playing a tumor-suppressive role [4]. In clear cell renal cell carcinoma, atractylenolide I promoted autophagic degradation of EPAS1/HIF2α by upregulating ATP6V0D2, inhibiting angiogenesis and reversing sunitinib resistance [5].

In conclusion, Epas1 plays essential roles in multiple biological processes. Model-based research, especially through KO/CKO mouse models in atherosclerosis, has revealed its atheroprotective function. In diseases like chronic mountain sickness, papillary thyroid carcinoma, and clear cell renal cell carcinoma, Epas1 is also involved in disease-related cellular processes, highlighting its significance in understanding these disease mechanisms.

References:

1. Pirri, Daniela, Tian, Siyu, Tardajos-Ayllon, Blanca, Fragiadaki, Maria, Evans, Paul C. 2024. EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake. In Circulation research, 135, 822-837. doi:10.1161/CIRCRESAHA.123.324054. https://pubmed.ncbi.nlm.nih.gov/39234692/

2. Schönenberger, Miriam J, Krek, Wilhelm, Kovacs, Werner J. . EPAS1/HIF-2α is a driver of mammalian pexophagy. In Autophagy, 11, 967-9. doi:10.1080/15548627.2015.1045180. https://pubmed.ncbi.nlm.nih.gov/25997392/

3. Liu, Huihui, Tang, Feng, Su, Juan, Ge, Ri-Li, Li, Zhanquan. 2020. EPAS1 regulates proliferation of erythroblasts in chronic mountain sickness. In Blood cells, molecules & diseases, 84, 102446. doi:10.1016/j.bcmd.2020.102446. https://pubmed.ncbi.nlm.nih.gov/32470757/

4. Zhang, Rui, Zhao, Jianguo, Zhao, Lu. 2023. EPAS1/HIF-2α Acts as an Unanticipated Tumor-Suppressive Role in Papillary Thyroid Carcinoma. In International journal of general medicine, 16, 2165-2174. doi:10.2147/IJGM.S409874. https://pubmed.ncbi.nlm.nih.gov/37284036/

5. Li, Qinyu, Zeng, Kai, Chen, Qian, Yuan, Xianglin, Liu, Bo. 2024. Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α. In Autophagy, 21, 619-638. doi:10.1080/15548627.2024.2421699. https://pubmed.ncbi.nlm.nih.gov/39477683/