Hypoxia‐Induced KDM3A Binding With AP‐1 Promotes Angiogenesis by Mediating ANGPT2 in the Development of Small Bowel Angiodysplasia

BACKGROUND AND AIMS: Small bowel angiodysplasia (SBAD) is the leading cause of small bowel hemorrhage, with recurrent lesions that severely affect the lives of patients. Pathological angiogenesis induced by chronic hypoxia is a key component in the pathogenesis of SBAD, but the underlying epigenetic mechanisms remain unclear. METHODS: KDM3A expression was evaluated in SBAD specimens by immunohistochemistry. Functional studies in human umbilical vein endothelial cells (HUVECs) under hypoxia included migration, invasion, and tube formation assays. RNA sequencing and chromatin immunoprecipitation identified downstream targets and mechanisms. In vivo angiogenesis was assessed using Matrigel plug assays. The KDM3A inhibitor IOX1 was evaluated for therapeutic potential. RESULTS: We found KDM3A is induced by hypoxia and overexpressed in malformed vessels compared to normal vessels in patients with SBAD. By downregulating or overexpressing KDM3A in endothelial cells and observing changes in cell functions through in vitro and in vivo experiments, we found that KDM3A can affect angiogenesis under hypoxia. Mechanistic studies showed that KDM3A can bind to AP-1 under hypoxia and act on the promoter region of the proangiogenic factor ANGPT2 to promote the transcriptional expression, thereby affecting the angiogenic function of endothelial cells. In addition, we found that the KDM3A inhibitor IOX1 exerted a significant antiangiogenic effect during hypoxia. CONCLUSION: KDM3A/AP-1-ANGPT2 axis plays an important role in the pathogenesis of SBAD and is expected to be a new therapeutic target for SBAD.