Elabela-APJ axis mediates angiogenesis via YAP/TAZ pathway in cerebral ischemia/reperfusion injury

Angiogenesis helps to improve neurological recovery by repairing damaged brain tissue and restoring cerebral blood flow (CBF). The role of the Elabela (ELA)-Apelin receptor (APJ) system in angiogenesis has gained much attention. We aimed to investigate the function of endothelial ELA on post-ischemic cerebral angiogenesis. Here, we demonstrated that the endothelial ELA expression was upregulated in the ischemic brain and treatment with ELA-32 mitigated brain injury and enhanced the restoration of CBF and newly formed functional vessels following cerebral ischemia/reperfusion (I/R) injury. Furthermore, ELA-32 incubation potentiated proliferation, migration, and tube formation abilities of the mouse brain endothelial cells (bEnd.3 cells) under oxygen-glucose depriva-tion/reoxygenation (OGD/R) condition. RNA sequencing analysis indicated that ELA-32 incubation had a role in the Hippo signaling pathway, and improved angiogenesis-related gene expression in OGD/R-exposed bEnd.3 cells. Mechanistically, we depicted that ELA could bind to APJ and subsequently activate YAP/TAZ signaling pathway. Silence of APJ or pharmacological blockade of YAP abolished the pro-angiogenesis effects of ELA-32. Together, these findings highlight the ELA-APJ axis as a potential therapeutic strategy for ischemic stroke by showing how activation of this pathway promotes post-stroke angiogenesis.

Automated summary

This study investigated the role of endothelial Elabela (ELA) in post-ischemic cerebral angiogenesis. The research found that treatment with ELA-32 could mitigate brain injury, enhance restoration of cerebral blood flow, and promote the formation of functional vessels after cerebral ischemia/reperfusion (I/R) injury. Furthermore, it was demonstrated that ELA-32 could enhance the proliferation, migration, and tube formation abilities of brain endothelial cells under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Mechanistically, ELA was found to bind to Apelin receptor (APJ) and activate the YAP/TAZ signaling pathway. Silencing APJ or pharmacological blockade of YAP abolished the pro-angiogenesis effects of ELA-32. Overall, these findings highlight the potential therapeutic strategy of the ELA-APJ axis in ischemic stroke.