Long noncoding RNA Gpr137b-ps mediates 15-PGDH-induced angiogenesis in brain microvasculature following tMCAO in mice

Abstract

Background Angiogenesis is essential for recovery following ischemic stroke, as brain microvascular endothelial cells (BMVECs) drive vascular repair. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a major regulator of endothelial function in some vascular contexts, but it is unknown whether 15-PGDH plays a significant role in angiogenesis following stroke. Notably, based on preliminary bioinformatics prediction of their 3’UTR interaction, we hypothesize that Gpr137b-ps—a pseudogene-derived lncRNA originating from Gpr137b—forms a regulatory link with 15-PGDH to modulate this process (i.e., post-stroke angiogenesis) by regulating 15-PGDH expression, though its specific functional mechanism in this context remains largely unknown. Methods To address this gap, we used mouse middle cerebral artery occlusion (MCAO) model in vivo and BMVEC oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. We modulated 15-PGDH via siRNA and Gpr137b-ps via mimics, and assessed angiogenesis using migration, tube formation, and cell-cycle assays, with expression and localization of key molecules verified by standard molecular techniques. Results Both MCAO and OGD/R successfully induced ischemia, with significant upregulation of 15-PGDH and Gpr137b-ps in ischemic tissues and BMVECs (P < 0.05). Despite this concurrent upregulation, 15-PGDH promoted angiogenesis (silencing reduced BMVEC proliferation, migration, and tube formation; P < 0.01), whereas Gpr137b-ps overexpression suppressed 15-PGDH protein levels and inhibited angiogenesis—effects that were rescued by re-expressing 15-PGDH. Conclusion Together, our findings identify Gpr137b-ps/15-PGDH as a key feedback regulatory axis: while both Gpr137b-ps and 15-PGDH are upregulated under ischemia, Gpr137b-ps (a negative regulator of angiogenesis) suppresses 15-PGDH (a pro-angiogenic factor) to repress excessive post-stroke angiogenesis via inhibiting BMVEC proliferation, migration, and cell-cycle progression. The data support an association and partial dependency between this axis and angiogenic processes, highlighting it as a potential therapeutic target (e.g., via inhibiting Gpr137b-ps) for vascular repair after ischemic stroke.