Endothelial miR-7052 Safeguards Blood-Brain Barrier Integrity During Endotoxemia by Co-repressing ANGPT2 and PDE5A

Sepsis-associated inflammation compromises the blood-brain barrier (BBB), yet the endothelial microRNA circuitry that buffers barrier failure remains poorly defined. Here we identify endothelial miR-7052 as a stress-suppressed regulator of BBB integrity. In human and murine brain microvascular endothelium, lipopolysaccharide (LPS) reduces mature miR-7052 via a VEGFR2-JNK signaling arm. Loss of miR-7052 de-represses ANGPT2 and PDE5A, attenuates Tie2 signaling, and perturbs cGMP homeostasis, yielding disrupted junctional continuity, reduced transendothelial electrical resistance (TEER), and increased macromolecular flux. Restoring miR-7052 increases TEER, lowers 4- and 70-kDa tracer permeability, and preserves ZO-1/claudin-5 organization. Mechanistically, dual-luciferase reporters confirm direct repression of ANGPT2 and PDE5A; prime-editing of endogenous 3'UTR seed sites abolishes miR-7052 control and eliminates miR-dependent changes in transcript half-life. Epistasis tests position both targets downstream: recombinant ANGPT2 partially reverses miR-7052-mediated protection, whereas pharmacological PDE5 inhibition phenocopies barrier stabilization. In vivo, endothelial-specific AAV9 delivery of miR-7052 limits LPS-evoked BBB leakage and reduces microvessel ANGPT2 with concordant reinforcement of BBB transcripts. Together, these data establish miR-7052 as a nodal controller coupling inflammatory receptor input to multi-target suppression of permeability drivers, nominating miR-7052 replacement and combinatorial targeting of the ANGPT2/Tie2 and PDE5A/cGMP axes as therapeutic strategies to preserve the BBB in sepsis.