Abstract Body:
Introduction: Radial injury to the coronary arteries due to chronic systemic hypertension or acute balloon inflation during PCI induces perivascular inflammation and remodeling. In mice, transverse aortic constriction (TAC) increases coronary pressure, radial stretch, and mechanical injury. The cellular and molecular response to radial coronary injury remains undefined.

Hypothesis: Radial mechanical stretch of coronary arteries induces a pathologic type I interferon response that drives perivascular inflammation and represents a therapeutic target.

Methods: Adult male C57BL/6J mice underwent TAC and were analyzed at days 7 and 28 by Masson’s trichrome, spatial transcriptomics (Xenium, 5050 probes), and duplex RNAscope (Ifit1, Nppa). To test the involvement of the type I interferon response and dependence on the master regulator, interferon regulatory factor 3 (IRF3), experiments were repeated in IRF3-/- mice. To assess the potential for therapeutic modulation, mice received anti-IFNAR antibody (day −1 to +4; analyzed day 7).

Results/Data: Spatial transcriptomics identified a distinct post-TAC perivascular niche with altered endothelial, immune, and stromal programs in both ventricles, consistent with a luminal pressure–driven response. Interferon-stimulated genes (ISGs) were spatially clustered adjacent to vessels and largely absent in distant myocardium. IRF3 deficiency significantly reduced ISG induction after TAC. Anti-IFNAR treatment markedly suppressed ISG expression, demonstrating this response is pharmacologically modifiable in vivo.

Conclusions: Radial coronary injury induces a multicellular perivascular inflammatory niche driven by spatially restricted type I interferon signaling. This pathway is both genetically and pharmacologically targetable, suggesting new therapeutic opportunities to limit perivascular inflammation and adverse cardiac remodeling.