Hypoxia-Induced Epas1-Myl9/12 Axis Shapes the Pathology of Pulmonary Hypertension.

Summary

Using Sugen/hypoxia mice and patient samples, the authors identified Myl9/12-containing microthrombi and showed that hypoxia upregulates Myl9/12 via EPAS1 in proliferating lung endothelial cells. Therapeutic anti-Myl9/12 antibody reduced microthrombus formation, inflammation, tissue hypoxia, and vascular remodeling, attenuating established PH in mice; serum Myl9 levels reflected PH severity in patients.

Key Findings

• Myl9/12-containing microthrombi were present in PH patients and Sugen/hypoxia mice.
• Hypoxia upregulated Myl9/12 expression through EPAS1 in proliferated lung endothelial cells, releasing Myl9/12 extracellularly.
• Anti-Myl9/12 antibody attenuated established PH in mice by reducing microthrombi, inflammatory cell infiltration, hypoxia, and vascular remodeling.
• Serum Myl9 levels correlated with PH severity, whereas MYL12A/B did not.

Clinical Implications

Serum Myl9 could serve as a severity biomarker, and anti-Myl9/12 therapeutics merit early-phase trials in PH. The findings support mechanistically targeted strategies beyond vasodilation.

Limitations

• Preclinical mouse model may not capture full heterogeneity of human PH subtypes
• Limited patient sample size and lack of interventional human data; potential off-target or safety concerns of anti-Myl9/12 remain untested in humans

Future Directions

Conduct phase I/II trials of anti-Myl9/12 in selected PH phenotypes; validate serum Myl9 as a prognostic/theranostic biomarker; map cell-type–specific EPAS1–Myl9/12 regulation in human PH.