A107-14 Targeting Notch4 Signaling in Pulmonary Arterial Hypertension

Abstract Background Pulmonary Arterial Hypertension (PAH) is a lethal disease driven by pulmonary vascular remodeling, increased resistance, and right ventricular failure, with a 15-20% 1-year mortality rate in severe cases. Current vasodilator therapies targeting endothelin, nitric oxide,prostacyclin pathway, and newly approved activin inhibitor alleviate symptoms but fail to reverse vascular pathology or cure PAH. Our data show upregulated Notch4 expression in PAH lungs,but its precise contribution and therapeutic potential require further exploration. Objective We aim to define the role of Notch4 signaling in PAH and to evaluate the therapeutic potential of targeting Notch4. Methods We assessed the effects of Notch4 inhibition (siRNA) and activation (NICD4 overexpression) inhuman pulmonary vascular endothelial cells (hPVECs). In vivo, we tested the effects of Notch4deletion in Egln1CDH5CreERT2 (iCKO) mice and anti-Notch4 antibodies treatment in iCKO mice with established pulmonary hypertension. We evaluated heart function and vascular remodeling via measuring right ventricular systolic pressure (RVSP), RV/LV+S and immunostaining, respectively. We performed bulk RNA sequencing to elucidate the underlying mechanisms ofNotch4-involved PAH. Results We discovered that Notch4 is upregulated in rodent PAH models and IPAH lungs. NICD4overexpression in hPVECs induced cell proliferation and upregulation of arterial genes (e.g.,HEY1, HES4, CXCL12). Deletion or antibody-mediated neutralization of Notch4 in vivo significantly attenuated RVSP, RV hypertrophy, and vascular remodeling in established PAHmodels. Conclusion Our findings identify that Notch4 plays a significant role in vascular remodeling and pathogenesis of PAH. Targeted inhibition of Notch4 prevents vascular remodeling and improves heart function, providing a promising therapeutic strategy for this devastating disease. This abstract is funded by: NIH