Notch signaling enhances PASMC proliferation and vascular remodeling in CTEPH

The Notch signaling pathway is implicated in pulmonary vascular remodeling (PVR) in Chronic Thromboembolic Pulmonary Hypertension (CTEPH). This study investigated the role of Notch signaling in PVR using a rat model of CTEPH and performed measurements including Right Ventricular Systolic Pressure (RVSP), Mean Pulmonary Arterial Pressure (MPAP), and histological analysis of pulmonary small arteries. Western blot analysis revealed elevated levels of Notch1, Notch3, Jagged1, and Hes1 proteins in CTEPH rats. Furthermore, the Notch pathway proteins (Notch1, Notch3, Jagged1, and Hes1) were even more elevated in the CTEPH + VPA group. In contrast, protein levels were reduced in the CTEPH + DAPT (a γ-secretase inhibitor) group. The medial wall thickness percentage (MWT%) and markers of smooth muscle cell proliferation, including PCNA and α-SMA, were significantly increased in the CTEPH and CTEPH + VPA groups and decreased after DAPT treatment. These findings suggest that activation of the Notch signaling pathway promotes the proliferation of Pulmonary Artery Smooth Muscle Cells (PASMCs), contributing to PVR in CTEPH. Inhibition of Notch signaling with DAPT mitigated vascular remodeling, suggesting a potential therapeutic target for CTEPH.