WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by proliferative vascular remodeling. Abnormal vascular smooth muscle cell (VSMC) phenotype switching is crucial to this process, highlighting the need for VSMC metabolic changes to cover cellular energy demand in CTEPH. We report that elevated Wnt family member 5B (WNT5B) expression is associated with vascular remodeling and promotes VSMC phenotype switching via mitochondrial dynamics regulation in CTEPH. Using primary culture of pulmonary artery smooth muscle cells, we show that high WNT5B expression activates VSMC proliferation and migration and results in mitochondrial fission via noncanonical Wnt signaling in CTEPH. Abnormal VSMC proliferation and migration were abolished by mitochondrial division inhibitor 1, an inhibitor of mitochondrial fission. Secreted frizzled‐related protein 2, a soluble scavenger of Wnt signaling, attenuates VSMC proliferation and migration by accelerating mitochondrial fusion. These findings indicate that WNT5B is an essential regulator of mitochondrial dynamics, contributing to VSMC phenotype switching in CTEPH.

Current Understanding of the Pivotal Role of Mitochondrial Dynamics in Cardiovascular Diseases and Senescence

“…In the pulmonary vessels of patients with CTEPH, expression of phosphorylation of Drp1 at serine 616 was upregulated, whereas that of Opa1 was downregulated. Moreover, Wnt family member 5B contributed to VSMC phenotype switching in CTEPH through CAMKII-dependent phosphorylation of Drp1 at serine 616 ( 144 ). PAEC from patients with CTEPH had decreased expression of Mfn1, Mfn2 and Opa1, and increased ROS production ( 145 ).…”