PAK5 drives vascular remodeling in hypoxic pulmonary hypertension via Drp1-dependent mitochondrial midzone division

Mitochondrial dynamics play an indispensable role in maintaining the proliferation-apoptosis balance of pulmonary artery smooth muscle cells (PASMCs), a process closely linked to hypoxic pulmonary hypertension (HPH). P21-activated kinase 5 (PAK5) has been implicated in cancer-related mitochondrial dysfunction to induce cell proliferation/apoptosis and pulmonary hypertension (PH) shares numerous similarities with cancer, yet its pathophysiological role in HPH, and its mechanistic connection to mitochondrial fission remains unclear. Here, we demonstrated that PAK5 expression was upregulated in the lungs and pulmonary vasculature and mitochondrial fission was dysregulated following HPH injury. In tissue samples from PH patients, PAK5 expression positively correlated with pulmonary vascular remodeling. In vivo, PAK5-silenced mice exhibited significantly improved hemodynamic parameters and right ventricular function compared to control mice. In vitro, hypoxia-induced upregulation of PAK5 promoted dynamin-related protein 1 (Drp1) activation, leading to the occurrence of mitochondrial midzone division, reduced expression of the mitochondrial fusion protein Mfn1, and enhanced expression of proliferative proteins including PCNA, Cyclin A, and Cyclin D. Pharmacological or viral-induced PAK5 deficiency resulted in enhanced Mfn1 expression, reduced levels of Drp1, Mff, PCNA, Cyclin A, and Cyclin D, and consequently attenuated mitochondrial midzone division and excessive PASMC proliferation. Our findings indicate that PAK5 participates in the development of HPH by driving mitochondrial fission through Drp1, and this study provides a new potential therapeutic target for HPH.