PAI-1 Induces Cell Migration of Pulmonary Arterial Smooth Muscle Cells - Implications for Pulmonary Arterial Remodeling

The glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), enzymopathy is common in humans. Several deficient and non-deficient mutants/variants of G6PD are found world-wide in the regions with malarial endemic. G6PD deficiency is often associated with hemolytic anemia. However, the effect of deficient and non-deficient G6PD variants on cardiovascular system is rarely studied. Therefore, our laboratory recently developed CRISPR-edited rats with the non-deficient G6PD variant (N126D) found in the sub-Sahara Africa. These rats when exposed to vascular endothelial growth factor receptor (VEGFR) blockers like Sugen-5416 (SU) exhibit elevated plasminogen activator inhibitor-1 (PAI-1) levels and increased inflammatory cytokine expression in the lungs. However, the effects of PAI-1 on pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (ECs), which are critical components of the pulmonary vasculature, remain poorly understood. Therefore, we determined the effects of PAI-1 on PASMC proliferation and migration. The CyQuant Assay revealed a significant increase in PASMC proliferation upon treatment with PAI-1 (500 ng/µL) compared to control groups. However, the Bromodeoxyuridine (BrdU) assay, which measures DNA replication and progression in the cell cycle, revealed no significant difference in BrdU uptake between treated and control groups, the b-galactosidase assay indicated PAI-1 elicited senescence of PASMCs. Furthermore, the Transwell invasion assay showed enhanced cell migration in cells treated with PAI-1. These data suggest that PAI-1 induces cell senescence and migration potentially contributing to the remodeling of pulmonary artery and pathogenesis of PAH seen in the G6PD N126D variant rat model treated with SU. Ongoing experiments aim to elucidate the effects of PAI-1 on endothelial cells and further clarify the molecular mechanisms involved in the development of PAH. Supported by National Heart, Lung, and Blood Institute grants R01HL132574 (S.A.G. and J.M.M.) and R01HL166546 (S.A.G. and J.M.M.) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.