PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hy-pertension

Kudryashova, T. V.; Zaitsev, S. V.; Jiang, L.; Buckley, B. J.; McGuckin, J. P.; Goncharov, D.; Zhyvylo, I.; Lin, D.; Newcomb, G.; Piper, B.; Bogamuwa, S.; Saiyed, A.; Teos, L.; Ranson, M.; Wolters, P.; Kelso, M. J.; Poncz, M.; DeLisser, H. M.; Cines, D. B.; Goncharova, E. A.; Farkas, L.; Stepanova, V.

doi:10.1101/2023.09.21.558893

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bioRxiv · 10.1101/2023.09.21.558893

PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hy-pertension

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Abstract

Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.

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Kudryashova, T. V., Zaitsev, S. V., Jiang, L., Buckley, B. J., McGuckin, J. P., Goncharov, D., Zhyvylo, I., Lin, D., Newcomb, G., Piper, B., Bogamuwa, S., Saiyed, A., Teos, L., Ranson, M., Wolters, P., Kelso, M. J., Poncz, M., DeLisser, H. M., Cines, D. B., Goncharova, E. A., Farkas, L., Stepanova, V.. 2023-09-22. PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hy-pertension. https://doi.org/10.1101/2023.09.21.558893

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