PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Cell Biology

Background:

• Pulmonary arterial hypertension (PAH) is a severe disease characterized by pulmonary artery vasoconstriction and remodeling, leading to right heart failure.
• The plasminogen activator system, particularly plasminogen activator inhibitor-1 (PAI-1), is implicated in vascular remodeling processes.

Approach:

• Investigated PAI-1 expression in remodeled pulmonary arteries (PAs) and human pulmonary artery smooth muscle cells (PASMC) from PAH patients.
• Utilized PAI-1 deficient (PAI1-/-) mice to study spontaneous pulmonary hypertension (PH) development.
• Examined the effects of urokinase plasminogen activator (uPA) inhibitors (upamostat and BB2-30F) on human PAH PASMC and a mouse model of SU5416/Hypoxia (SuHx)-induced PH.

Key Points:

• PAI-1 was found to be deficient in remodeled PAs and PASMC from PAH subjects.
• PAI1-/- mice exhibited spontaneous pulmonary vascular remodeling and PH.
• uPA inhibitors reduced proliferation, induced apoptosis in human PAH PASMC, and protected mice from SuHx-induced PH by down-regulating mTORC1 and SMAD3.

Conclusions:

• PAI-1 downregulation in PASMC promotes hyper-proliferation, remodeling, and PH in PAH due to unopposed uPA activity.
• Targeting the PAI-1/uPA imbalance offers a potential therapeutic strategy for attenuating or reversing PAH progression and vascular remodeling.