ArticleArteriosclerosis, thrombosis, and vascular biology2024
PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- IGF-1 axis: The signalling bond in cancer-associated thrombosis and cachexia?Journal of thrombosis and thrombolysis · 2026Review
- circRNA-Associated ceRNA Regulatory Networks in Cardiac Responses to High-Altitude Hypoxia in Tibetan Pigs (International journal of molecular sciences · 2026Article
- Integration of Multi-Omics and Machine Learning Identifies TGFB1 and SERPINE1 as Biomarkers of Vascular Smooth Muscle Cell Senescence in Intracranial Aneurysms.Translational stroke research · 2026Article
- Integrin αScientific reports · 2026Article
- PAI-1 is a common driver of aging and diverse diseases.Biomedical journal · 2026Review
- PAI-1: A Key Signal at the Crossroads of Stem Cell Differentiation and Senescence.International journal of molecular sciences · 2025Review
- TPM2 regulates contractility and biomechanical properties in trabecular meshwork cells.Scientific reports · 2025Article
- Pharmacological activation of NO-sensitive guanylyl cyclase ameliorates obesity-induced arterial stiffness.Vascular pharmacology · 2025Article
- Transcriptome Insights into Protective Mechanisms of Ferroptosis Inhibition in Aortic Dissection.International journal of molecular sciences · 2025Article
- Understanding the Role of Adipokines in Cardiometabolic Dysfunction: A Review of Current Knowledge.Biomolecules · 2025Review
- Role of plasminogen activator inhibitor-1 (PAI-1) in age-related cardiovascular pathophysiology.The journal of cardiovascular aging · 2025Article
- Targeting Vascular Stiffness.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
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18 authors.
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Abstract
backgroundPlasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness.
methodsPAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1-deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity.
resultsPAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1-deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content.
conclusionsPAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening.
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