title: Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation.
abstract: Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo.
  
  
  
  PAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its antimigratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of signal transducers and activators of transcription-1 in SMCs, but had no discernable effect on signal transducer and activator of transcription-1 signaling in ECs. Expression of low-density lipoprotein receptor-related protein 1, a motogenic PAI-1 receptor that activates Janus kinase/signal transducers and activators of transcription-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury.
  
  
  
  PAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which seems to be because of differences in PAI-1-dependent low-density lipoprotein receptor-related protein 1/Janus kinase/signal transducer and activator of transcription-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ji
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Weng
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Philip
authors.initials: P
authors.lastname: Fish
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Neha
authors.initials: N
authors.lastname: Goyal
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Mao
authors.initials: M
authors.lastname: Luo
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Myears
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Strawn
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO. fayw@missouri.edu.
authors.forename: William P
authors.initials: WP
authors.lastname: Fay
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006801:Humans; D006965:Hyperplasia; D007210:Indoleacetic Acids / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D058426:Neointima; D010641:Phenotype; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D062326:Re-Epithelialization / Q000187:drug effects; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D066253:Vascular Remodeling / Q000187:drug effects; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
chemical_list: D007210:Indoleacetic Acids; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D011973:Receptors, LDL; C051321:SERPINE1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015842:Serine Proteinase Inhibitors; C494080:Stat1 protein, mouse; D025521:Tumor Suppressor Proteins; C488103:tiplaxtinin; D053612:Janus Kinases
keywords: inhibitors; muscle, smooth; pharmacology; plasminogen activators; remodeling