title: Antiangiogenic activity of rPAI-1(23) promotes vasa vasorum regression in hypercholesterolemic mice through a plasmin-dependent mechanism.
abstract: BACKGROUND
  The antiangiogenic activity of rPAI-1(23), a truncated plasminogen activator inhibitor-1 (PAI-1) protein, induces vasa vasorum collapse and significantly reduces plaque area and plaque cholesterol in hypercholesterolemic low-density lipoprotein receptor-deficient/apolipoprotein B48-deficient mice.
  
  
  OBJECTIVE
  The objective of this study was to examine rPAI-1(23)-stimulated mechanisms that cause vasa vasorum collapse.
  
  
  RESULTS
  The rPAI-1(23) protein opposed PAI-1 antiproteolytic function by stimulating a 1.6-fold increase in plasmin activity compared with the saline-treated counterpart. The increased proteolytic activity corresponded to increased activity of matrix metalloproteinase-3 and degradation of fibrin(ogen), nidogen, and perlecan in the adventitia of descending aortas. PAI-1 activity was reduced by 48% in response to rPAI-1(23); however, PAI-1 protein expression levels were similar in the rPAI-1(23)- and saline-treated hypercholesterolemic mice. Coimmunoprecipitation assays demonstrated a novel PAI-1-plasminogen complex in protein from the descending aorta of rPAI-1(23)- and saline-treated mice, but complexed PAI-1 was 1.6-fold greater in rPAI-1(23)-treated mice. Biochemical analyses demonstrated that rPAI-1(23) and PAI-1 binding interactions with plasminogen increased plasmin activity and reduced PAI-1 antiproteolytic activity.
  
  
  CONCLUSIONS
  We conclude that rPAI-1(23) causes regression or collapse of adventitial vasa vasorum in hypercholesterolemic mice by stimulating an increase in plasmin activity. The rPAI-1(23)-enhanced plasmin activity was achieved through a novel mechanism by which rPAI-1(23) and PAI-1 bound plasminogen in a cooperative manner to increase plasmin activity and reduce PAI-1 activity.
authors.affiliation: Department of Surgery, Vascular Section, Dartmouth Medical School, Borwell 530 E, 1 Medical Center Dr, Lebanon, NH 03756, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mollmark
authors.forename: Saranya
authors.initials: S
authors.lastname: Ravi
authors.forename: Baiming
authors.initials: B
authors.lastname: Sun
authors.forename: Samantha
authors.initials: S
authors.lastname: Shipman
authors.forename: Maarten
authors.initials: M
authors.lastname: Buitendijk
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Mulligan-Kehoe
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism*; D058258:Serpin E2 / Q000494:pharmacology*; D014651:Vasa Vasorum / Q000378:metabolism* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D010958:Plasminogen; D005341:Fibrinolysin