title: Fibroblast growth factor-2 is required for vasa vasorum plexus stability in hypercholesterolemic mice.
abstract: OBJECTIVE
  Vasa vasorum are angiogenic in advanced stages of human atherosclerosis and hypercholesterolemic mouse models. Fibroblast growth factor-2 (FGF-2) is the predominant angiogenic growth factor in the adventitia and plaque of hypercholesterolemic low-density lipoprotein receptor-deficient/apolipoprotein B(100/100) mice (DKO). FGF-2 seems to play a role in the formation of a distinct vasa vasorum network. This study examined the vasa vasorum structure and its relationship to FGF-2.
  
  
  RESULTS
  DKO mice treated with saline, antiangiogenic recombinant plasminogen activator inhibitor-1(23) (rPAI-1(23)), or soluble FGF receptor 1 were perfused with fluorescein-labeled Lycopersicon esculentum lectin. Confocal images of FGF-2-probed descending aorta adventitia show that angiogenic vasa vasorum form a plexus-like network in saline-treated DKO similar to the FGF-2 pattern of distribution. Mice treated with rPAI-1(23) and soluble FGF receptor 1 lack a plexus; FGF-2 and vasa vasorum density and area are significantly reduced. A perlecan/FGF-2 complex is critical for plexus stability. Excess plasmin produced in rPAI-1(23)-treated DKO mice degrades perlecan and destabilizes the plexus. Plasmin activity and plaque size measured in DKO and DKO/plasminogen activator inhibitor-1(-)(/-) mice demonstrate that elevated plasmin activity contributes to reduced plaque size.
  
  
  CONCLUSIONS
  An FGF-2/perlecan complex is required for vasa vasorum plexus stability. Elevated plasmin activity plays a significant inhibitory role in vasa vasorum plexus and plaque development.
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Mollmark
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Andrew J-H
authors.initials: AJ
authors.lastname: Park
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Justin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Thomas Z
authors.initials: TZ
authors.lastname: Wang
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Sarah
authors.initials: S
authors.lastname: Katzenell
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Shipman
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Lyubomir G
authors.initials: LG
authors.lastname: Zagorchev
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.affiliation: Departments of Surgery, Vascular Section (J.I.M., A.J.-H.P., J.K., T.Z.W., M.J.M.-K.), Immunology and Microbiology (S.K.), Medicine, Cardiology Section (S.L.S.), and Thayer School of Engineering (L.G.Z.), Dartmouth Medical School, Lebanon, NH; and Department of Internal Medicine, Cardiovascular Medicine Section, Yale University School of Medicine, New Haven, CT (M.S.).
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Mulligan-Kehoe
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D018014:Gene Transfer Techniques; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic; D058226:Plaque, Atherosclerotic; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012422:Rupture, Spontaneous; D014651:Vasa Vasorum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D019812:Heparan Sulfate Proteoglycans; D011973:Receptors, LDL; D016222:Fibroblast Growth Factor 2; C071927:perlecan; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005341:Fibrinolysin