title: The antiangiogenic activity of rPAI-1(23) inhibits vasa vasorum and growth of atherosclerotic plaque.
abstract: Plaque vascularity has been implicated in its growth and stability. However, there is a paucity of information regarding the origin of plaque vasculature and the role of vasa vasorum in plaque growth. To inhibit growth of vasa vasorum in atherogenic mice and assess its effect on plaque growth, we used a truncated plasminogen activator inhibitor (PAI)-1 protein, rPAI-1(23), that has significant antiangiogenic activity. Female LDLR(-/-)ApoB-48-deficient mice fed Paigen's diet without cholate for 20 weeks received rPAI-1(23) treatment (n=21) for the last 6 weeks. Plaque size and vasa vasorum density were compared to 2 controls: mice fed Paigen's diet and treated with saline for the last 6 weeks (n=16) and mice fed Paigen's diet until the onset of treatment (n=14). The rPAI-1(23) treatment significantly reduced plaque area and plaque cholesterol in the descending aorta and plaque area in the innominate artery. Measurements of reconstructed confocal microscopy images of vasa vasorum demonstrate that rPAI-1(23) treatment decreased vasa vasorum area and length, which was supported by microCT images. Confocal images provide evidence for vascularized plaque in the saline-treated group but not in rPAI-1(23)-treated mice. The increased vessel density in saline-treated mice is attributable, in part, to upregulated fibroblast growth factor-2 expression, which is inhibited by rPAI-1(23). In conclusion, rPAI-1(23) inhibits growth of vasa vasorum, as well as vessels within the adjacent plaque and vessel wall, through inhibition of fibroblast growth factor-2, leading to reduced plaque growth in atherogenic female LDLR(-/-)ApoB-48-deficient mice.
authors.affiliation: Angiogenesis Research, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Drinane
authors.forename: Jessica
authors.initials: J
authors.lastname: Mollmark
authors.forename: Lyubomir
authors.initials: L
authors.lastname: Zagorchev
authors.forename: Karen
authors.initials: K
authors.lastname: Moodie
authors.forename: Baiming
authors.initials: B
authors.lastname: Sun
authors.forename: Amy
authors.initials: A
authors.lastname: Hall
authors.forename: Samantha
authors.initials: S
authors.lastname: Shipman
authors.forename: Peter
authors.initials: P
authors.lastname: Morganelli
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 / Q000502:physiology*; D000818:Animals; D053283:Apolipoprotein B-48 / Q000235:genetics; D001158:Arteries / Q000473:pathology; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014651:Vasa Vasorum / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D053283:Apolipoprotein B-48; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D011973:Receptors, LDL; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2