Arteriosclerosis, thrombosis, and vascular biology · 2012
Fibroblast growth factor-2 is required for vasa vasorum plexus stability in hypercholesterolemic mice.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Mollmark Jessica I, Park Andrew J-H, Kim Justin, Wang Thomas Z, Katzenell Sarah, Shipman Samantha L, Zagorchev Lyubomir G, Simons Michael, Mulligan-Kehoe Mary Jo
Аннотация
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.
METHODS AND 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.
METHODS AND 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.
Предметные рубрики MeSH
Angiogenesis InhibitorsAnimalsAortaAortic DiseasesApolipoprotein B-100Apolipoproteins BAtherosclerosisCholesterol, DietaryDisease Models, AnimalFibrinolysinFibroblast Growth Factor 2Gene Transfer TechniquesHeparan Sulfate ProteoglycansHypercholesterolemiaMiceMice, 129 StrainMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalNeovascularization, PathologicPlaque, AtheroscleroticReceptor, Fibroblast Growth Factor, Type 1Receptors, LDLRupture, SpontaneousVasa Vasorum