Fibroblast Growth Factor-2 Is Required for Vasa Vasorum Plexus Stability in Hypercholesterolemic Mice
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 B100/100 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-123, 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 recombinant plasminogen activator inhibitor-123 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 recombinant plasminogen activator inhibitor-123-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.
Conclusion—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.
- Received April 28, 2012.
- Accepted August 27, 2012.
- © 2012 American Heart Association, Inc.