Abstract 12: rPAI-123 Inhibits Vasa Vasorum Plexus Development in Atherosclerotic Mice
Objective— Vasa vasorum are angiogenic in more advanced stages of human atherosclerosis and in mouse models of atherosclerosis. Fibroblast growth factor-2 (FGF-2) is the predominant angiogenic growth factor in the adventitia and plaque of hypercholesterolemic LDLR-/-ApoB100+ mice (DKO). Our previous studies suggest that FGF-2 plays an important role in guiding angiogenic vasa vasorum into a distinct plexus-like network. This study further investigated the role of FGF-2 in plexus development and the ability of an angiogenesis inhibitor, rPAI-123, to inhibit the plexus.
Methods and Results— DKO mice treated with saline, anti-angiogenic rPAI-123 or adeno-soluble FGFR1 (sFGFR1) were perfused with fluorescein-labeled Lycopersicon esculentum lectin. Descending aortas were probed for FGF-2 and whole mounts were imaged by confocal microscopy. Angiogenic vasa vasorum are abundant and form a plexus-like network in saline treated DKO that is similar to the FGF-2 pattern of distribution. Mice treated with rPAI-123 and sFGFR1 lack a plexus; FGF-2 and vasa vasorum density and area are significantly reduced. Examination of potential FGF-2 binding partners indicates that a perlecan/FGF-2 complex is critical for plexus development. Excess plasmin produced in rPAI-123 treated DKO/PAI-1-/- mice degrades perlecan, disperses FGF-2 causing collapse of the plexus and destabilization of the vascular tree.
Conclusion— Vasa vasorum develop an angiogenic plexus essential for maintaining a vascular tree during the atherosclerotic disease process. A perlecan/FGF-2 complex is required for structural organization and stability of the plexus. Disruption of the complex by rPAI-123 results in loss of the plexus causing the vasa vasorum to collapse. We conclude that a novel rPAI-123 stimulated pathway for regulating plasmin activity is the mechanism for inhibiting the expanded vasa vasorum in atherosclerotic DKO mice.
- © 2012 by American Heart Association, Inc.