Abstract 12: rPAI-123 Inhibits Vasa Vasorum Plexus Development in Atherosclerotic Mice

Abstract

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-1 23 , to inhibit the plexus. Methods and Results— DKO mice treated with saline, anti-angiogenic rPAI-1 23 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-1 23 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-1 23 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-1 23 results in loss of the plexus causing the vasa vasorum to collapse. We conclude that a novel rPAI-1 23 stimulated pathway for regulating plasmin activity is the mechanism for inhibiting the expanded vasa vasorum in atherosclerotic DKO mice.