The Antiangiogenic Activity of rPAI-1 ₂₃ Inhibits Vasa Vasorum and Growth of Atherosclerotic Plaque

Abstract

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 Ϫ/Ϫ ApoB-48 -deficient mice fed Paigen's diet without cholate for 20 weeks received rPAI-1 23 treatment (nϭ21) 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 (nϭ16) and mice fed Paigen's diet until the onset of treatment (nϭ14). 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 Ϫ/Ϫ ApoB-48 -deficient mice.

ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish

“…To test the effect of ERK1/2 activation on arteriogenesis in this model, an Ad-ME-LA or control virus was placed on the adventitial surface of the descending aorta of high-fat diet-fed Ldlr -/-ApoB48-modified mice. After 3 weeks, the extent of adventitial vasculature formation was assessed using confocal microscopy, as previously described (29). Exposure to the dominant-active MEK-ERK construct resulted in a highly significant increase in the arterial vasculature ( Figure 5, E and F), demonstrating the ability of ERK1/2 activation to drive arteriogenesis in a resistant mouse model.…”

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

“…Thermocycler conditions were as follows: one cycle at 95°C for 1 min, followed by 40 cycles of 95°C for 45 s, 56°C for 45 s, 72°C for 60 s, and one cycle at 72°C for 5 min. LDLR / S4 −/− were fed normal chow diet for 12 wk, followed by 14-20 wk PD (Research Diets), as previously described (17)(18)(19). PD consists of 20% protein, 45% carbohydrate, 35% fat, and no cholate (54).…”

“…−/− male mice at 12 wk were put on the lipid-enriched Paigen diet without cholate (PD) for 16-20 additional weeks to induce atherosclerotic lesions (17)(18)(19)(20). In DKO/S4 +/+ mice, small lesions in the descending aorta were visible after 16 wk of PD ( Fig.…”

“…Our results showed that S4 is specifically required in alignment of endothelial cells (ECs) in flow and suggest that loss of this atheroprotective mechanism leads to increased atherosclerosis in S4 −/− mice. [17][18][19][20]. In DKO/S4 +/+ mice, small lesions in the descending aorta were visible after 16 wk of PD ( Fig.…”

Id1 induces tubulogenesis by regulating endothelial cell adhesion and cytoskeletal organization through β1-integrin and Rho-kinase signalling

“…In addition, angiogenesis is a key event in the pathogenesis of some forms of cardiovascular disease (2). Although angiogenesis has been identified as a key development in many progressive diseases, the specific molecular mechanisms of angiogenesis are not well understood.…”