Angiogenesis In Coronary Atherosclerotic Plaques And Its Relationship To Plaque Stabilization

Background and Purpose Rupture of coronary atheroscleroticplaques (especially vulnerable plaques) and superimposed thrombosisare the events preceding the vast majority of acute coronary syndromes.It is believed that the lipid core and the inflammatory cells are themajor factors resulting in plaque rupture. But the importance ofneovessel-an important component within the plaque-in plaquedestabilization has not attracted people's atteotion. The present studywas designed to compare the angiogenesis in unstable plaques with that in stable plaques and to investigate the potential role of neovessels increating vulnerable sites in atherosclerotic plaques.Materials and methods l. Specimens of coronary arteries wereobtained at autopsy from 52 patients with acute coronary syndromes.Plaque morphology was evaluated by using hematoxylin and eosinstained slides. Then, 922 tissue blocks of late-stage lesions wereclassified into two groups as either unstable (n=l53), in which theplaque characterized by a large extracellular lipid core(more than 40%of the plaque area) or stable(n=769), in which the lipid core was lessthan 40% of the plaque area. 2. 40 blocks were selected randomly fromeach group and serial sections were immunohistochemicallyinvestigated by using monoclonal or polyclonal antibodies againstendothelial cell (F-Vâ…¢), vascular endothelial growth factor(VEGF),basic fibroblast growth factor(bFGF), macrophage(CD~68) and T-lymphocyte(CD~3). 3. Among 40 blocks in each group, l0 blocks wereselected again and double-immunostaining was employed to investigatethe relation between neovessels and inflammatory cells. 4. Computer-a1ded planimeter was used in quantitative analysis.Results 1. ln unstable plaques, the occurence of neovessels was morefrequent and the neovessel density (number/mm') was significantlyincreased as compared to stable plaques. (frequency 80.39% vs66.58%, P<0.01, density: shoulder' 22 l6 i l9.96 vs 10.04 I 11 .52,base: 2l .68 i 20.44 vs 9.68 i 11 .52, fibrous capt 3.80 t 5.32 vs 1 .48 f2.28, P<0.05). And most neovessels were located in the shoulderregion and at the base of plaques 2. The rat1os (%o) of immunoreactlvepositlve areas of CD,,, CD,, VEGF and bFGF in the shoulder region ofunstable plaques were significantly increased than that in stableplaques (CD,,: 13.54I 12 62 vs 6 01 f5.25, CD,. 3.03 I3 95 vs 0.79t0.90, VEGF' 10 2619 70 vs 4.58 I4.54, bFGF: 6.58 I6.16 vs 3. l3i3 00, P<0.01). VEGF and bFGF mainly expressed by macrophagesand inflammatory cells most abundantly present in the proxlmlty ofneovessels. 3 There was slgnificant1y positive relatlon betweenneovessels and inflammatory cel1s (F-VIII/CD,, r = 0.91, F-VIII/CD,r = 0.81, P<0.0l) 4. The occurrence of ifltraplaque hemorrhage due torupture of neovessels was more frequent in unstabIe plaques than thatin stable plaques (3 l 7l% vs 20 31 %, P<0.01).Conclusions These findings suggest that neovessels in coronaryatherosc1erotic plaques are c1osely associated with the decreasedstabilization of the plaques. Neovessels at the site of unstable plaquesmay sustain the influx of inflammatory cells and hence, couldcontribute to plaque destabiIlzation. Inflammation may direct1ystlmulate angiogenesis and sustain the positive feedback relationbetween neovessels and inflammatory cells In addition, the rupture ofneovesssels in atherosclerotic plaques could directly contribute to thedecrease of plaque stabilization.