Apoptosis Of Macrophages By Flt-4 Singnaling And Angiogenesis: Effect To The Plaque Stability Of Human Atherosclerosis Coronary Artery

Aim:To investigate angiogenesis and the corralation btween Flt-4 expree- ssion and macrophage apoptosis,and analyze their Relationship with coronary plaque stability.Methods:Seventy-nine left anterior descending coronary arteries from 79 autopsied cases were enrolled.Analyzed by light microscope after the process of HE staining,then the Samples were divided into threen groups: stable plaque group(32 samples),unstable plaque group(35 samples) and normal coronary arteries(12 samples).The lipid core size of unstable plaque exceeds 40% of plaque area,while stable group is just the opposite.The exppressions of Flt-4, Caspase-3, VEGF-C, VEGF-D, Flk-1, CD34 and CD68 were detected with immunohistochemistory. Cell apoptosis was in site detected with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL).Analyzed the changes of stable and unstable plaques in cell morphology with light microscope,and compared their differeces in apoptosis and angiogenesis.Rsults:①Significant differeces in the expressions of Flt-4, Caspase-3, VEGF-C, VEGF-D, Flk-1, CD34 and CD68 were shown in comparing stable and unstable plaques respectively(p<0.05).Their expression levles are higher in unstable plaques than those in stable ones,and no exoression in normal coronary arteries.②Macrophages within inflammatory perivascular regions coexpressed Flt-4,VEGF-C and VEGF-D.Interestingly, microvascular endothelial cells stained positive for VEGF-C and VEGF- D,but not for Flt-4.In unstable plaques Flt-4, VEGF-C and VEGF-D are mainly expressed in macrophages. Moreover,Flt-4 was shown positive almost in macrophage cytoplasm,indeividually in several nucleuses.③There were positive correlations of Flt-4 expression with the expressions of Caspase-3, VEGF-C and VEGF-D(Caspase-3 r=0.742,p<0.05; VEGF-C r=0.764,p<0.05; VEGF-D r=0.839,p<0.05;),and also of CD34 with Flk-1 (r=0.799,p<0.05;).④The rate of apoptotic macrophages in unstable plaques was higher than that in stable ones(p<0.05). Moreover,positive associations between the rate of positive TUNEL results and Flt-4 expression intensity showed in Spearman tests(r=0.852,p<0.05;).⑤The counts of apoptotic macrophages and new vessels in unstable plaques both are more than those in stable,and most of them distribute in shoulders of plaques.Conclusion:Human macrophages express VEGF-C , VEGF-D and their receptors Flt-4 and Flk-1 within advanced atherosclerotic lesions. Flt-4 mediates macrophage apoptosis and may this way alter plaque stability.Flk-1 is benefit to angiogenesis,and the after is an important contributor of progression and destabilization of atherosclerosis coronary plaque.