| Objective①to evaluate the effect of sirolimus and paclitaxel on neointimal hyperplasia andvessel wall remodeling after PTA.②to investigate the effect of sirolimus andpaclitaxel on endothelialization and related coagulation factors in the vessel after PTA.③to compare the effect of different ways of administration of paclitaxel onrendothelialization and related coagulation factors in the vessel after PTA.Materials and methods1.Establishment of experimental common carotid artery injury model in the rat.2.Adventitial administration (Pluronic gel containing sirolimus or paclitaxel wasapplied to the exposed adventitial surface of the injured carotid artery)was applied.The neointimal thickness and area,medial thickness and area,the ratio of intimal areato medial area,stenotic ratio,internal elastic lamina area,and external elastic laminaarea were measured or calculated 15 and 30 days after injury respectively,which werecompared to those of controls,in order to evaluate the morphological changes of thevessel wall under the influence of the anti-proliferative agents.3.Adventitial administration was applied.CD31 antibody was used to label theendothelial cells in order to assess the effect of anti-proliferative agents onrendothelialization.The influence of anti-proliferative agents on the expression of TF,PAI-1 and t-PA of the vessel wall was observed by immunohistochemistry (IHC)andin situ hybridization (ISH).4.Local intra-arterial administration (an admixture of paclitaxel to contrast medium)was applied,and the effects of short-term delivery of paclitaxel on neointimalhyperplasia,vessel wall remodeling and related coagulation factors in the vessel wereevaluated.Relults1.Adventitial administration:15 and 30 days after injury,the neointimal thicknessand area,the ratio of intimal area to medial area and stenotic ratio were significantlydecreased in sirolimus (300μg/100μl,600μg/100μl)and paclitaxel (20μg/100μl,40μg/100μl)groups compared to control group (P＜0.01);Compared to controlgroup,the decrease of internal and external elastic lamina area could be seen (P＜0.05)30 days after injury;No significant difference of the effects of sirolimus andpaclitaxel on the vessel of could be seen between two concentrations respectively.2.Adventitial administration:15 and 30 days after injury,rendothelization of thevessel wall in sirolimus and paclitaxel experimental groups was delayed anduncompleted,and the inside surface of intima was uneven with enlarged and deformed endothelial cells diffusely distributed;Compared to control group,theexpression of TF mRNA and TF in neointima of sirolimus and paclitaxel groups wasincreased significantly (P＜0.05),and the expression of TF mainly located at theinside surface of intima,especially 30 days after injury;The expression of PAI-1mRNA and PAI-1 was increased significantly (P＜0.05),but the expression of t-PAwas decreased significantly (P＜0.05)in neointima of sirolimus and paclitaxel groupscompared to controls.3.Local intra-arterial administration:15 and 30 days after injury,the neointimalthickness and area,the ratio of intimal area to medial area and stenotic ratio weresignificantly decreased in paclitaxel high concentration (180μg/30μl)2 min,10mingroup and low concentration (180μg/30μl)10 min group(P＜0.05);No significantdifference of the internal and external elastic lamina area could be seen betweenpaclitaxel experimental groups and controls;Compared to controls,no obviouslysignificant changes for the expression of TF mRNA and TF exists in the neointima ofpaclitaxel experimental groups;there was no significant difference for the expressionof PAI-lmRNA in the intima between experimental groups and controls;Theexpression of PAI-1 in the intima of high concentration 10 min group was higher thancontrol group (P＜0.05),but no statistical difference was found between other 3groups(high concentration 2min,low concentration 2min and 10min groups)andcontrols;The expression t-PA in neointima of high concentration 2 min groupdecreased significantly than control group (P＜0.05),and for other 3 groups,Theexpression t-PA in neointima seemed to be lower than control group,but no statisticalsignificance could be seen.Conclusion1.A sustained release of sirolimus and paclitaxel with adventitial administrationcould inhibit the neointimal hyperplasia effectively after PTA.2.There was a negative remodeling effect after PTA (30 days after injury in theexperiment)for sustained release of sirolimus and paclitaxel with adventitialadministration.Although the negative remodeling effect seemed to have no effects forstent-based local drug delivery,but for non-stent-based local drug delivery or for thenew therapy of restenosis prevention,it had practical significance.3.A sustained release of sirolimus and paclitaxel with adventitial administrationdelayed rendothelization and caused the remained or regenerative cell deformed orenlarged after PTA.4.A sustained release of sirolimus and paclitaxel with adventitial administrationinduced high expression of TF mRNA and TF in intima.5.A sustained release of sirolimus and paclitaxel with adventitial administrationcaused high expression of PAI-1mRNA and PAI-1 in intima,however the expressionof t-PA in intima had a decreasing tendency. 6.A short-term release of paclitaxel with local intra-arterial administration(180μg/30μl 2 min and 10 min,90μg/30μl 10 min group in the experiment)couldeffectively suppress the neointimal hyperplasia in the long term (30 days in theexperiment).7.A short-term release of paclitaxel with local intra-arterial administration(180μg/30μl 2 min and 90μg/30μl 10min group in the experiment)could effectivelysurpress the neointimal hyperplasia,meanwhile,have no influence on the expressionof TF and PAI-1 in intima.
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