Effect Of Expression Of PPAR-γ On Phenotypic Transformation Of Vascular Smooth Muscle Cell After Balloon Injury And Stenting In Minipigs

BackgoundIn recent years, with the continuous development of technology and interventionalendovascular interventional devices, cerebrovascular stent implantation therapy as a newtreatment method because of its minimally invasive, safe and effective features，has beenwidely used in ischemic stroke secondary prevention, significantly reducing the rate ofrecurrence of stroke, and effectively improve the prognosis of patients with stroke.But20%to30%of patients with stent restenosis after six months, has seriously affected the cerebralvascular stenting long-term effect, therefore stent restenosis is a clinicalchallenge.Prevention of restenosis after minimally invasive treatment of cerebrovasculardisease is important and difficult.Unfortunately, mechanisms of restenosis are not clear, there is no satisfactory wayspreventing restonosis yet,in-depth study of the mechanism is to find effective ways ofprevention. Cerebral vascular stent restenosis is a complex process with multiple factorsinvolved, includes thrombosis formation, intimal hyperplasia and vascular remodeling.Previous study of restenosis prevention mainly focus mainly on endometrial changes,including drug intervention, new stent technology and so on,which focus on promotingre-endothelialization of vascular intima.In recently years, vascular smooth muscle cells(VSMC) phenotypic transformation has been a focus in stent restenosis. Previous studysuggest that the proliferation and migration of VSMC play a importment role in restenosisafter stenting.Studies have found that the nuclear transcription factor peroxisomeproliferator-activated receptor-γ (PPAR-γ) of cerebral vascular remodeling has an importantregulatory role.PPAR-γ is a ligand-activated nuclear transcription factors, with a variety of biologicaleffects, such as the regulation of lipid and glucose metabolism, anti-atherosclerotic, inducetumor cell apoptosis. Pathological changes in the pig and human after stenting is basically the same. This study was to establish minipig model of carotid artery stenting and partial ofthe models will be given PPAR-γ agonist drugs rosiglitazone.Observe the expression ofPPAR-γ and its effect on VSMC phenotypic transformation, to investigate the effect andmechanism of PPAR-γ on VSMC phenotype transformation, which aimed providing atheoretical basis clinical cerebrovascular prevention after stenting.PurposeMinipig model of carotid artery stenting.Application angiography, pathology studies, immunohistochemistry and other methodsto observe vascular pathology and the expression of PPAR-γ and smooth muscle22α(SM22α).Explore the role of PPAR-γ in the stent restenosis.MethodsBama minipigs12, were randomly divided into three groups, implanted stent group,stent implantation and given rosiglitazone (ROSI)group and the control group. The controlgroup was not implanted stent.In the other two groups, Bare-metal stents (BMS) are placedin the random carotid arterie after balloon dilation of each minipig. Angiograms areperformed on before stenting, immediately after stenting and12weeks later. Animals weresacrificed at12weeks after surgery, immunohistochemistry and Western blot (WB) wereused to detect the expression of PPAR-γ and SM22α.Results1) Angiography showed that in the stent group, Vascular diameter is (4.88±0.12)mmafter stenting,which is (3.41±0.15)mm12weeks after stenting;in the ROSI group, Vasculardiameter is (5.08±0.11)mm after stenting,which is (4.17±0.12)mm12weeks afterstenting.Angiography showed that stenting group compared with ROSI group has moresignificant stenosis12weeks after stent implantation[(1.46±0.14)、(0.91±0.13)mm，(P<0.05)].2) The results of HE staining found that the disordered layer elastic fiber stentimplantation group showed vascular intimal hyperplasia, a lot of VSMC can be seen inproliferative endometrium. ROSI treatment of vascular stent group HE staining in the filmelastic fibers aligned in order, intravascular VSMC proliferation was not obvious;Immunohistochemistry showed vascular stent group in PPAR-γ expression score lower thanthe control group and ROSI treatment stent group [(0.90±0.22)、(5.85±0.29)、(5.04±0.46)， (P<0.05)], the expression of PPAR-γ between ROSI treatment stent group and normalcontrol group had no significant difference (P>0.05).3) Western blot analysis showed that: the expression level of PPAR-γ/SM22α in thestent group is lower than the control group [(3.12±1.42)%/(16.72±5.34)%、(19.87±5.33)%/(68.85±9.73)%，(P<0.05)], VSMC phenotype from the contractile tosynthetic transformation; the expression level of PPAR-γ/SM22α in ROSI group[(23.17±4.23)%/(58.63±12.81)%]was higher than stenting group (P <0.05), VSMCphenotype from the contractile phenotype to asynthetic transformation; the expression levelof PPAR-γ/SM22α in ROSI group compared with the control group had no significantdifference (P>0.05).Conclusions1. Stent implantation could result in stent restenosis.2. PPAR-γ could be involved in the regulation of restenosis after carotid artery stentimplantation by regulating of vascular smooth muscle phenotype transformation inminipigs.3. PPAR-γ may be one of the target of prevention for cerebrovascular in-stentrestenosis.