张晓婷,刘峰,王炳银

• 1:徐州医科大学研究生学院
• 2:上海交通大学附属苏州九龙医院心内科

摘要(Abstract)：

目的观察血管内皮生长因子(VEGF)、胎盘生长因子(PLGF)单独使用和联合使用对急性心肌梗死大鼠心肌梗死缺血边缘区血管新生和心功能的影响。方法 75只雄性SD大鼠随机分为5组:sham组(假手术组),NS组(250μl生理盐水),VEGF组(1μg重组鼠VEGF溶于250μl生理盐水),PLGF组(1μg重组鼠PLGF溶于250μl生理盐水),VEGF+PLGF组(重组鼠VEGF 0.5μg+重组鼠PLGF 0.5μg溶于250μl生理盐水)。sham组大鼠仅开胸,不结扎左前降支,并且不注射药物,其余所有大鼠均结扎左前降支近端,建立急性心肌梗死模型,并于心肌梗死缺血边缘区注射VEGF和PLGF。术后3周,以超声心动图评估大鼠心脏结构及功能,测定梗死范围,用免疫组织化学方法检测大鼠心肌梗死缺血边缘区Ⅷ因子相关抗原(v WF)染色阳性的内皮细胞评估新生血管数量,α平滑肌肌动蛋白(α-SMA)染色阳性的平滑肌细胞评估新生小动脉数量。结果冠状动脉结扎3周后,sham组大鼠LVEDD、LVESD、LVEF及LVFS明显优于其余各组,差异均有统计意义(均P<0.01);与NS组、VEGF组及PLGF组比较,VEGF+PLGF组LVEF、LVFS显著增高,而LVEDD及LVESD则显著减少(均P<0.05)。sham组心肌梗死范围显著小于其余四组,差异均有统计意义(均P<0.01);VEGF+PLGF组大鼠梗死范围显著小于NS组[(19.75±3.98)%比(38.70±7.45)%,P<0.01]、VEGF组[(19.75±3.98)%比(32.20±6.00)%,P<0.05]及PLGF组[(19.75±3.98)%比(25.09±5.52)%,P<0.05],差异均有统计学意义。sham组v WF阳性细胞数量和α-SMA阳性细胞数量显著小于其余四组,差异均有统计学意义(均P<0.01);其余四组大鼠v WF阳性细胞数量和α-SMA阳性细胞数量比较,差异均有统计学意义(均P<0.05);而VEGF+PLGF组v WF阳性细胞数量[(64.08±10.89)个/mm2比(55.09±8.20)个/mm2,P<0.05]、α-SMA阳性细胞数量[(11.42±3.15)个/mm2比(9.00±2.19)个/mm2,P<0.05]均高于PLGF组,差异均有统计学意义。结论将半剂量的VEGF与PLGF联合应用可使心肌梗死缺血边缘区毛细血管和小动脉生成增多,心肌梗死范围减小,并且明显改善心功能。

关键词(KeyWords)： 急性心肌梗死;血管内皮生长因子;胎盘生长因子;血管新生

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 张晓婷,刘峰,王炳银

参考文献(References)：

• [1]Lassaletta AD,Chu LM,Sellke FW.Therapeutic neovascularization for coronary disease:current state and future prospects.Basic Res Cardiol,2011,106(6):897-909.
• [2]Terzic A,Nelson TJ.Regenerative medicine advancing health care 2020.J Am Coll Cardiol,2010,55(20):2554-2557.
• [3]Gospodarowicz D,Abraham J,Schilling J.Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells.Proc Natl Acad Sci U S A,1989,86(19):7311-7315.
• [4]Binsalamah ZM,Paul A,Khan AA,et al.Intramyocardial sustained delivery of placental growth factor using nanoparticles as a vehicle for delivery in the rat infarct model.Int J Nanomedicine,2011,6:2667-2678.
• [5]许官学,石蓓,盛瑾,等.改良大鼠急性心肌梗死模型的制备方法.中国老年学杂志,2013,33(14):3367-3370.
• [6]Wykrzykowska JJ,Rosinberg A,Lee SU,et al.Autologous cardiomyotisue implantation promotes myocardial regeneration,decreases infarct size,and improves left ventricular function.Circulation,2011,123(1):62-69.
• [7]Douvaras P,Antonatoa DG,Kekou K,et al.Association of VEGF gene polymorphisms with the development of heart failure in patients after myocardial infarction.Cardiology,2009,114(1):11-18.
• [8]Destaing O,Planus E,Bouvard D,et al.β1A integrin is a master regulator of invadosome organization and function.Mol Biol Cell,2010,21(23):4108-4119.
• [9]Takahashi T,Yamaguchi S,Chida K,et al.A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-Adependent activation of PLC-γand DNA synthesis in vascular endothelial cells.EMBO J,2001,20(11):2768-2778.
• [10]Sarbassov DD,Guertin DA,Ali SM,et al.Phosphorylation and regulation of Akt/PKB by the rictor-m TOR complex.Science,2005,307(5712):1098-10101.
• [11]Jacinto E,Facchinetti V,Liu D,et al.SIN1/MIP1 maintains rictor-m TOR complex integrity and regulates Akt phosphorylation and substrate specificity.Cell,2006,127(1):125-137.
• [12]Rotllan N,Wanschel AC,Fernández-Hernando A,et al.Genetic evidence supports a major role for Akt1 in VSMCs during atherogenesis.Circ Res,2015,116(11):1744-1752.
• [13]Aspalter IM,Gordon E,Dubrac A,et al.Alk1 and Alk5inhibition by Nrp1 controls vascular sprouting downstream of Notch.Nat Commun,2015,6:7264.
• [14]Thurston G,Suri C,Smith K,et al.Leakage-resistant blood vessels in mice tansgenically overexpressing angiopoietin-1.Science,1999,286(5449):2511-2514.
• [15]Hershey JC,Baskin EP,Corcoran HA,et al.Vascular endothelial growth factor stimulates angiogenesis without improving collateral blood flow following hindlimb ischemia in rabbits.Heart Vessels,2003,18(3):142-149.
• [16]阿迪拉·阿扎提,马翔,刘芬,等.可降解材料纤维蛋白胶介导血管内皮细胞生长因子对心肌梗死组织血管再生的影响.中国组织工程研究,2008,12(27):5253-5256.
• [17]Cheng C,Li P,Wang YG,et al.Study on the expression of VEGF and HIF-1αin infarct area of rats with AMI.Eur Rev Med Pharmacol Sci,2016,20(1):115-119.
• [18]Tchaikovski V,Fellbrich G,Waltenberger J.The molecular basis of VEGFR-1 signal transduction pathways in primary human monocytes.Arterioscler Thromb Vasc Biol,2008,28(2):322-328.
• [19]Bellik L,Vinic MC,Filippi S,et al.Intracellular pathways triggered by the selective FLT-1-agonist placental growth factor in vascular smooth muscle cells exposed to hypoxia.Br J Pharmacol,2005,146(4):568-575.
• [20]Roncal C,Buysschaert I,Chorianopoulos E,et al.Beneficial effects of prolonged systemic administration of PLGF on late outcome of post-ischaemic myocardial performance.J Pathol,2008,216(2):236-244.
• [21]Kiselyov A,Balakin KV,Tkachenko SE.VEGF/VEGFR signaling as a target for inhibiting angiogenesis.Expert Opin Investig Drugs,2007,16(1):83-107.
• [22]Luttun A,Tjwa M,Moons L,et al.Revascularization of ischemic tissues by PLGF treatment,and inhibition of tumor angiogenesis,arthritis and atherosclerosis by anti-Flt1.Nat Med,2002,8(8):831-840.