嚴(yán)力 綜述 褚海波 審校

（中國人民解放軍第八十九醫(yī)院 普外中心，山東 濰坊 261021）

大隱靜脈曲張（great saphenous varicose vein，GSVV）是下肢常見疾病之一，以靜脈瓣功能不全、靜脈反流、靜脈擴(kuò)張和迂曲、管腔內(nèi)靜脈壓力增高為主要臨床特征，可并發(fā)靜脈血栓形成、淺表血栓性靜脈炎和靜脈性潰瘍[1-2]。大隱靜脈曲張發(fā)生率為20%～40%，老年人為高發(fā)人群[3]。多年來，盡管許多學(xué)者[4-5]致力于大隱靜脈曲張發(fā)病機(jī)制的研究，但一直尚無定論。研究[6-7]顯示，靜脈壁中細(xì)胞和細(xì)胞外基質(zhì)成分的改變，包括內(nèi)膜增生、平滑肌細(xì)胞功能失調(diào)、膠原和彈力纖維比例的變化、基質(zhì)金屬蛋白酶（matrix metalloproteinases，MMPs）及其組織抑制劑（tissue inhibitor of metalloproteinase，TIMPs）的失衡，可能是導(dǎo)致靜脈壁松弛、薄弱，繼而靜脈膨張、靜脈瓣關(guān)閉不全和反流的主要因素。生物組織中含有多種具有特定表型的細(xì)胞群，在組織穩(wěn)態(tài)中依據(jù)各自的作用相互間調(diào)節(jié)，通過細(xì)胞微環(huán)境中的信號(hào)維持這些細(xì)胞靜息與激活之間的平衡。近年來，在控制細(xì)胞命運(yùn)和功能的微環(huán)境刺激中，機(jī)械力的重要性逐漸受到關(guān)注[8]?，F(xiàn)已明確，外部壓力（如流體靜力壓、拉伸張力或鞘壓）和細(xì)胞內(nèi)細(xì)胞骨架張力能驅(qū)動(dòng)轉(zhuǎn)錄調(diào)節(jié)改變[9]。此外，血管平滑肌細(xì)胞（vascular smooth muscle cells，VSMCs）的相對(duì)動(dòng)態(tài)環(huán)境，還涉及多種細(xì)胞內(nèi)外生物化學(xué)分子以及機(jī)械力的變化：包括生長因子、炎癥因子、血管活性因子、血流機(jī)械力以及活性氧等因素。鑒于靜脈高壓是靜脈曲張形成的一個(gè)重要因素，研究機(jī)械力在靜脈曲張病理形成中所起的作用已成為熱門課題。本文就大隱靜脈源性VSMCs表型轉(zhuǎn)化研究進(jìn)行歸納敘述，旨在為尋找防治靜脈曲張相關(guān)的藥物作用靶點(diǎn)奠定理論基礎(chǔ)。

1 VSMCs表型轉(zhuǎn)化的概念及特點(diǎn)

1989年，Baumbach等[10]提出“血管重塑”的概念，由此人們逐漸認(rèn)識(shí)到靜脈疾病的病理生理過程不僅是管壁形態(tài)結(jié)構(gòu)的改變，VSMCs表型轉(zhuǎn)化才是血管重塑的細(xì)胞學(xué)基礎(chǔ)和關(guān)鍵環(huán)節(jié)。與骨骼肌和心肌細(xì)胞不同，靜脈源性VSMCs表型具有分化可逆性和多樣性的特點(diǎn)。在胚胎發(fā)育過程中，VSMCs由未分化表型逐漸轉(zhuǎn)化為具有成熟特征的分化表型。當(dāng)血管受損或VSMCs受到生長因子、機(jī)械作用、血管活性物質(zhì)以及血流動(dòng)力學(xué)等因素刺激時(shí)，VSMCs又從分化型轉(zhuǎn)化為去分化型，并獲得增殖能力，對(duì)這一演變過程稱之為表型轉(zhuǎn)化（phenotypic transformation）。VSMCs是一種高度特異性細(xì)胞，其主要功能為收縮和血管張力調(diào)節(jié)，以控制血壓和血流[11]。根據(jù)細(xì)胞結(jié)構(gòu)和功能的不同，VSMCs有兩種表型，即收縮型（分化型）和合成型（去分化型或未分化型）。收縮型VSMCs，分化程度高，呈紡錘狀，胞漿內(nèi)肌絲豐富，高爾基復(fù)合體和線粒體較少，增殖和遷移能力差，其主要功能是維持血管壁的彈性和收縮血管。合成型VSMCs內(nèi)含大量的高爾基復(fù)合體、粗面內(nèi)質(zhì)網(wǎng)，肌絲含量少，合成和分泌功能旺盛，增殖和遷移能力強(qiáng)，并能產(chǎn)生大量的細(xì)胞外基質(zhì)，其主要功能是合成分泌基質(zhì)蛋白，并參與到血管壁重塑和損傷修復(fù)[12]。

2 VSMCs表型轉(zhuǎn)化標(biāo)志物

當(dāng)VSMCs受到外界刺激后，可通過激活多種信號(hào)通路來激發(fā)VSMCs表型轉(zhuǎn)化，以適應(yīng)靜脈高壓和缺氧對(duì)血管壁的影響。檢測VSMCs表型轉(zhuǎn)化的標(biāo)記物種類繁多，一般可分為收縮型標(biāo)記物和合成型標(biāo)記物，收縮性標(biāo)記物主要有平滑肌α-肌動(dòng)蛋白（α-SM-actin，α-SMA）、平滑肌22α（smooth muscle 22α，SM22α）、平滑肌肌球蛋白重鏈（smooth muscle-myosin heavy chain，SMMHC）、平滑肌蛋白（smoothelin）、以及H-鈣調(diào)素結(jié)合蛋白（caldesmon），合成型標(biāo)記物主要有骨橋蛋白（osteopontin，OPN）、上皮調(diào)節(jié)蛋白（epiregulin）等[13-18]。

2.1 收縮型表型標(biāo)志物

α-SMA是一種維持VSMCs形態(tài)和收縮的重要細(xì)胞骨架蛋白，在收縮型VSMCs中優(yōu)勢表達(dá)，是VSMC分化早期特異性標(biāo)志物；SM22α屬細(xì)胞骨架的結(jié)構(gòu)成分，但不是控制VSMCs收縮的必需蛋白；SM-MHC則是在胚胎形成時(shí)期VSMCs特異性表達(dá)的一種標(biāo)志蛋白，且SM-MHC在非SMCs細(xì)胞中不表達(dá)[19]。因此，SM-MHC被認(rèn)為是鑒別收縮型VSMCs的最常用標(biāo)志物之一。Smoothelin表達(dá)下調(diào)則提示收縮型VSMCs向合成型VSMCs轉(zhuǎn)化，常用于協(xié)同SM-MHC區(qū)分收縮型VSMCs和合成型VSMCs[20]。

2.2 合成型表型標(biāo)志物

合成型VSMCs的標(biāo)志物包括OPN和Epiregulin。OPN是一種富含唾液酸磷酸化和糖基化修飾的基質(zhì)糖蛋白。OPN是VSMCs表型轉(zhuǎn)化的起始促進(jìn)因子，其表達(dá)與VSMCs的增殖密和遷移密切相關(guān)。Epiregulin是表皮生長因子家族的成員之一，可促進(jìn)VSMCs的增殖。Takahashi等[21]研究顯示，Epiregulin是VSMCs去分化的主要自分泌和旁分泌因子，可通過趨化因子以及ERK和p38MAPK等信號(hào)通路來調(diào)控VSMCs的增殖和表型轉(zhuǎn)化，從而影響到“血管重塑”的病理生理過程。

VSMCs具有高度可塑性，并能在不同的表型狀態(tài)下生存[22]。VSMCs由收縮型調(diào)節(jié)至合成型依賴于環(huán)境改變，即增殖和遷移活性增加，收縮性喪失，細(xì)胞外基質(zhì)異常[23-24]。此外，VSMCs不同表型標(biāo)志物的表達(dá)受多種因素的調(diào)節(jié)如轉(zhuǎn)化生長因子β（transforming grow th factor β，TGF-β）、血小板衍生生長因子（platelet derived growth factor，PDGF）、miRNA等。Ha等[25]觀察大鼠胸主動(dòng)脈VSMCs表型轉(zhuǎn)化，發(fā)現(xiàn)收縮型VSMCs α-SMA和SM22α呈陽性表達(dá)。Hao等[26]研究發(fā)現(xiàn)，SM-MHC表達(dá)受TGF-β1信號(hào)通路的促進(jìn)，維持平滑肌收縮表型，Gareri等[27]則通過PDGF刺激VSMCs表型轉(zhuǎn)化，使得SM-MHC表達(dá)大量下降。Feng等[28]研究顯示，在體外血管收縮素（angiotensin II，Ang-II）可誘導(dǎo)VSMCs骨源性表型轉(zhuǎn)化和鈣化，同時(shí)發(fā)現(xiàn)α-SMA和SM22α標(biāo)記物下調(diào)，OPN標(biāo)記物上調(diào)。由此可見，在生理和病理狀態(tài)下，SMCs參與血管重塑，不同的標(biāo)記物反映不同的VSMCs表型，且表型變異和可逆性轉(zhuǎn)化是一個(gè)復(fù)雜和動(dòng)態(tài)的過程[29-31]。

3 細(xì)胞增殖、遷移與表型轉(zhuǎn)化

VSMCs表型轉(zhuǎn)化是血管重塑的細(xì)胞學(xué)基礎(chǔ)。成熟的VSMCs為收縮和分化表型，細(xì)胞的增生和合成能力低下，可表達(dá)多種收縮蛋白、離子通路、細(xì)胞收縮功能分子信號(hào)[32-33]。在病理狀態(tài)下，VSMCs由收縮表型轉(zhuǎn)化為合成和去分化表型，其特征是收縮能力喪失，細(xì)胞增生、遷移和基質(zhì)分泌異常[34]。動(dòng)物實(shí)驗(yàn)[35-36]表明，移植大隱靜脈管腔狹窄的主要原因是中膜和外膜的SMCs遷移至內(nèi)膜，導(dǎo)致新生內(nèi)膜增生。機(jī)械力和炎癥的協(xié)調(diào)可導(dǎo)致VSMCs增殖和遷移，其中炎性介子可通過白介素1β（interleukin 1β，IL-1β）和白介素18（interleukin 18，IL-18）信號(hào)通路誘導(dǎo)增殖和遷移[37]。Zhang等[38-39]研究發(fā)現(xiàn)，腫瘤壞死因子α（tumor necrosis factor α，TNF-α）可抑制絲裂素活化蛋白激酶磷酸酶（mitogen-activated protein kinase phosphatase，MAKP）炎性通路，降低炎性反應(yīng)。在刺激過程中，VSMCs表型由靜止收縮型轉(zhuǎn)化為促炎反應(yīng)型，SMCs向內(nèi)膜遷移，提示VSMCs增殖和遷移與炎癥相關(guān)。動(dòng)物實(shí)驗(yàn)顯示，血管細(xì)胞黏附分子1（vascular cell adhesion molecule-1，VCAM-1）或VCAM-1 siRNA表達(dá)能阻止單核/巨噬細(xì)胞募集反應(yīng)，抑制VSMCs增殖、遷移和新生內(nèi)膜形成[40-41]。在血管重塑過程中，VSMCs收縮表型和合成表型存在本質(zhì)性差異（即標(biāo)記物表達(dá)、細(xì)胞形態(tài)和活性）。合成型VSMCs源于中膜去分化收縮型VSMCs和外膜分化成纖維細(xì)胞及未分化間質(zhì)干細(xì)胞。合成型VSMCs收縮器（肌絲，致密體和斑）少，合成器（粗面內(nèi)質(zhì)網(wǎng)，高爾基體）增多[42]。諸多因素（物理、機(jī)械、缺氧、激素、氧化應(yīng)激、基因、鈣離子等）影響VSMCs表型，而VSMCs的增殖和遷移改變?nèi)Q于VSMCs表型。李源等[43]發(fā)現(xiàn)，源于曲張靜脈的VSMCs增殖和遷移能力比正常靜脈增加，提示VSMCs表型轉(zhuǎn)化影響細(xì)胞功能。有學(xué)者[44-45]認(rèn)為，VSMCs在分化和去分化之間表型轉(zhuǎn)化是一種可逆性變化，并伴隨著細(xì)胞與細(xì)胞、細(xì)胞基質(zhì)黏附網(wǎng)絡(luò)形態(tài)和功能的改變。因此，如何在分子水平調(diào)節(jié)VSMCs的增殖與遷移，控制細(xì)胞表型的轉(zhuǎn)化，可視為分子通路靶標(biāo)研究的發(fā)展趨勢[46-51]。

4 MMPs與表型轉(zhuǎn)化

MMPs是一種依賴于鋅離子的內(nèi)肽酶，具有降解細(xì)胞外基質(zhì)（extracellular matrix，ECM）蛋白作用。MMPs可與細(xì)胞膜上的生物活性分子相互作用，并能調(diào)節(jié)偶聯(lián)G蛋白受體和細(xì)胞信號(hào)。MMPs參與多種生理過程，并影響細(xì)胞增殖、遷移、變異。MMPs還涉及細(xì)胞凋亡、免疫反應(yīng)、組織修復(fù)、血管生成[52]。MMPs家族依據(jù)消化底物的不同分為膠原酶類，明膠酶類，基質(zhì)溶解素類、膜型金屬蛋白酶類和未分類[53]。MMPs有助于VSMCs增殖和遷移，遷移可促進(jìn)血管新生內(nèi)膜增生（即內(nèi)皮細(xì)胞和SMCs通過MAPK信號(hào)激活，刺激生長因子、細(xì)胞因子和MMPs的分泌）[54]。VSMCs表型變化決定MMPs代謝異常。合成表型收縮型喪失，ECM產(chǎn)生異常，VSMCs遷移增加；收縮表型低蛋白含量和增殖率，具有獨(dú)特的收縮蛋白和信號(hào)分子[55]。動(dòng)物實(shí)驗(yàn)表明，MMP-2和MMP-9在不同靜脈層表達(dá)有所差異。MMP-2表達(dá)主要位于外膜，MMP-9表達(dá)則位于內(nèi)皮細(xì)胞、中膜SMCs、外膜微血管。與此同時(shí)，炎癥可促進(jìn)MMP-2和MMP-9表達(dá)[56-57]。人體外細(xì)胞培養(yǎng)顯示，異常VSMCs其MMP-2和MMP-9呈高表達(dá)[55,58]。研究[59]發(fā)現(xiàn)，抵抗素可誘導(dǎo)MMP-2和MMP-9表達(dá)（mRNA和蛋白水平），抗MMP-2和MMP-9 IgG可抑制抵抗素誘導(dǎo)VSMCs遷移。TIMP-1優(yōu)先結(jié)合MMP-9，TIMP-2優(yōu)先結(jié)合MMP-2，抵抗素抑制TIMPs表達(dá)；WNT1誘導(dǎo)信號(hào)通道蛋白1（WNT1 inducible signaling pathway protein 1，WISPI）可促進(jìn)SMCs內(nèi)MMPs和TIMPs高表達(dá)[60]；氫可降低p38MAPK活性導(dǎo)致移植靜脈MMP-2和MMP-9低表達(dá)，抑制VSMCs遷移[61]；在增生的血管內(nèi)膜中，MMP-3 mRNA和蛋白呈高表達(dá)[62]；OPN和MMPs具有密切的關(guān)聯(lián)性，這與動(dòng)脈壓對(duì)移植靜脈刺激的適應(yīng)性有關(guān)[63]。VSMCs釋放MMPs降解ECM，并產(chǎn)生TIMPs，因此，MMPs和TIMPs的平衡決定ECM的動(dòng)態(tài)平衡[64-65]。動(dòng)物實(shí)驗(yàn)顯示，小鼠移植靜脈TIMP-1呈高表達(dá)。這一結(jié)果提示，TIMP-1可抑制MMPs，阻止斑塊發(fā)展，并增加其穩(wěn)定性[66]。結(jié)締組織生長因子是一種異常的纖維化介質(zhì)，它能通過結(jié)締組織生長因子信號(hào)通道調(diào)節(jié)ECM的合成，從而改變靜脈管壁纖維化的進(jìn)程[67]?？梢姡琈MPs與SMCs表型轉(zhuǎn)化關(guān)系密切，在VSMCs發(fā)生重構(gòu)過程中，MMPs和TIMPs通過分子信號(hào)通道調(diào)節(jié)發(fā)揮重要的生理和病理生理功能。

5 細(xì)胞凋亡與表型轉(zhuǎn)化

細(xì)胞凋亡是細(xì)胞內(nèi)有規(guī)律的自我消亡過程，細(xì)胞死亡的一種生理形式，受誘導(dǎo)基因（p53、bclxs、bax）、抑制基因（Bcl-2、bcl-xl、mcl-1）及參與基因（c-myc、c-fos）的調(diào)控[68]。細(xì)胞凋亡的作用是維持組織內(nèi)環(huán)境的穩(wěn)定性，以減少細(xì)胞的更新。細(xì)胞凋亡包括內(nèi)源性和外源性兩條通道。內(nèi)源性通道又稱線粒體通道，調(diào)節(jié)細(xì)胞凋亡啟動(dòng)蛋白（bax或Bcl-2）及特異胱門蛋白酶（caspase）刺激線粒體釋放細(xì)胞色素C進(jìn)入胞漿與凋亡蛋白酶活化因子1（APAF-1）結(jié)合引發(fā)細(xì)胞凋亡。外源性通道又稱跨膜通道，在細(xì)胞凋亡信號(hào)的刺激下，F(xiàn)asL和TNF-α作用相應(yīng)的受體導(dǎo)致細(xì)胞凋亡[69]。Whiteley等[70]獲取人曲張大隱靜脈標(biāo)本，采用免疫組化和免疫熒光法標(biāo)記p53，發(fā)現(xiàn)曲張靜脈SMCs凋亡上調(diào)，并與炎性標(biāo)記物呈正相關(guān)。研究發(fā)現(xiàn)，膜聯(lián)蛋白A2過表達(dá)和IncRNA低表達(dá)可促進(jìn)SMCs增殖與遷移，并減少SMCs凋亡[50]。誘導(dǎo)VSMCs缺氧模型顯示，VSMCs增殖與遷移增加，但與細(xì)胞凋亡無相關(guān)性[71]。在缺氧狀態(tài)下，金屬硫蛋白可阻止VSMCs凋亡，這一結(jié)果有可能為靜脈曲張的靶標(biāo)治療提供理論依據(jù)[72]。許多學(xué)者[1,73]認(rèn)為，VSMCs凋亡與年齡和性別密切相關(guān)。＞50歲和女性細(xì)胞凋亡明顯增加，故研究VSMCs凋亡與表型轉(zhuǎn)化應(yīng)考慮年齡和性別因素。文獻(xiàn)[74]報(bào)道，炎性因子可增加VSMCs增殖與遷移，并經(jīng)p38MAPK-HSPS27分子通道誘導(dǎo)細(xì)胞凋亡。同源異型盒蛋白過表達(dá)可促進(jìn)VSMCs增殖與遷移及抗凋亡能力，上調(diào)OPN可有利于VSMCs表型轉(zhuǎn)化[30]。細(xì)胞自體吞噬作用可抑制肌餓誘導(dǎo)VSMCs凋亡，而異常自體吞噬作用可調(diào)節(jié)VSMCs的功能[75]。小窩蛋白3能調(diào)節(jié)VSMCs收縮和合成型的轉(zhuǎn)型，抑制細(xì)胞凋亡[76]。由此可見，VSMCs凋亡的變化是建立在表型變化的基礎(chǔ)上，表型的異常必定影響細(xì)胞的凋亡。

6 表觀遺傳學(xué)調(diào)控與表型轉(zhuǎn)化

VSMCs的表型轉(zhuǎn)化受多種因素影響，其中，表觀遺傳學(xué)調(diào)控機(jī)制在VSMCs表型轉(zhuǎn)化中所起到的重要作用日益受到人們重視。表觀遺傳通常被定義為不涉及DNA核苷酸序列改變的基因表達(dá)和調(diào)控的可遺傳修飾，通常是由于環(huán)境因素而引發(fā)改變，主要包括DNA甲基化、組蛋白修飾、非編碼RNA以及染色質(zhì)重塑等。研究表明，表觀遺傳對(duì)VSMCs表型轉(zhuǎn)化的調(diào)控主要是通過對(duì)其表型標(biāo)志基因（例如：α-SMA、SM22α、SM-MHC、OPN等）表達(dá)的調(diào)控來實(shí)現(xiàn)[34,77-78]。Hiltunen等[79]的早期研究通過高效液相色譜法檢測體內(nèi)VSMCs染色體5-甲基胞嘧啶含量發(fā)現(xiàn)，動(dòng)脈粥樣硬化模型VSMCs表型轉(zhuǎn)化過程中呈現(xiàn)全基因組的低甲基化狀態(tài)；同樣在體外實(shí)驗(yàn)，細(xì)胞增殖過程中collagen type VX α1基因的低甲基化誘導(dǎo)相應(yīng)基因高表達(dá)進(jìn)而調(diào)控VSMCs的表型轉(zhuǎn)化并影響動(dòng)脈粥樣硬化的發(fā)展[80]。近年來，更多的實(shí)驗(yàn)研究發(fā)現(xiàn)，DNA的異常甲基化可通過特定的基因修飾來調(diào)控VSMCs的表型轉(zhuǎn)化并影響到相關(guān)血管疾病進(jìn)程。Jiang等[34]研究發(fā)現(xiàn)靜脈曲張VSMCs中OPN基因啟動(dòng)子的低甲基化可能是誘導(dǎo)OPN高表達(dá)的重要因素，提示異常的表觀遺傳修飾參與了VSMCs的表型轉(zhuǎn)化并導(dǎo)致新生血管內(nèi)膜增厚進(jìn)而影響靜脈曲張的發(fā)生與發(fā)展。Ali等[81]證實(shí)腫瘤壞死因子α（tumor necrosis factor-α，TNT-α）可誘導(dǎo)SMCs收縮型基因（α-SMA、SM-MHC）啟動(dòng)子甲基化并通過Krupper樣因子4（Krupper like factor-4，KLF-4）調(diào)節(jié)通路來誘導(dǎo)大鼠腦SMCs表型變化。組蛋白修飾多發(fā)生于細(xì)胞生長發(fā)育期，通過調(diào)控血清反應(yīng)因子（serum response factor，SRF）及其輔助因子與染色質(zhì)模板的結(jié)合來改變外環(huán)境，從而影響VSMCs分化過程[82-83]。由于組蛋白修飾的VSMCs限制性位點(diǎn)位于VSMCs基因染色質(zhì)的CArG box序列，SRF及其輔助因子與VSMCs染色質(zhì)啟動(dòng)子CArG box DNA序列相互反應(yīng)是引起VSMCs在生長發(fā)育和表型轉(zhuǎn)化過程中的信號(hào)通路關(guān)鍵環(huán)節(jié)。此外，有研究[84]表明，高脂飲食可誘導(dǎo)DNA甲基轉(zhuǎn)移酶1（DNA methyltransferase 1，DNMT-1）負(fù)性調(diào)控因子miR-152下調(diào)，進(jìn)而導(dǎo)致主動(dòng)脈VSMCs雌激素受體α基因（Estrogen receptor α gene，ER-α）高甲基化，而染色質(zhì)重塑亦被發(fā)現(xiàn)在VSMCs分化過程中起到關(guān)鍵作用[77]。與此同時(shí)，一些新的調(diào)控靶點(diǎn)如TET-2（ten-eleven translocation 2）以及YAP（yesassociated protein）相關(guān)研究的出現(xiàn)進(jìn)一步完善了VSMCs表型轉(zhuǎn)化與血管性疾病發(fā)生發(fā)展的機(jī)制探索[85-86]。由此可見，VSMCs的可塑性與細(xì)胞外部環(huán)境和表觀遺傳調(diào)控機(jī)制密切相關(guān)，然而，不同于DNA序列的改變，許多表觀遺傳的改變是可逆的，因此，如何從表觀遺傳調(diào)控水平去調(diào)節(jié)并控制VSMCs表型轉(zhuǎn)化，可作為相應(yīng)血管類疾病靶向治療的研究思考方向。

7 結(jié) 語

綜上所述，大隱靜脈源性VSMCs表型轉(zhuǎn)化是血管重塑的細(xì)胞學(xué)基礎(chǔ)。VSMCs表型轉(zhuǎn)化除了與其基因表達(dá)譜改變有關(guān)外，還受細(xì)胞骨架結(jié)構(gòu)與功能的影響。設(shè)想建立人正常靜脈VSMCs和曲張靜脈VSMCs細(xì)胞單層培養(yǎng)系統(tǒng)，從VSMCs增殖、遷移、黏附、衰老、骨架、MMPs和TIMPs分泌和細(xì)胞凋亡方面研究曲張大隱靜脈來源VSMCs的生物學(xué)變化特征，有助于初步證實(shí)曲張大隱靜脈、淺表血栓性靜脈炎及缺氧誘導(dǎo)正常靜脈VSMCs從收縮型向合成型轉(zhuǎn)化并獲得增生、遷移和分泌大量細(xì)胞外基質(zhì)的能力。

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