王 瑞， 沈 靂

復(fù)旦大學(xué)附屬中山醫(yī)院心內(nèi)科，上海市心血管病研究所，上海 200032

血管平滑肌細(xì)胞(vascular smooth muscle cells, VSMCs)是血管壁的重要組成部分，也是維持血管張力的主要細(xì)胞成分[1-2]。血管平滑肌表型改變引起的結(jié)構(gòu)和功能變化在高血壓、肺動脈高壓等大血管疾病的病理生理過程中發(fā)揮重要作用[3-6]。此外，血管平滑肌的遷移、增殖、凋亡及表型轉(zhuǎn)變在動脈粥樣硬化的發(fā)生發(fā)展和靜脈旁路移植和金屬支架植入后血管壁的重構(gòu)過程中也起著關(guān)鍵作用[7-9]。

生理狀態(tài)下心臟泵出的周期搏動的血流維持著血管系統(tǒng)的穩(wěn)態(tài)，產(chǎn)生的兩種主要生物機械力，包括剪切力(shear stress)和牽張應(yīng)力(stretch stress)，它們通過力學(xué)感受器影響著細(xì)胞內(nèi)信號轉(zhuǎn)導(dǎo)、基因和蛋白的表達(dá)，調(diào)節(jié)著內(nèi)皮細(xì)胞和平滑肌細(xì)胞的功能。剪切力主要作用于內(nèi)皮細(xì)胞，因其與內(nèi)皮的直接作用，較早地被人們所認(rèn)識[2]。牽張力由頻率、幅度和時間3個主要要素構(gòu)成，其大小為剪切力的數(shù)十倍，引起血管壁發(fā)生的形變被稱為牽張應(yīng)變(stretch strain)。平滑肌細(xì)胞是血管壁中主要承受脈動血流產(chǎn)生的牽張力的細(xì)胞，二者的相互作用對血管重構(gòu)的進程發(fā)揮著至關(guān)重要的影響。因此，本文旨在從血管平滑肌細(xì)胞的角度就牽張應(yīng)力對血管重構(gòu)的影響作一綜述。

1 力學(xué)感受器及信號通路

近年來，人們一直致力于特異性機械力感受器的尋找，它的發(fā)現(xiàn)將為高血壓藥物的開發(fā)提供靶標(biāo)，也將對心血管疾病引起的血管重構(gòu)提供有效的治療手段，遺憾的是至今仍無明確結(jié)果。但細(xì)胞膜上固有的一些細(xì)胞連接蛋白和受體也可以發(fā)揮非特異性機械力感受器的職能。

1.1 整合素(integrin) Wernig等[10]發(fā)現(xiàn)對于培養(yǎng)在預(yù)包被不同物質(zhì)基底上的大鼠VSMCs，只有對培養(yǎng)在包被Ⅰ型膠原基底上的VSMCs施加周期性張應(yīng)力時，可觀察到明顯的細(xì)胞凋亡，提示與Ⅰ型膠原連接相關(guān)的整合素β1可能是機械力的感受器。進一步采用整合素β1抗體及整合素抑制劑細(xì)胞松弛素B可阻斷張應(yīng)力引起的p38MAPK(mitogen-activated protein kinase, 絲裂原活化蛋白激酶)磷酸化及p53的表達(dá)。結(jié)果進一步證實了張應(yīng)力-Ⅰ-integrin-rac-p38-p53這一凋亡調(diào)控通路。10%周期性牽張的條件下整合素αvβ3表達(dá)增加，同時增加大鼠VSMCs表面血凝素的表達(dá)，這個過程可以被整合素αvβ3拮抗劑cRGDPV、αv-siRNA及選擇性阻滯αvβ3內(nèi)到信號轉(zhuǎn)導(dǎo)的talin-siRNA所阻斷[11]。整合素αvβ3可能通過對PINCH-1的穩(wěn)定來發(fā)揮其生理性保護作用[12]。

整合素力學(xué)傳導(dǎo)功能的發(fā)揮離不開脂筏及整合素相關(guān)蛋白如人黏著斑激酶(focal adhesion kinase, FAK)、富含脯氨酸的非受體酪氨酸激酶(proline-rich tyrosine kinase 2, PYK2)、尿激酶纖維蛋白溶酶原激活物受體(urokinase-type plasminogen activator receptor, uPAR)的協(xié)助。牽張力作用于整合素，在uPAR的協(xié)助下下調(diào)細(xì)胞因子信號抑制物1(suppressor of cytokine signaling 1, SOCS-1)的表達(dá)，從而減少FAK的泛素化和降解，影響平滑肌細(xì)胞外基質(zhì)的分泌和表型轉(zhuǎn)變[13]。而牽張力引起的PYK2磷酸化水平的提高僅與平滑肌細(xì)胞的增殖有關(guān)，并未顯著改變其收縮表型[14]。

1.2 牽張激活性離子通道(stretch-activated channel, SAC) 牽張相關(guān)的鈣離子通道廣泛存在于平滑肌細(xì)胞中，如豬冠脈平滑肌、大鼠腸系膜動脈平滑肌、大鼠主動脈平滑肌以及大鼠肺動脈平滑肌等[4,6,15-16]。牽張可以引起這類通道的開放導(dǎo)致非選擇性的K+、Ca2+、Na+的內(nèi)流，使細(xì)胞膜去極化，可以被SAC阻滯劑Gd、鏈霉素、GsMTx-4等抑制[17]。牽張同時可引起瞬時受體電位通道4(transient receptor potential channels 4, TRPC4)蛋白的下調(diào)，這可能是一種保護機制，防止過多的Ca2+內(nèi)流。VSMCs的Ca2+內(nèi)流激活一系列下游通路，如EGFR、ERK1/2。CAKβ(cell adhesion kinase β)也與非選擇性離子通道的開放有關(guān)[18]，同時發(fā)現(xiàn)c-Src是通過與CAKβ結(jié)合發(fā)揮作用的CAKβ的下游信號通路。SAC的激活與生理狀態(tài)下細(xì)胞對牽張應(yīng)力的反應(yīng)有關(guān)；而在病理狀態(tài)，如肺動脈高壓時，內(nèi)質(zhì)網(wǎng)RyR受體的空間分布異常和胞內(nèi)Ca2+儲量增加與牽張是引起的Ca2+釋放的關(guān)鍵因素[19]。Naruse等[20]在人臍靜脈內(nèi)皮細(xì)胞上證實樁蛋白(paxillin)、FAK、Crk相關(guān)底物(Crk-associated substrate, pp130CAS)的激活與SAC有關(guān)，但在VSMCs上尚缺乏驗證。除鈣離子通道外，Wan等[20-21]報道了牽張力作用下大電導(dǎo)鈣激活鉀通道(large conductance calcium and voltage-activated potassium, BKca)的激活，并探究了應(yīng)激調(diào)控外顯子(stress axis-regulated exons, STREX)對BKca感受機械牽張的重要作用。Hayabuchi等[22-23]發(fā)現(xiàn)，中等電導(dǎo)鈣激活鉀離子通道(intermediate-conductance Ca2+-activated K+, IKca)因細(xì)胞膜牽張而激活，而IKca的激活還可被PKC抑制劑GF109203X、松胞素D抑制。

1.3 血小板衍生因子受體(platelet derived growth factor, PDGFR) PDGFR是一種跨膜糖蛋白，具有酪氨酸蛋白激酶活性，當(dāng)受體與其配體結(jié)合后激活細(xì)胞內(nèi)結(jié)構(gòu)域酪氨酸殘基自身磷酸化，或促使激活特殊靶蛋白的酪氨酸殘基磷酸化，將信號傳入細(xì)胞內(nèi)。PDGFR由2種亞單位α及β構(gòu)成，各自與PDGF結(jié)合力不同，α單位與PDGFA鏈及B鏈有較高的親和力，而β亞單位僅與B鏈有高親和力[24]。機械牽張力可以同時激活PDGFR-α和PDGFR-β，但僅PDGFR-β與Akt通路的激活有關(guān)并引起基質(zhì)金屬蛋白酶2(matrix metallopeptidase, MMP-2)表達(dá)增加。且牽張應(yīng)力僅引起血管平滑肌PDGFR-β表達(dá)增加，而對內(nèi)皮無影響[25]。Hu等[26]也觀察到了牽張應(yīng)力引起的PDGFR-α激活，且證明了張應(yīng)力不是通過受體-配體途徑激活PDGFR，而是可能由于力的直接作用擾亂細(xì)胞膜功能或引起受體構(gòu)象改變而造成。

1.4 G蛋白偶聯(lián)受體(G protein-coupled receptors, GPCRs) GPCRs為7次跨膜蛋白，廣泛存在于真核細(xì)胞細(xì)胞膜表面，調(diào)控著細(xì)胞對激素、神經(jīng)遞質(zhì)、趨化因子等的應(yīng)答，參與視覺、嗅覺和味覺的形成，是40%藥物的作用靶標(biāo)。心肌細(xì)胞牽張應(yīng)力激活血管緊張素受體-1(angiotensin type 1 receptor, AT1 receptor)的過程與血管緊張素2(AngⅡ)無關(guān)，可被AT-1受體反向激動劑抑制[27]。增加對機械力無反應(yīng)的大鼠主動脈A7r5細(xì)胞的AT-1受體密度，可以使細(xì)胞出現(xiàn)機械力感受能力，應(yīng)用AT-1受體反向激動劑后，大鼠大腦動脈和腎動脈肌源性緊張極度降低[28]。這些發(fā)現(xiàn)證實了G蛋白偶聯(lián)受體在VSMCs也發(fā)揮著機械力感受器的作用。

1.5 斑聯(lián)蛋白(zyxin) 斑聯(lián)蛋白是一種結(jié)構(gòu)蛋白，調(diào)節(jié)著肌動蛋白在黏著斑處的聚合，通過召集血管舒張劑刺激磷蛋白(vasodilator-stimulated phosphoprotein, VASP)參與應(yīng)力纖維的修復(fù)與重建[29-30]。Cattaruzza等[31]首先觀察到使用15%機械牽張刺激大鼠主動脈血管平滑肌細(xì)胞時，斑聯(lián)蛋白從黏著斑上脫離，并在細(xì)胞核內(nèi)聚集，且證實斑聯(lián)蛋白的存在與機械力傳導(dǎo)相關(guān)的基因表達(dá)有關(guān)。這一發(fā)現(xiàn)使得斑聯(lián)蛋白成為第1個能直接接受機械力刺激向細(xì)胞核內(nèi)轉(zhuǎn)位，從而發(fā)揮轉(zhuǎn)錄因子作用的分子。Ghosh等[32]驗證了Cattaruzza團隊在細(xì)胞學(xué)層面的發(fā)現(xiàn)，他們通過使用斑聯(lián)蛋白敲除鼠證實90%左右與牽張力有關(guān)的基因表達(dá)與斑聯(lián)蛋白有關(guān)。且缺乏斑聯(lián)蛋白的小鼠血管平滑肌明顯轉(zhuǎn)變?yōu)榉置诒硇?，增殖加快，凋亡減少。雖然細(xì)胞學(xué)改變明顯，但使用醋酸去氧皮質(zhì)酮(DOCA)鹽誘導(dǎo)小鼠高血壓時，斑聯(lián)蛋白敲除小鼠與野生型小鼠相比并未表現(xiàn)出血壓的差異和明顯的動脈重構(gòu)。斑聯(lián)蛋白在細(xì)胞層面的作用可能被動物機體的某些因素所掩蓋了。因此，未來需要更多動物層面的實驗來闡明斑聯(lián)蛋白作為力學(xué)感受器的作用。

2 牽張應(yīng)力對平滑肌細(xì)胞功能的影響

2.1 細(xì)胞增殖 機體在高血壓狀態(tài)下，主動脈平滑肌細(xì)胞張應(yīng)變可以較常人增加30%，大多數(shù)實驗將10%以上的張應(yīng)變定義為病理性，將5%～7%的張應(yīng)變定義為生理性。VSMCs增殖狀態(tài)與張應(yīng)變大小密切相關(guān)[33]。5%的張應(yīng)變抑制動脈VSMCs增殖，使其處于穩(wěn)定狀態(tài)；15%的張應(yīng)變顯著刺激動脈VSMCs增殖，可能與血管重構(gòu)等病理過程有關(guān)[34]。Morrow和Waard等研究團隊發(fā)現(xiàn)，10%的張應(yīng)變可使動脈VSMCs維持一個相對靜息的狀態(tài)，增殖活性降低[35-36]。而其他研究[33-37]發(fā)現(xiàn)10%的張應(yīng)變能通過增加AngII和PDGF的表達(dá)，促進動脈VSMCs增殖。這種矛盾結(jié)果的出現(xiàn)可能與細(xì)胞的種屬來源有關(guān)，前兩者的實驗結(jié)果是基于兔和人來源的原代動脈平滑肌細(xì)胞，而后兩者使用的則是鼠源動脈平滑肌，種屬間生理性牽張應(yīng)力存在差異。靜脈VSMCs對牽張應(yīng)力的反應(yīng)與動脈VSMCs反應(yīng)大不相同，10%張應(yīng)變可引起人大隱靜脈VSMCs發(fā)生明顯增殖，而乳內(nèi)動脈VSMCs處于一個相對靜息的狀態(tài)[36]。除上述途徑外，張應(yīng)力對細(xì)胞增殖的影響還可能通過Rho-GDIα(guanine dissociation inhibitor, GDP解離抑制因子α)、植物血凝素樣氧化低密度脂蛋白受體(lectin like Ox-LDL receptor-1,LOX-1)、雷帕霉素靶蛋白(mTOR)/核糖體S6蛋白激酶、Notch受體以及L-脯氨酸轉(zhuǎn)運等途徑實現(xiàn)[33,35,37-39]。Ochoa等[3]在肺動脈管壁細(xì)胞中發(fā)現(xiàn)，內(nèi)皮細(xì)胞與平滑肌細(xì)胞的交互作用也是生理性張應(yīng)力抑制平滑肌細(xì)胞增殖的機制之一。結(jié)果發(fā)現(xiàn)暴露于生理性張應(yīng)變下內(nèi)皮細(xì)胞的條件培養(yǎng)液可抑制肺動脈平滑肌細(xì)胞增殖，而這一過程可以被血小板反應(yīng)蛋白-1(thrombospondin-1, TSP-1)逆轉(zhuǎn)。同時，ox-LDL和AngⅡ可與病理性張應(yīng)變協(xié)同促進VSMCs的增殖。辛伐他汀可通過部分抑制LOX-1途徑來抑制ox-LDL與張應(yīng)變協(xié)同引起的VSMCs增殖[38]。

2.2 細(xì)胞凋亡 15%的張應(yīng)變可激活氧化DNA損傷與rac-p38MAPK通路，從而介導(dǎo)p53依賴的細(xì)胞凋亡[40]。Wernig等[41]證實了此通路并提出整合素β1作為其上游分子。內(nèi)質(zhì)網(wǎng)應(yīng)激也參與了病理性牽張力引起的細(xì)胞凋亡過程，20%的張應(yīng)變可引起內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)蛋白GADD153(growth arrest and DNA damage-inducible gene153)、p53上調(diào)凋亡調(diào)節(jié)因子(p53 upregulated modulator of apoptosis, PUMA)的表達(dá)，導(dǎo)致平滑肌細(xì)胞凋亡，而10%的張應(yīng)變對GADD153和PUMA的表達(dá)無影響[42-43]。但Morrow等[44]研究發(fā)現(xiàn)，10%的張應(yīng)變就足以誘導(dǎo)血管平滑肌的凋亡，10%的張應(yīng)變可顯著降低Notch1和Notch3的表達(dá)水平，并具有時間依賴性，Notch3表達(dá)降低增加了Bax并降低了Bcl-xL的表達(dá)，從而啟動了血管平滑肌的凋亡。一系列細(xì)胞死亡相關(guān)受體，如腫瘤壞死因子α受體1(tumor necrosis factor-α receptor-1, TNFR-1)及其相關(guān)因子TRAF-2(TNF-α receptor-associated factor-2)也與機械牽張引起的細(xì)胞凋亡有關(guān)[44]。

2.3 細(xì)胞遷移 VSMCs遷移在血管成形術(shù)后再狹窄以及動脈粥樣硬化的病理過程中發(fā)揮重要作用[45]。Zhang與Qi等團隊的研究均發(fā)現(xiàn)15%的張應(yīng)變與5%張應(yīng)變相比顯著增加VSMCs的遷移率[39,46]。Akt/PKB、Rac1/p38通路及組氨酸去乙酰化酶(histone deacetylases, HDACs)的激活是細(xì)胞遷移率增加的可能機制[47]。此外，高牽張應(yīng)變激活活化T細(xì)胞核因子-5(nuclear factor of activated T cells 5, NFAT-5)來調(diào)節(jié)腱生蛋白-C(tenascin-C)的表達(dá)，可能是導(dǎo)致VSMCs遷移增加促進高血壓引起的動脈硬化的機制，NFAT-5的激活可能與c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)有關(guān)[48-49]。

2.4 細(xì)胞表型 培養(yǎng)狀態(tài)下的VSMCs可快速從生理性的收縮表型轉(zhuǎn)換為相對分化程度低的分泌表型，這種去分化可使平滑肌細(xì)胞發(fā)生收縮功能障礙，促進血管重構(gòu)，引起血管壁硬化[50]。于是有人假設(shè)血管壁生理狀態(tài)下所受的力學(xué)刺激可以阻止這種去分化的過程，使VSMCs保持收縮表型。這一假設(shè)得到了Rodríguez等的證實，他們發(fā)現(xiàn)周期性牽張可以增加VSMCs內(nèi)氧化應(yīng)激水平，導(dǎo)致細(xì)胞的去分化，肌細(xì)胞增強因子2B(myocyte enhancer binding factor 2B, MEF2B)介導(dǎo)了NADPH氧化酶1(Nox-1)來源的活性氧簇(ROS)的增加[51]。Jiang等[52]隨后的實驗也顯示機械應(yīng)變可增加平滑肌細(xì)胞α肌動蛋白(α-actin)、calponin以及細(xì)胞骨架相關(guān)蛋白SM22α蛋白的表達(dá)，周期性牽張應(yīng)變引起的平滑肌細(xì)胞表型改變是通過SIRT1/FoxO通路激活介導(dǎo)的。

Hu等[53]的研究顯示，與生理性機械刺激相反，病理性牽張應(yīng)變(16%)抑制miRNA145表達(dá)，降低VSMCs收縮表型的標(biāo)志物水平，miRNA145的過表達(dá)可使其部分恢復(fù)。miRNA145類似物的應(yīng)用可改變周期性牽張引起的VSMCs表型主要的調(diào)控蛋白心肌素(myocardin)和Krüppel樣因子4(Krüppel-like factor4, KLF4)蛋白的表達(dá)。周期性牽張應(yīng)變引起的ERK通路的激活和ACE的表達(dá)可能與miRNA145抑制有關(guān)。

總之，血管的負(fù)性重構(gòu)主要表現(xiàn)為血管順應(yīng)性的降低、血管外彈力膜面積的縮小和管腔的狹窄。病理性牽張力通過平滑肌力學(xué)感受器感知，通過下游信號的調(diào)節(jié)，促進血管中膜平滑肌細(xì)胞向內(nèi)膜遷移，并引起平滑肌增殖，使其由穩(wěn)定的收縮表型向分泌型轉(zhuǎn)變，進而引起MMP-2分泌增加，細(xì)胞外基質(zhì)構(gòu)成改變，最終造成血管重構(gòu)[54]。此外，血管平滑肌細(xì)胞血管內(nèi)皮生長因子(vascular endothelial growth factor, VEGF)和缺氧誘導(dǎo)因子1α(hypoxia-inducible factor-1α, HIF1α)基因的表達(dá)也可能在牽張應(yīng)力引起的血管重構(gòu)中發(fā)揮著一定的作用[55-56]。

3 牽張應(yīng)力與臨床疾病

血管生理環(huán)境的變化及外部因素的影響可引起牽張應(yīng)力的改變，從而啟動血管重構(gòu)的進程，這些因素與其他心血管病危險因素協(xié)同，共同參與臨床疾病的發(fā)生。

3.1 高血壓 在原發(fā)性高血壓患者中，早期血管壁的生物力學(xué)變化主要為逐漸增高的血壓而帶來的病理性牽張。病理性牽張導(dǎo)致的VSMCs增殖及其從穩(wěn)定的收縮表型向分泌型的轉(zhuǎn)變已被大量體內(nèi)、體外實驗所證實。血管平滑肌細(xì)胞的過度增殖和多種細(xì)胞外基質(zhì)的合成將導(dǎo)致血管壁力學(xué)性質(zhì)的改變[57-58]，MMP家族也參與了血管重構(gòu)的過程[59]，這些生理學(xué)變化最終將導(dǎo)致動脈硬化，血管順應(yīng)性降低，反應(yīng)為超聲多普勒下脈搏傳導(dǎo)速度(pulse wave velocity, PWV)的減低。而PWV是高血壓患者發(fā)生主要冠狀動脈事件以及腦卒中和慢性腎病患者心血管病死亡的獨立預(yù)測因子[60-61]。

3.2 動脈粥樣硬化 通常認(rèn)為，與動脈粥樣硬化密切相關(guān)的生物力是剪切力，而近來的研究表明，牽張應(yīng)力也在粥樣硬化斑塊的進展中發(fā)揮著重要的作用。在多個動脈粥樣硬化動物模型中發(fā)現(xiàn)，高血壓可加速粥樣硬化斑塊的形成，該現(xiàn)象可能與炎癥、氧化應(yīng)激有關(guān)[62]。

3.3 血管植入物反應(yīng) 經(jīng)皮冠狀動脈成形術(shù)(PTCA)最早被用于冠狀動脈疾病的器械治療，此后為防止管腔的彈性回縮，維持管腔通暢，冠脈支架應(yīng)運而生。但支架植入后，管壁長期處于較高的非生理性牽張狀態(tài)下，因此而產(chǎn)生的牽張應(yīng)力會刺激血管平滑肌細(xì)胞，通過力學(xué)感受器激活細(xì)胞內(nèi)信號通路，促進VSMCs的增殖和遷移，增加VSMCs細(xì)胞內(nèi)氧化應(yīng)激水平，是支架內(nèi)再狹窄發(fā)生的潛在機制之一[63-64]。

3.4 靜脈移植物疾病 大隱靜脈是最常被用于外周和冠狀動脈旁路移植的橋血管之一，但40%～50%的靜脈橋在10年后會發(fā)生閉塞[65]。手術(shù)過程中對血管的牽拉以及從靜脈循環(huán)的低牽張應(yīng)力到動脈循環(huán)的高牽張應(yīng)力的轉(zhuǎn)變，使得血管平滑肌細(xì)胞轉(zhuǎn)變?yōu)榉置诒硇停w移能力增強，在內(nèi)皮下不斷增殖，合成細(xì)胞外基質(zhì)，引起內(nèi)膜增生，從而導(dǎo)致管腔狹窄閉塞。周期性牽張力可引起大隱靜脈平滑肌細(xì)胞的顯著增殖，而對乳內(nèi)動脈平滑肌細(xì)胞無明顯影響[66]。而且血管外支架的應(yīng)用，可顯著減少周期性牽張對動脈移植物的影響，能有效移植血管平滑肌的增生[67]。

4 總結(jié)與展望

經(jīng)過近30年的不懈努力，眾多機械力與細(xì)胞功能相聯(lián)系的途徑被人類發(fā)現(xiàn)。但在是否存在特異性機械力受體、生物機械力如何作用于已發(fā)現(xiàn)的受體引起一系列病理生理變化等方面仍存在很多未解之謎。這些問題的闡明將有助于指導(dǎo)高血壓、肺動脈高壓和動脈粥樣硬化的治療。生物可降解支架(bioresorbable vascular scaffold, BVS)被稱為冠脈介入治療的第4個里程碑，與傳統(tǒng)金屬支架引起的“金屬外殼”現(xiàn)象相比，血管順應(yīng)性的恢復(fù)是其主要優(yōu)勢，血管壁生理性牽張的恢復(fù)有助于平滑肌細(xì)胞收縮性表型的恢復(fù)，避免長期過度牽張引起的血管重構(gòu)，以期減少臨床不良事件的發(fā)生率，然而在隨后進行的幾項大型臨床研究中并未發(fā)現(xiàn)BVS較傳統(tǒng)藥物洗脫支架在主要臨床終點上的優(yōu)勢[68-69]。血管順應(yīng)性與管壁細(xì)胞尤其是平滑肌細(xì)胞的牽張應(yīng)變關(guān)系密切，牽張應(yīng)變對平滑肌細(xì)胞影響的闡明將有助于驗證生物可降解支架“血管功能恢復(fù)”的理論優(yōu)勢，從而指導(dǎo)支架的改進與下一代的研發(fā)。

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