肾内血管紧张素系统在高血压性肾损害中的作用

目的:探讨血管紧张素II(AngII)及血管紧张素II受体(AT₁R)在缺血性肾损害时肾脏局部的作用。方法:采用放射免疫法及逆转录-聚合酶链反应(RT-PCR)技术,检测双肾动脉狭窄时大鼠血浆和肾脏的AngII含量和AT₁RmRNA的表达。结果:缺血性肾损害时大鼠血浆及肾组织AngII水平均高于对照组,P <0.0 5,而肾组织AT₁RmRNA的表达也较对照组高,P <0.0 1。结论:在双肾动脉狭窄缺血性肾损害时存在AngII及其AT₁R的异常,它们可参与肾脏损害作用.     

血管紧张素Ⅱ受体在压力超负荷致左室肥大中的作用

目的:探讨血管紧张素Ⅱ受体(ATRs)在压力超负荷致左室肥大中的作用。 方法:采用大鼠腹主动脉缩窄模型,通过放免法测心肌组织血管紧张素Ⅱ(Ang Ⅱ)含量,放射性配基结合分析法检测心肌组织ATRs及其亚型的变化。结果:手术组AngⅡ含量显著增高,与左室重量指数(LVMI)呈正相关(r=0.8066,P<0.01)。ATRs最大结合容量 (Bmax) 显著高于对照组(P＜0.01),但两组之间的平衡解离常数(kd)、血管紧张素Ⅱ1型受体(AT₁R)和血管紧张素Ⅱ2型受体(AT₂R)之间的比例无显著差异。非肽类AT₁R 拮抗剂Irbesartan可显著抑制Ang Ⅱ的升高和左室肥大,非肽类AT₂R 拮抗剂CGP42112A则无此作用。结论: 压力超负荷时心肌组织ATRs上调,Ang Ⅱ致左室肥大的作用主要由AT₁R介导。     

血管紧张素Ⅱ和血管紧张素-(1-7)对大鼠血管平滑肌细胞肾素(原)受体表达的影响

目的: 研究血管紧张素Ⅱ(Ang II)和血管紧张素-(1-7) 对大鼠血管平滑肌细胞(VSMCs)肾素(原)受体 表达的影响。方法: 将VSMCs按以下分组:(1)对照组:不加干预因素;(2)不同浓度AngⅡ组:分别加入AngⅡ10、100、1 000 nmol/L;(3)不同浓度Ang-(1-7)组:分别加入Ang-(1-7) 10、100、1 000 nmol/L; (4)AngⅡ+ losartan(AT₁受体拮抗剂)组:losartan 10^-6 mol/L预处理30 min后,再加入AngⅡ100 nmol/L; (5)AngⅡ+ PD123319(AT₂受体拮抗剂)组: 先用10^-5 mol/LPD123319预处理30 min后,再用终浓度为100 nmol/L AngⅡ;(6)CGP42112A(AT₂受体激动剂)组:加入10^-7 mol/L CGP42112A。各组用real-time PCR法和Western blotting法检测(P)RR的表达情况。结果: 与对照组比,不同浓度AngⅡ可以促进(P)RR mRNA和蛋白的表达,并且呈浓度依赖性(均P<0.01);不同浓度Ang-(1-7)可抑制 (P)RR mRNA和蛋白表达(均P<0.01),各浓度之间比较无显著差异(均P>0.05);加入CGP42112A可以促进(P)RR mRNA和蛋白的表达(均P<0.01),与AngⅡ处理组比较,加入PD123319可抑制(P)RR mRNA和蛋白表达(均P<0.01),加入losartan不能抑制(P)RR mRNA和蛋白表达(P>0.05)。结论: AngⅡ可通过AT₂受体促进(P)RR mRNA和蛋白表达,而Ang-(1-7) 可抑制(P)RR mRNA和蛋白的表达。     

血管紧张素Ⅱ对血管平滑肌血小板源生长因子

目的:观察血管紧张素Ⅱ对血管平滑肌血小板源生长因子(PDGF)受体β亚单位的调节,探讨两条信号转导途径的交互作用在血管平滑肌细胞(VSMC)增殖中的意义。方法:制备两肾一夹肾性高血压大鼠模型,免疫印迹法检测主动脉组织PDGF受体β亚单位的含量。培养大鼠主动脉VSMC,观察血管紧张素Ⅱ(AngⅡ)对PDGF受体β亚单位的影响。结果:两肾一夹大鼠术后8周动脉血压明显增高,同时主动脉PDGF受体β亚单位的表达高于对照组126.6%(P＜0.05)。AngⅡ刺激培养的VSMC可导致PDGF受体β亚单位上调192.74%(P＜0.01),该效应可被Ⅰ型AngⅡ受体(AT₁)的拮抗剂losartan和磷脂酶C(phospholipasec,PLC)的抑制剂U73122完全阻断(P＜0.01),但仅被丝裂原活化蛋白激酶激酶抑制剂PD98059部分阻断(P＜0.01)。结论:AngⅡ可以通过AT₁及下游的信号分子PLC上调PDGF受体β亚单位的表达,而细胞外信号调节激酶可能参与AngⅡ的胞内信号转导。     

老年大鼠肾脏微分离肾小球、肾小管及动脉血管紧张素Ⅱ受体的表达

目的: 观察老年大鼠肾脏不同部位不同亚型的血管紧张素Ⅱ受体(ATR)基因表达的改变。方法: 取3月龄及24月龄雄性Wistar大鼠肾脏,行Western印迹杂交及Northern 印迹杂交检测肾皮质AT₁R的蛋白及基因表达,行冰冻切片(厚5 μm),通过激光切割、弹射微分离系统分离肾小球、肾小管及动脉,提取RNA,利用RT-PCR方法观察AT_1aR mRNA、AT_1bR mRNA及AT₂R mRNA的表达。结果: 24月龄大鼠肾脏的AT₁R在蛋白水平及基因水平均低于3月龄大鼠。应用自动激光微分离技术成功分离了大鼠肾脏的肾小球、肾小管及小动脉。24月龄大鼠肾小球AT_1aR mRNA的表达与3月龄大鼠比较无明显差异,在肾小管表达低于3月龄大鼠,动脉表达高于3月龄大鼠;AT_1bR mRNA在肾小球、肾小管表达均低于3月龄大鼠,在动脉的表达高于3月龄大鼠;AT₂R mRNA的表达在肾小管明显高于3月龄大鼠,在肾小球及动脉的表达无明显差异。结论: 老年大鼠的肾小球、肾小管及肾内动脉各型血管紧张素受体的改变不同,有可能在肾脏增龄性改变中起重要作用。     

辛伐他汀对高脂血症大鼠动脉血管紧张素Ⅱ1型受体mRNA表达的下调作用

目的:观察高脂血症时动脉血管紧张素Ⅱ1型受体(AT₁)mRNA表达水平、外周血血管活性物质的变化特点及降脂治疗的作用, 探讨辛伐他汀逆转内皮功能障碍的机制。方法:实验包括正常对照组, 另两组通过4周建立高脂血症模型, 此后继续高脂喂养, 其中辛伐他汀治疗组在高脂喂养同时喂服辛伐他汀10mg·kg^-1·d^-1)而高脂血症组不予药物治疗, 第20周检测3组的血脂变化及观察AT₁mRNA表达水平、外周血AngⅡ和NO浓度。结果:高脂血症组AT₁mRNA表达水平高于、血NO水平低于正常对照组、而AngⅡ和收缩压无显著差异。辛伐他汀治疗组总胆固醇(TC)、甘油三脂(TG)、低密度胆固醇(LDL-C)显著低于高脂血症组, 且动脉组织AT₁mRNA表达水平也显著低于高脂血症组, 血NO含量高于高脂血症组、但血AngⅡ浓度和收缩压未见显著差异。结论:辛伐他汀在调脂的同时, 下调AT₁mRNA的表达、促进一氧化氮的生成, 从而逆转内皮功能障碍、阻止动脉硬化进展。     

血管紧张素ⅡⅠ型受体拮抗剂和血管紧张素转换酶抑制剂的肾保护作用及其对肾内肾素-血管紧张素系统的影响

目的:比较血管紧张素受体拮抗剂(AT₁RA)和血管紧张素转换酶抑制剂(ACEI)的肾脏保护作用,观察这两类药物对肾脏局部肾素-血管紧张素系统的影响。方法:肾病综合征模型由反复给SD大鼠腹腔注射嘌呤霉素诱导而成。28只大鼠随机分为4组:正常对照组、肾病对照组、AT₁RA治疗组和ACEI治疗组。12周后收集血、尿和肾组织标本进行检测。结果:两治疗组尿蛋白明显少于肾病对照组,且到实验期末,肾功能仍在正常范围,肾小球和肾间质损伤指数也低于肾病对照组,但两治疗组间无明显差异(P＞0.05)。肾病对照组的肾组织ACE活性、血管紧张素Ⅱ浓度显著高于正常对照组(P＜0.01)。在ACEI和AT₁RA治疗组,肾组织ACE活性和ANGⅡ浓度显著低于肾病对照组(P＜0.01)。结论:AT₁RA和ACEI在肾病综合征进行性肾损伤中,具有相似的肾脏保护作用,这种作用可能与抑制肾脏局部的ANGⅡ有关。     

血管紧张素Ⅱ受体在大鼠肝星状细胞上的表达

目的: 了解血管紧张素Ⅱ的I_a亚型受体(AT_1a)在大鼠肝星状细胞中的表达情况。方法: 大鼠肝脏经链霉蛋白酶和Ⅳ型胶原酶循环灌注后, 以11% Nycodenz密度梯度离心, 分离获得肝星状细胞。提取肝星状细胞的总核糖核苷酸(RNA), 以逆转录-聚合酶链式反应(RT-PCR)技术和PCR产物测序方法检测AT_1a表达。结果: 采用RT-PCR技术检测到大鼠肝星状细胞有AT_1a mRNA表达, 且PCR产物的测序结果与GenBank上AT_1a cDNA序列有94%的一致性。结论: AT_1a mRNA在大鼠肝星状细胞上表达, 从而又为探索肝纤维化的发生机制提供了有力的依据。     

心衰大鼠室旁核微量注射AT1和AT2受体阻滞剂对肾交感神经活性的影响

目的: 研究慢性心衰大鼠室旁核微量注射血管紧张素II-1型和2型(AT₁和AT₂)受体阻滞剂对心率、血压和肾交感神经系统的影响,揭示心衰大鼠下丘脑室旁核对交感系统的调节机制。方法: 采用SD大鼠,手术组用左冠状动脉前降支结扎术制作心衰模型,假手术组大鼠左冠状动脉前降支下穿线但不结扎。术后4周,测定血流动力学评判心功能状态,测定心脏/体重比与肺/体重比,并进行心脏病理组织学观察。对符合标准的大鼠进行麻醉,经腹膜后途径暴露左肾,在手术显微镜下剥离肾交感神经,脑立体定位仪对大鼠室旁核定位,微量注射AT₁和AT₂受体阻滞剂(100 nL),POWERLAB 8/30系统采集信号,记录心率、血压和肾交感神经放电活动的改变,人工脑脊液组作为对照。结果: 肾交感神经放电:下丘脑室旁核微量注射AT₁受体阻滞剂导致肾交感神经兴奋性减弱,对心衰大鼠交感神经的兴奋性减弱较假手术组明显。下丘脑室旁核微量注射AT₂受体阻滞剂及人工脑脊液对心衰大鼠及假手术大鼠交感神经的兴奋性改变不明显。结论: 心衰时室旁核内注射AT₁、AT₂受体阻滞剂对交感神经的输出反应有差异。在中枢肾素-血管紧张素-醛固酮系统(RAAS),血管紧张素II主要通过AT₁受体起作用,而AT₂受体无相关介导作用。     

内源性血管紧张素Ⅱ对大鼠血管钙化的作用

目的:在大鼠血管钙化模型上观察内源性血管紧张素II(AngⅡ)对大鼠血管钙化的影响。方法:用VitD₃皮下注射和尼古丁灌胃诱导大鼠血管钙化模型。测定血管组织中钙含量、[⁴⁵Ca²⁺]聚集及碱性磷酸酶活性作为观察钙化的指标。结果:钙化血管组织中钙含量,[⁴⁵Ca²⁺]摄入及碱性磷酸酶活性分别高于对照组。血管组织中的血管紧张素原mRNA、血浆和血管AngⅡ含量均高于对照组水平。血管紧张素转换酶抑制剂卡托普利和AngⅡ受体AT₁阻断剂洛沙坦处理的大鼠血管内钙含量、[⁴⁵Ca²⁺]聚集及碱性磷酸酶活性显著低于单纯钙化组。卡托普利处理的钙化大鼠血浆和动脉中AngⅡ含量、动脉中血管紧张素原mRNA的含量也显著低于钙化组水平。结论:钙化大鼠血浆和血管组织中AngⅡ水平上调,卡托普利和洛沙坦可减轻大鼠血管钙化程度。     

腺病毒介导的反义AT1R转染对血管平滑肌细胞迁移的影响

目的:观察腺病毒介导的反义AT1基因转染对培养的大鼠动脉平滑肌细胞(VSMCs)迁移的影响。方法:用定向克隆和同源重组方法构建携带人反义AT1基因的复制缺陷型重组腺病毒(AdCMV/ahAT1),转染体外培养的VSMCs,用RT-PCR半定量法和免疫组化法检测AT1R的表达,用改良趋化小室法检测细胞迁移。结果:与对照组相比转染AdCMV/ahAT1后48h的VSMCs,AT1RmRNA表达少50%,AT1R的蛋白表达也显著低下(P＜0.01);迁移距离为(41.7±9.7)μm,显著短于空白对照组(77.5±12.7)μm和Ad/CMV.LacZ组(77.2±10.6)μm,均为P＜0.01。结论:腺病毒介导的反义hAT1R转染,通过抑制AT1R的表达,明显抑制了大鼠VSMCs的迁移。     

Mechanisms of angiotensin II signaling on cytoskeleton of podocytes

Podocytes are significant in establishing the glomerular filtration barrier. Sustained rennin–angiotensin system (RAS) activation is crucial in the pathogenesis of podocyte injury and causes proteinuria. This study demonstrates that angiotensin II (Ang II) caused a reactive oxygen species (ROS)-dependent rearrangement of cortical F-actin and a migratory phenotype switch in cultured mouse podocytes with stable Ang II type 1 receptor (AT1R) expression. Activated small GTPase Rac-1 and phosphorylated ezrin/radixin/moesin (ERM) proteins provoked Ang II-induced F-actin cytoskeletal remodeling. This work also shows increased expression of Rac-1 and phosphorylated ERM proteins in cultured podocytes, and in glomeruli of podocyte-specific AT1R transgenic rats (Neph-hAT1 TGRs). The free radical scavenger DMTU eliminated Ang II-induced cell migration, ERM protein phosphorylation and cortical F-actin remodeling, indicating that ROS mediates the influence of Rac-1 on podocyte AT1R signaling. Heparin, a potent G-coupled protein kinase 2 inhibitor, was found to abolish ERM protein phosphorylation and cortical F-actin ring formation in Ang II-treated podocytes, indicating that phosphorylated ERM proteins are the cytoskeletal effector in AT1R signaling. Moreover, Ang II stimulation triggered down-regulation of α actinin-4 and reduced focal adhesion expression in podocytes. Signaling inhibitor assay of Ang II-treated podocytes reveals that Rac-1, RhoA, and F-actin reorganization were involved in expressional regulation of α actinin-4 in AT1R signaling. With persistent RAS activation, the Ang II-induced phenotype shifts from being dynamically stable to adaptively migratory, which may eventually exhaust podocytes with a high actin cytoskeletal turnover, causing podocyte depletion and focal segmental glomerulosclerosis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Role of angiotensin II and angiotensin type-1 receptor in scorpion venom-induced cardiac and aortic tissue inflammation

Scorpion stings are mainly associated with cardiovascular disturbances that may be the cause of death. In this study, the involvement of angiotensin II (Ang II) in cardiac and aortic inflammatory response was studied. Mice were injected with Androctonus australis hector (Aah) scorpion venom (0.5 mg/kg, subcutaneously), in the presence or absence of an angiotensin converting enzyme (ACE) inhibitor, captopril (15 mg/kg/day/1 day intraperitoneally) or an angiotensin type-1 receptor (AT1R) antagonist, valsartan (15 mg/kg/day/15 days, orally). In the envenomed group, results revealed severe tissue alterations with a concomitant increase of metabolic enzymes (CK and CK-MB) in sera. An important inflammatory cell (neutrophil and eosinophil) infiltration into the heart and aorta were observed, accompanied by imbalanced redox status (NO, MDA, catalase and GSH) and high cytokine levels (IL-6 and TNF-α) in sera with the expression of MMP-2 and MMP-9 metalloproteinases. However, the blockade of the actions of AngII by the ACE inhibitor or by the AT1R antagonist prevented cardiac and aortic tissue alterations, inflammatory cell infiltration, as well as the oxidative stress generation and cytokine and metalloproteinase expression. These results suggest the involvement of AngII, through its AT1R in the inflammation induced by Aah venom, in the heart and the aorta.     

Influence of endogenous angiotensin II on control of sympathetic nerve activity in human dehydration

Arterial blood pressure can often fall too low during dehydration, leading to an increased incidence of orthostatic hypotension and syncope. Systemic sympathoexcitation and increases in volume regulatory hormones such as angiotensin II (AngII) may help to maintain arterial pressure in the face of decreased plasma volume. Our goals in the present study were to quantify muscle sympathetic nerve activity (MSNA) during dehydration (DEH), and to test the hypothesis that endogenous increases in AngII in DEH have a mechanistic role in DEH-associated sympathoexcitation. We studied 17 subjects on two separate study days: DEH induced by 24 h fluid restriction and a euhydrated (EUH) control day. MSNA was measured by microneurography at the peroneal nerve, and arterial blood pressure, electrocardiogram, and central venous pressure were also recorded continuously. Sequential nitroprusside and phenylephrine (modified Oxford test) were used to evaluate baroreflex control of MSNA. Losartan (angiotensin type 1 receptor (AT1) antagonist) was then administered and measurements were repeated. MSNA was elevated during DEH (42 ± 5 vs. EUH: 32 ± 4 bursts per 100 heartbeats, P = 0.02). Blockade of AT1 receptors partially reversed this change in MSNA during DEH while having no effect in the control EUH condition. The sensitivity of baroreflex control of MSNA was unchanged during DEH compared to EUH. We conclude that endogenous increases in AngII during DEH contribute to DEH-associated sympathoexcitation.     

Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target for renoprotective intervention

Ameliorating the function of the glomerular barrier to circulating proteins by blocking angiotensin II (Ang II) translates into less risk of progression toward end-stage renal failure in diabetic and nondiabetic nephropathies. However, the mechanisms underlying this barrier protection are not clear. Specialized contacts between adjacent podocytes are major candidate targets, and the actin cytoskeleton is emerging as a regulatory element. Here, we present data demonstrating that Ang II induced reorganization of F-actin fibers and redistribution of zonula occludens-1 (ZO-1) that is physically associated with actin in murine podocytes. These effects were paralleled by increased albumin permeability across podocyte monolayers. The F-actin stabilizer jasplakinolide prevented both ZO-1 redistribution and albumin leakage, suggesting that actin cytoskeleton rearrangement is instrumental to podocyte permselective dysfunction induced by Ang II. Changes in both F-actin and ZO-1 patterns were confirmed in glomeruli of rat isolated perfused kidneys on short infusion of Ang II, leading to increased protein excretion. Podocyte dysfunction was mediated by Ang II type 1 receptor and was partly dependent on Src kinase-phospholipase C activation. These data demonstrate that strategies aimed at stabilizing podocyte-podocyte contacts and targeting the relevant intracellular signal transduction are crucial to renoprotection.     

Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1 receptor in prostate cancer

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is reported to contribute to tumor progression and is regulated by the renin-angiotensin system in hypertensive disease. In this study, we investigated the clinical outcome of MCP-1 expression in patients with prostate cancer (CaP) and the regulation of MCP-1 through angiotensin II (AngII) type 1 receptor (AT1R) in CaP. Specimens were obtained from 138 CaP patients and analyzed by immunostaining for both MCP-1 and macrophages. We investigated the regulation of MCP-1 expression through AT1R both in vivo and in vitro using three human prostate cancer cell lines: LNCaP, C4-2, and C4-2AT6. Specimens with a high Gleason score (≥7) and a high pathological classification (≤pT3), and those with castration-resistant prostate cancer showed significantly higher MCP-1 expression and higher macrophage infiltration than low malignant potential CaP. High MCP-1 expression in CaP correlated significantly with high prostate-specific antigen (PSA) recurrence rates. AngII induced significantly higher MCP-1 levels in C4-2AT6 than in LNCaP, whereas AT1R blockade (ARB) inhibited MCP-1 production via the inhibition of the PI3K/Akt pathway in C4-2AT6. ARB also significantly suppressed MCP-1 expression in C4-2AT6 tumors. Our study is the first to demonstrate that both high MCP-1 expression and high macrophage infiltration in CaP specimens correlate with a high PSA recurrence rate and that ARB inhibits MCP-1 expression through the PI3K/Akt pathway and blocks macrophage infiltration in castration-resistant prostate cancer.     

Regulatory role of angiotensin II on progesterone production by cultured human granulosa cells. Expression of angiotensin II type-2 receptor

The role of angiotensin II (AngII) in ovarian steroidogenesis is not clearly understood. In order to study its action on progesterone synthesis and to determine which receptor subtype is involve, granulosa cells obtained from women undergoing in-vitro fertilization were cultured for 2 or 4 days and then incubated in the presence of AngII (10(-7) M) with or without human chorionic gonadotrophin (HCG, 10 IU/ml) for 3 or 18 h. In cells cultured for 2 days, incubation with AngII decreased progesterone secretion by 36%, and inhibited activity of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) by 87% (P < 0.05), although its expression was not significantly reduced. However, in cells cultured for 4 days, progesterone production was enhanced by incubation with AngII (38%), and no change was observed in 3 beta-HSD expression. Both inhibitory and stimulatory effects were dose- dependent. Progesterone secretion was increased (93%) by incubation with HCG of cells cultured for 4, but not for 2 days, and no potentiation was observed with AngII. Treatment with PD123177 completely blocked the action of AngII and decreased the HCG-stimulated secretion of progesterone by 27%. Angiotensin type-2 (AT2) receptor mRNA was expressed in cells cultured for 4 days. In conclusion, AngII showed a regulatory role in in-vitro progesterone production by human granulosa luteinized cells, modulating the activity of 3 beta-HSD. It is likely that these actions may be mediated via membrane receptors, possibly of the AT2 receptor family.      

Spinophilin regulates central angiotensin II-mediated effect on blood pressure

Central angiotensin II (AngII) plays an important role in the regulation of the sympathetic nervous system. The underlining molecular mechanisms are largely unknown. Spinophilin (SPL) is a regulator of G protein-coupled receptor signaling. Deletion of SPL induces sympathetically mediated arterial hypertension in mice. We tested the hypothesis that SPL restrains blood pressure (BP) by regulating AngII activity. We equipped SPL(-/-) and SPL(+/+) mice with telemetric devices and applied AngII (1.0?mg?kg(-1)?day(-1), minipumps) or the AngII subtype 1 receptor (AT1-R) blocker valsartan (50?mg?kg(-1)?day(-1), gavage). We assessed autonomic nervous system activity through intraperitoneal application of trimethaphan, metoprolol, and atropine. We also tested the effect of intracerebroventricular (icv) AngII on blood pressure in SPL(-/-) and in SPL(+/+) mice. Chronic infusion of AngII upregulates SPL expression in the hypothalamus of SPL(+/+) mice. Compared with SPL(+/+) mice, SPL(-/-) mice showed a greater increase in daytime BP with AngII (19.2?±?0.8 vs. 13.5?±?1.6?mmHg, p?相似文献   

Disruption of actin cytoskeleton mediates loss of tensile stress induced early phenotypic modulation of vascular smooth muscle cells in organ culture

Aorta organ culture has been widely used as an ex vivo model for studying vessel pathophysiology. Recent studies show that the vascular smooth muscle cells (VSMCs) in organ culture undergo drastic dedifferentiation within the first few hours (termed early phenotypic modulation). Loss of tensile stress to which aorta is subject in vivo is the cause of this early phenotypic modulation. However, no underlying molecular mechanism has been discovered thus far. The purpose of the present study is to identify intracellular signals involved in the early phenotypic modulation of VSMC in organ culture. We find that the drastic VSMC dedifferentiation is accompanied by accelerated actin cytoskeleton dynamics and downregulation of SRF and myocardin. Among the variety of signal pathways examined, increasing actin polymerization by jasplakinolide is the only one hindering VSMC dedifferentiation in organ culture. Moreover, jasplakinolide reverses actin dynamics during organ culture. Latrunculin B (disrupting actin cytoskeleton) and jasplakinolide respectively suppressed and enhanced the expression of VSMC markers, SRF, myocardin, and CArG-box-mediated SMC promoters in PAC1, a VSMC line. These results identify actin cytoskeleton degradation as a major intracellular signal for loss of tensile stress-induced early phenotypic modulation of VSMC in organ culture. This study suggests that disrupting actin cytoskeleton integrity may contribute to the pathogenesis of vascular diseases.