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The angiogenic role of the alpha 9-nicotinic acetylcholine receptor in triple-negative breast cancers α-9-烟碱乙酰胆碱受体在三阴性乳腺癌中的血管生成作用。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-08-23 DOI: 10.1007/s10456-024-09944-6
Sonjid Ochirbat, Tzu-Chun Kan, Chun-Chun Hsu, Tzu-Hsuan Huang, Kuo-Hsiang Chuang, Michael Chen, Chun-Chia Cheng, Chun-Chao Chang, Sri Rahayu, Jungshan Chang

Nicotine acts as an angiogenic factor by stimulating endogenous cholinergic pathways. Several subtypes of nicotinic acetylcholine receptors (nAChRs) have been demonstrated to be closely correlated to the formation and progression of different types of cancers. Recently, several studies have found that nicotinic acetylcholine receptors α9 (α9-nAChRs) are highly expressed in breast tumors, especially in tumors derived from patients diagnosed at advanced stages. In vitro studies have demonstrated that activation of α9-nAChRs is associated with increased proliferation and migration of breast cancer. To study the tumor-promoting role of α9-nAChRs in breast cancers, we generated a novel anti-α9-nAChR and methoxy-polyethylene glycol (mPEG) bispecific antibody (α9 BsAb) for dissecting the molecular mechanism on α9-nAChR-mediated tumor progression. Unexpectedly, we discovered the angiogenic role of α9-nAChR in nicotine-induced neovascularization of tumors. It revealed α9 BsAbs reduced nicotine-induced endothelial cell tube formation, blood vessel development in Matrigel plug assay and angiogenesis in microtube array membrane murine model (MTAMs). To unbraid the molecular mechanism of α9-nAChR in nicotine-mediated angiogenesis, the α9 BsAbs were applied and revealed the inhibitory roles in nicotine-induced production of hypoxia-inducible factor-2 alpha (HIF-2α), vascular endothelial growth factor A (VEGF-A), phosphorylated vascular endothelial growth factor receptor 2 (p-VEGFR2), vascular endothelial growth factor receptor 2 (VEGFR2) and matrix metalloproteinase-9 (MMP9) from triple-negative breast cancer cells (MDA-MB-231), suggesting α9-nAChRs played an important role in nicotine-induced angiogenesis. To confirm our results, the shRNA targeting α9-nAChRs was designed and used to silence α9-nAChR expression and then evaluated the angiogenic role of α9-nAChRs. The results showed α9 shRNA also played an inhibitory effect in blocking the nicotine-induced angiogenic signaling. Taken together, α9-nAChR played a critical role in nicotine-induced angiogenesis and this bispecific antibody (α9 BsAb) may serve as a potential therapeutic candidate for treatments of the α9 positive cancers.

尼古丁通过刺激内源性胆碱能通路起到血管生成因子的作用。尼古丁乙酰胆碱受体(nAChRs)的几种亚型已被证实与不同类型癌症的形成和发展密切相关。最近,一些研究发现,烟碱乙酰胆碱受体α9(α9-nAChRs)在乳腺肿瘤中高度表达,尤其是在晚期患者的肿瘤中。体外研究表明,α9-nAChRs 的激活与乳腺癌的增殖和迁移增加有关。为了研究α9-nAChRs在乳腺癌中的促瘤作用,我们制备了一种新型抗α9-nAChR和甲氧基聚乙二醇(mPEG)双特异性抗体(α9 BsAb),用于剖析α9-nAChR介导的肿瘤进展的分子机制。我们意外地发现了α9-nAChR在尼古丁诱导的肿瘤新生血管中的血管生成作用。研究发现,α9 BsAbs能减少尼古丁诱导的内皮细胞管形成、Matrigel塞试验中的血管发育以及微管阵列膜小鼠模型(MTAMs)中的血管生成。为了解开α9-nAChR在尼古丁介导的血管生成中的分子机制,应用α9 BsAbs揭示了其在尼古丁诱导的缺氧诱导因子-2α(HIF-2α)、血管内皮生长因子A(VEGF-A)生成中的抑制作用、这表明α9-nAChRs 在烟碱诱导的血管生成中发挥了重要作用。为了证实我们的研究结果,研究人员设计了靶向α9-nAChRs的shRNA,并利用它沉默了α9-nAChRs的表达,然后评估了α9-nAChRs的血管生成作用。结果表明,α9 shRNA 在阻断尼古丁诱导的血管生成信号方面也起到了抑制作用。综上所述,α9-nAChR在尼古丁诱导的血管生成中起着关键作用,这种双特异性抗体(α9 BsAb)可作为治疗α9阳性癌症的潜在候选疗法。
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引用次数: 0
Maternal serum PlGF associates with 3D power doppler ultrasound markers of utero-placental vascular development in the first trimester: the rotterdam periconception cohort 母体血清 PlGF 与妊娠头三个月子宫胎盘血管发育的 3D 功率多普勒超声标记物的关系:鹿特丹围孕期队列。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-08-14 DOI: 10.1007/s10456-024-09939-3
Eline S. de Vos, A. H. Jan Danser, Anton H. J. Koning, Sten P. Willemsen, Lotte E. van der Meeren, Eric. A. P. Steegers, Régine P. M. Steegers-Theunissen, Annemarie G. M. G. J. Mulders

Objective (s)

Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature.

Methods

In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7–9–11 weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm3. The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing- or vessel points and total vascular length. At 11 weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories.

Results

Serum PlGF was positively associated with uPVV and uPVS development (uPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development.

Conclusion(s)

Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS.

Clinical trial registration number Dutch Trial Register NTR6854.

目的:循环血管生成因子可用于预测胎盘相关并发症,但它们与第一胎胎盘发育的关系尚不清楚。本研究探讨了母体血管生成因子与子宫胎盘血管体积(uPVV)和子宫胎盘血管骨架(uPVS)之间的关系,它们是第一孕期子宫胎盘血管体积和形态(分支)发育的新型成像标记:VIRTUAL胎盘研究是鹿特丹前瞻性围孕期队列的一个子队列,在该研究的185名孕妇中,于胎龄7-9-11周时进行了胎盘三维动力多普勒超声检查。uPVV作为体积发育参数进行测量,并报告以立方厘米为单位的血管数量。uPVS是作为形态(分支)发育参数生成的,报告了血管末端、分叉交叉点或血管点的数量以及血管总长度。怀孕 11 周时,评估了反映胎盘(血管)发育的母体血清生物标志物:胎盘生长因子(PlGF)、可溶性酪氨酸激酶-1(sFlt-1)和可溶性内胚叶素(sEng)。使用调整后的多变量线性回归估计血清生物标志物与uPVV和uPVS轨迹之间的关系:结果:血清 PlGF 与 uPVV 和 uPVS 的发展呈正相关(uPVV:β = 0.39,95% CI = 0.15;0.64;分叉点:β = 4.64,95% CI = 0.04;9.25;交叉点:β = 4.01,95% CI = 0.65;7.37;血管总长度:β = 13.33,95% CI = 3.09;23.58,所有 p 值 结论:血清 PlGF 与 uPVV 和 uPVS 的发展呈正相关:母体血清中 PlGF 浓度越高,胎儿第一妊娠期子宫胎盘血管发育就越快,uPVV 和 uPVS 反映了这一点。临床试验注册号:荷兰试验注册 NTR6854。
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引用次数: 0
PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer PDPN/CCL2/STAT3反馈回路改变CAF异质性,促进结直肠癌血管生成。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-08-08 DOI: 10.1007/s10456-024-09941-9
Die Yu, Hanzheng Xu, Jinzhe Zhou, Kai Fang, Zekun Zhao, Ke Xu

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.

结直肠癌(CRC)是常见的临床恶性肿瘤之一,也是全球第四大癌症相关死亡原因。肿瘤微环境(TME)在促进肿瘤血管生成方面起着至关重要的作用,而癌相关成纤维细胞(CAFs)是肿瘤微环境的关键组成部分之一。然而,由于CAFs的高度异质性,阐明CAF介导肿瘤血管生成的分子机制仍是一个难题。在我们的研究中,我们发现结直肠癌中的CAFs存在促血管生成功能异质性,并明确了Podoplanin(PDPN)可特异性标记具有促血管生成功能的CAF亚群。我们还发现,PDPN + CAF 可通过自分泌的 CCL2 形成 PDPN/CCL2/STAT3 反馈环,从而维持 CAF 的异质性,同时通过旁分泌的 CCL2 激活内皮细胞中的 STAT3 信号通路,促进血管生成。我们的研究表明,WP1066可通过阻断CAFs中的PDPN/CCL2/STAT3反馈环和内皮细胞中的STAT3信号通路抑制结直肠癌血管生成。总之,我们的研究表明,STAT3 可能是阻断结直肠癌血管生成的潜在治疗靶点。我们的研究为结直肠癌的临床治疗提供了理论依据和新的治疗策略。
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引用次数: 0
Mitochondrial control of hypoxia-induced pathological retinal angiogenesis 线粒体控制缺氧诱导的病理性视网膜血管生成
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-08-03 DOI: 10.1007/s10456-024-09940-w
Hitomi Yagi, Myriam Boeck, Shen Nian, Katherine Neilsen, Chaomei Wang, Jeff Lee, Yan Zeng, Matthew Grumbine, Ian R. Sweet, Taku Kasai, Kazuno Negishi, Sasha A. Singh, Masanori Aikawa, Ann Hellström, Lois E. H. Smith, Zhongjie Fu

Objective

Pathological retinal neovascularization is vision-threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and hypoxia-induced neovascularization, and to test interventions addressing those changes to prevent neovascularization.

Methods

OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome changes and the ratio of mitochondrial to nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented to OIR mice either prior to or during neovessel formation.

Results

In OIR vs. control retinas, global proteomics showed decreased retinal mitochondrial respiration at peak neovascularization. OCR and mtDNA/nDNA were also decreased at peak neovascularization suggesting impaired mitochondrial respiration. In vivo pyruvate administration during but not prior to neovessel formation (in line with mitochondrial activity time course) suppressed NV.

Conclusions

Mitochondrial energetics were suppressed during retinal NV in OIR. Appropriately timed supplementation of pyruvate may be a novel approach in neovascular retinal diseases.

目的病理性视网膜新生血管会威胁视力。在小鼠氧诱导视网膜病变(OIR)中,我们试图确定高氧诱导血管缺失和低氧诱导新生血管形成过程中线粒体呼吸的纵向变化,并测试针对这些变化的干预措施,以防止新生血管形成。我们评估了OIR与对照组视网膜的总蛋白质组变化、线粒体与核DNA拷贝数之比(mtDNA/nDNA),以及OIR与对照组视网膜(BaroFuse)的线粒体耗氧率(OCR)。结果在 OIR 与对照组视网膜中,全蛋白质组学显示在新生血管形成高峰期视网膜线粒体呼吸减少。在新生血管形成高峰期,OCR 和 mtDNA/nDNA 也出现下降,表明线粒体呼吸功能受损。在新血管形成期间而非之前(与线粒体活动时间进程一致)体内注射丙酮酸可抑制新血管形成。适时补充丙酮酸可能是治疗新生血管性视网膜疾病的一种新方法。
{"title":"Mitochondrial control of hypoxia-induced pathological retinal angiogenesis","authors":"Hitomi Yagi,&nbsp;Myriam Boeck,&nbsp;Shen Nian,&nbsp;Katherine Neilsen,&nbsp;Chaomei Wang,&nbsp;Jeff Lee,&nbsp;Yan Zeng,&nbsp;Matthew Grumbine,&nbsp;Ian R. Sweet,&nbsp;Taku Kasai,&nbsp;Kazuno Negishi,&nbsp;Sasha A. Singh,&nbsp;Masanori Aikawa,&nbsp;Ann Hellström,&nbsp;Lois E. H. Smith,&nbsp;Zhongjie Fu","doi":"10.1007/s10456-024-09940-w","DOIUrl":"10.1007/s10456-024-09940-w","url":null,"abstract":"<div><h3>Objective</h3><p>Pathological retinal neovascularization is vision-threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and hypoxia-induced neovascularization, and to test interventions addressing those changes to prevent neovascularization.</p><h3>Methods</h3><p>OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome changes and the ratio of mitochondrial to nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented to OIR mice either prior to or during neovessel formation.</p><h3>Results</h3><p>In OIR vs. control retinas, global proteomics showed decreased retinal mitochondrial respiration at peak neovascularization. OCR and mtDNA/nDNA were also decreased at peak neovascularization suggesting impaired mitochondrial respiration. In vivo pyruvate administration during but not prior to neovessel formation (in line with mitochondrial activity time course) suppressed NV.</p><h3>Conclusions</h3><p>Mitochondrial energetics were suppressed during retinal NV in OIR. Appropriately timed supplementation of pyruvate may be a novel approach in neovascular retinal diseases.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"691 - 699"},"PeriodicalIF":9.2,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09940-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141887393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction 对血管内皮损伤相关疾病的发病机制和治疗策略的新认识:关注线粒体功能障碍。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-07-26 DOI: 10.1007/s10456-024-09938-4
Boxian Pang, Guangtong Dong, Tieliang Pang, Xinyao Sun, Xin Liu, Yifeng Nie, Xing Chang

As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for “energy information transfer,” can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.

作为血管的重要组成部分,内皮细胞驻留在循环血液和半固体组织之间,在维持整体生理功能方面发挥着关键作用。各种应激刺激都会诱发内皮损伤,导致人体出现相应的疾病。近年来,线粒体在血管内皮损伤中的重要性日益凸显。线粒体作为细胞有氧呼吸的主要场所和 "能量信息传递 "的细胞器,可以通过整合和接收各种外部应激信号来检测内皮细胞损伤。活性氧(ROS)的产生和线粒体功能障碍往往决定着内皮细胞损伤向坏死或凋亡的演变。因此,线粒体与内皮细胞功能密切相关,有助于决定临床疾病的进展。本文全面综述了线粒体诱导的血管内皮细胞损伤在心血管疾病、肾脏疾病、肺部相关疾病、脑血管疾病以及糖尿病相关微血管疾病中的相互联系和发病机制。还提供了相应的治疗方法。此外,还讨论了使用临床药物治疗基于血管内皮损伤的疾病的策略,旨在为相关血管损伤的临床诊断提供新的见解和治疗方案。
{"title":"Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction","authors":"Boxian Pang,&nbsp;Guangtong Dong,&nbsp;Tieliang Pang,&nbsp;Xinyao Sun,&nbsp;Xin Liu,&nbsp;Yifeng Nie,&nbsp;Xing Chang","doi":"10.1007/s10456-024-09938-4","DOIUrl":"10.1007/s10456-024-09938-4","url":null,"abstract":"<div><p>As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for “energy information transfer,” can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"623 - 639"},"PeriodicalIF":9.2,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09938-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition 动静脉畸形中的体细胞 RIT1 delins 可使 RAS-MAPK 信号超活化,从而适用于 MEK 抑制。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-07-05 DOI: 10.1007/s10456-024-09934-8
Friedrich G. Kapp, Farhad Bazgir, Nagi Mahammadzade, Mehrnaz Mehrabipour, Erik Vassella, Sarah M. Bernhard, Yvonne Döring, Annegret Holm, Axel Karow, Caroline Seebauer, Natascha Platz Batista da Silva, Walter A. Wohlgemuth, Aviv Oppenheimer, Pia Kröning, Charlotte M. Niemeyer, Denny Schanze, Martin Zenker, Whitney Eng, Mohammad R. Ahmadian, Iris Baumgartner, Jochen Rössler

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

动静脉畸形(AVM)是一种良性血管畸形,容易引起疼痛、出血和进行性生长。动静脉畸形主要是由 RAS-MAPK 通路的镶嵌致病变体引起的。然而,并非所有患者都能找到致病变体。通过超深度测序,我们在三名 AVM 患者的病变组织中发现了新型体细胞 RIT1 delins 变异。RIT1 编码一种 RAS 样蛋白,可调节 RAS-MAPK 信号转导。我们在 HEK293T 细胞中表达了 RIT1 变体,这导致 ERK1/2 磷酸化强烈增加。在斑马鱼胚胎中,内皮特异性镶嵌式过表达 RIT1 delins 会诱导 AVM 的形成,这突显了它们在血管发育中的重要功能。体外的 ERK1/2 过度激活和体内的 AVM 形成均可被药物 MEK 抑制所抑制。使用MEK抑制剂曲美替尼治疗后,一名患者的出血发作和AVM大小明显减少。我们的研究结果表明 RIT1 与 AVM 的形成有关,并为靶向治疗的临床试验提供了依据。
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引用次数: 0
A streamlined method to generate endothelial cells from human pluripotent stem cells via transient doxycycline-inducible ETV2 activation 通过瞬时强力霉素诱导的 ETV2 激活,从人多能干细胞生成内皮细胞的简化方法。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-07-05 DOI: 10.1007/s10456-024-09937-5
Allen Chilun Luo, Jiuhai Wang, Kai Wang, Yonglin Zhu, Liyan Gong, Umji Lee, Xiang Li, Daniel M. Tremmel, Ruei-Zeng Lin, Donald E. Ingber, James Gorman, Juan M. Melero-Martin

The development of reliable methods for producing functional endothelial cells (ECs) is crucial for progress in vascular biology and regenerative medicine. In this study, we present a streamlined and efficient methodology for the differentiation of human induced pluripotent stem cells (iPSCs) into induced ECs (iECs) that maintain the ability to undergo vasculogenesis in vitro and in vivo using a doxycycline-inducible system for the transient expression of the ETV2 transcription factor. This approach mitigates the limitations of direct transfection methods, such as mRNA-mediated differentiation, by simplifying the protocol and enhancing reproducibility across different stem cell lines. We detail the generation of iPSCs engineered for doxycycline-induced ETV2 expression and their subsequent differentiation into iECs, achieving over 90% efficiency within four days. Through both in vitro and in vivo assays, the functionality and phenotypic stability of the derived iECs were rigorously validated. Notably, these cells exhibit key endothelial markers and capabilities, including the formation of vascular networks in a microphysiological platform in vitro and in a subcutaneous mouse model. Furthermore, our results reveal a close transcriptional and proteomic alignment between the iECs generated via our method and primary ECs, confirming the biological relevance of the differentiated cells. The high efficiency and effectiveness of our induction methodology pave the way for broader application and accessibility of iPSC-derived ECs in scientific research, offering a valuable tool for investigating endothelial biology and for the development of EC-based therapies.

开发生产功能性内皮细胞(ECs)的可靠方法对于血管生物学和再生医学的发展至关重要。在本研究中,我们提出了一种简化、高效的方法,利用强力霉素诱导系统瞬时表达ETV2转录因子,将人类诱导多能干细胞(iPSC)分化为诱导EC(iEC),并在体外和体内保持血管生成能力。这种方法简化了方案,提高了不同干细胞系之间的可重复性,从而减轻了直接转染方法(如mRNA介导的分化)的局限性。我们详细介绍了多西环素诱导 ETV2 表达的 iPSCs 的生成及其随后向 iECs 的分化,在四天内达到 90% 以上的效率。通过体外和体内试验,衍生的 iECs 的功能和表型稳定性得到了严格验证。值得注意的是,这些细胞表现出关键的内皮标志物和能力,包括在体外微生理平台和小鼠皮下模型中形成血管网络。此外,我们的研究结果表明,通过我们的方法生成的 iECs 与原代 ECs 在转录和蛋白质组方面非常接近,这证实了分化细胞的生物学相关性。我们的诱导方法的高效性和有效性为 iPSC 衍生 ECs 在科学研究中的更广泛应用和可及性铺平了道路,为研究内皮生物学和开发基于 EC 的疗法提供了宝贵的工具。
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引用次数: 0
Site-specific genetic and functional signatures of aortic endothelial cells at aneurysm predilection sites in healthy and AngII ApoE−/− mice 健康小鼠和 AngII ApoE-/- 小鼠动脉瘤预选部位主动脉内皮细胞的特异性基因和功能特征。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-07-04 DOI: 10.1007/s10456-024-09933-9
Alexander Brückner, Adrian Brandtner, Sarah Rieck, Michaela Matthey, Caroline Geisen, Benedikt Fels, Marta Stei, Kristina Kusche-Vihrog, Bernd K. Fleischmann, Daniela Wenzel

Aortic aneurysm is characterized by a pathological dilation at specific predilection sites of the vessel and potentially results in life-threatening vascular rupture. Herein, we established a modified “Häutchen method” for the local isolation of endothelial cells (ECs) from mouse aorta to analyze their spatial heterogeneity and potential role in site-specific disease development. When we compared ECs from aneurysm predilection sites of healthy mice with adjacent control segments we found regulation of genes related to extracellular matrix remodeling, angiogenesis and inflammation, all pathways playing a critical role in aneurysm development. We also detected enhanced cortical stiffness of the endothelium at these sites. Gene expression of ECs from aneurysms of the AngII ApoE−/− model when compared to sham animals mimicked expression patterns from predilection sites of healthy animals. Thus, this work highlights a striking genetic and functional regional heterogeneity in aortic ECs of healthy mice, which defines the location of aortic aneurysm formation in disease.

主动脉瘤的特征是血管特定部位的病理扩张,并可能导致危及生命的血管破裂。在此,我们建立了一种改良的 "Häutchen 法",用于从小鼠主动脉局部分离内皮细胞(ECs),以分析其空间异质性和在特定部位疾病发展中的潜在作用。当我们比较健康小鼠动脉瘤预选部位的内皮细胞与邻近对照节段的内皮细胞时,发现了与细胞外基质重塑、血管生成和炎症有关的基因调控,而所有这些途径都在动脉瘤的发展中发挥着关键作用。我们还检测到这些部位内皮的皮质硬度增强。与假动物相比,AngII ApoE-/- 模型动脉瘤内皮细胞的基因表达模拟了健康动物偏爱部位的表达模式。因此,这项工作强调了健康小鼠主动脉内皮细胞在遗传和功能上的显著区域异质性,这也确定了疾病中主动脉瘤形成的位置。
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引用次数: 0
ACVR1/ALK2-p21 signaling axis modulates proliferation of the venous endothelium in the retinal vasculature ACVR1/ALK2-p21 信号轴调节视网膜血管中静脉内皮的增殖。
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-07-02 DOI: 10.1007/s10456-024-09936-6
Boryeong Pak, Minjung Kim, Orjin Han, Heon-Woo Lee, Alexandre Dubrac, Woosoung Choi, Jee Myung Yang, Kevin Boyé, Heewon Cho, Kathryn M. Citrin, Injune Kim, Anne Eichmann, Victoria L. Bautch, Suk-Won Jin

The proliferation of the endothelium is a highly coordinated process to ensure the emergence, expansion, and homeostasis of the vasculature. While Bone Morphogenetic Protein (BMP) signaling fine-tunes the behaviors of endothelium in health and disease, how BMP signaling influences the proliferation of endothelium and therefore, modulates angiogenesis remains largely unknown. Here, we evaluated the role of Activin A Type I Receptor (ACVR1/ALK2), a key BMP receptor in the endothelium, in modulating the proliferation of endothelial cells. We show that ACVR1/ALK2 is a key modulator for the proliferation of endothelium in the retinal vessels. Loss of endothelial ALK2 leads to a significant reduction in endothelial proliferation and results in fewer branches/endothelial cells in the retinal vessels. Interestingly, venous endothelium appears to be more susceptible to ALK2 deletion. Mechanistically, ACVR1/ALK2 inhibits the expression of CDKN1A/p21, a critical negative regulator of cell cycle progression, in a SMAD1/5-dependent manner, thereby enabling the venous endothelium to undergo active proliferation by suppressing CDKN1A/p21. Taken together, our findings show that BMP signaling mediated by ACVR1/ALK2 provides a critical yet previously underappreciated input to modulate the proliferation of venous endothelium, thereby fine-tuning the context of angiogenesis in health and disease.

内皮的增殖是一个高度协调的过程,以确保血管的出现、扩张和平衡。虽然骨形态发生蛋白(BMP)信号调节内皮在健康和疾病中的行为,但 BMP 信号如何影响内皮的增殖并进而调节血管生成在很大程度上仍是未知数。在这里,我们评估了内皮中的一个关键 BMP 受体--Activin A I 型受体(ACVR1/ALK2)在调节内皮细胞增殖中的作用。我们发现 ACVR1/ALK2 是视网膜血管内皮细胞增殖的关键调节因子。内皮 ALK2 的缺失会导致内皮增殖显著减少,并导致视网膜血管中的分支/内皮细胞减少。有趣的是,静脉内皮似乎更容易受到 ALK2 缺失的影响。从机理上讲,ACVR1/ALK2 以 SMAD1/5 依赖性方式抑制细胞周期进展的关键负调控因子 CDKN1A/p21 的表达,从而通过抑制 CDKN1A/p21 使静脉内皮细胞积极增殖。综上所述,我们的研究结果表明,由 ACVR1/ALK2 介导的 BMP 信号为调节静脉内皮的增殖提供了一种关键的、但以前未得到充分重视的输入,从而对健康和疾病中的血管生成进行了微调。
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引用次数: 0
Botulinum neurotoxin serotype A inhibited ocular angiogenesis through modulating glial activation via SOCS3 肉毒杆菌神经毒素血清型A通过SOCS3调节神经胶质活化抑制眼部血管生成
IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Pub Date : 2024-06-26 DOI: 10.1007/s10456-024-09935-7
Austin T. Gregg, Tianxi Wang, Manon Szczepan, Enton Lam, Hitomi Yagi, Katherine Neilsen, Xingyan Wang, Lois E. H. Smith, Ye Sun

Background

Pathological angiogenesis causes significant vision loss in neovascular age-related macular degeneration and other retinopathies with neovascularization (NV). Neuronal/glial-vascular interactions influence the release of angiogenic and neurotrophic factors. We hypothesized that botulinum neurotoxin serotype A (BoNT/A) modulates pathological endothelial cell proliferation through glial cell activation and growth factor release.

Methods

A laser-induced choroidal NV (CNV) was employed to investigate the anti-angiogenic effects of BoNT/A. Fundus fluorescence angiography, immunohistochemistry, and real-time PCR were used to assess BoNT/A efficacy in inhibiting CNV and the molecular mechanisms underlying this inhibition. Neuronal and glial suppressor of cytokine signaling 3 (SOCS3) deficient mice were used to investigate the molecular mechanisms of BoNT/A in inhibiting CNV via SOCS3.

Findings

In laser-induced CNV mice with intravitreal BoNT/A treatment, CNV lesions decreased > 30%; vascular leakage and retinal glial activation were suppressed; and Socs3 mRNA expression was induced while vascular endothelial growth factor A (Vegfa) mRNA expression was suppressed. The protective effects of BoNT/A on CNV development were diminished in mice lacking neuronal/glial SOCS3.

Conclusion

BoNT/A suppressed laser-induced CNV and glial cell activation, in part through SOCS3 induction in neuronal/glial cells. BoNT/A treatment led to a decrease of pro-angiogenic factors, including VEGFA, highlighting the potential of BoNT/A as a therapeutic intervention for pathological angiogenesis in retinopathies.

背景:病理性血管生成会导致新生血管性老年黄斑变性和其他伴有新生血管(NV)的视网膜病变的视力严重下降。神经元/胶质细胞-血管之间的相互作用会影响血管生成因子和神经营养因子的释放。我们假设肉毒杆菌神经毒素血清型 A(BoNT/A)通过激活神经胶质细胞和释放生长因子来调节病理性内皮细胞增殖:方法:采用激光诱导的脉络膜无视网膜病变(CNV)来研究 BoNT/A 的抗血管生成作用。眼底荧光血管造影术、免疫组化和实时 PCR 被用来评估 BoNT/A 在抑制 CNV 方面的功效以及这种抑制作用的分子机制。利用神经元和胶质细胞因子信号转导抑制因子 3(SOCS3)缺陷小鼠研究 BoNT/A 通过 SOCS3 抑制 CNV 的分子机制:研究结果:激光诱导的CNV小鼠经玻璃体内BoNT/A治疗后,CNV病变减少> 30%;血管渗漏和视网膜胶质细胞活化被抑制;Socs3 mRNA表达被诱导,而血管内皮生长因子A(Vegfa)mRNA表达被抑制。在缺乏神经元/胶质细胞 SOCS3 的小鼠中,BoNT/A 对 CNV 发生的保护作用减弱:结论:BoNT/A抑制了激光诱导的CNV和神经胶质细胞活化,部分原因是通过诱导神经元/神经胶质细胞中的SOCS3。BoNT/A治疗导致促血管生成因子(包括VEGFA)减少,突出了BoNT/A作为视网膜病变中病理性血管生成治疗干预的潜力。
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引用次数: 0
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Angiogenesis
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