Angiogenesis最新文献

{"title":"Angiogenesis is limited by LIC1-mediated lysosomal trafficking","authors":"Dymonn Johnson,&nbsp;Sarah Colijn,&nbsp;Jahmiera Richee,&nbsp;Joseph Yano,&nbsp;Margaret Burns,&nbsp;Andrew E. Davis,&nbsp;Van N. Pham,&nbsp;Amra Saric,&nbsp;Akansha Jain,&nbsp;Ying Yin,&nbsp;Daniel Castranova,&nbsp;Mariana Melani,&nbsp;Misato Fujita,&nbsp;Stephanie Grainger,&nbsp;Juan S. Bonifacino,&nbsp;Brant M. Weinstein,&nbsp;Amber N. Stratman","doi":"10.1007/s10456-024-09951-7","DOIUrl":"10.1007/s10456-024-09951-7","url":null,"abstract":"<div><p>Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, <i>DYNC1LI1</i>) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified a <i>dync1li1</i> zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis. In vitro, LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling. In vivo, endothelial-specific expression of constitutively active <i>Rab11a</i> leads to excessive angiogenesis, similar to the <i>dync1li1</i> mutants. Increased angiogenesis is also evident in zebrafish harboring mutations in <i>rilpl1/2</i>, the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"943 - 962"},"PeriodicalIF":9.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Similarities and differences between brain and skin GNAQ p.R183Q driven capillary malformations","authors":"Sana Nasim,&nbsp;Colette Bichsel,&nbsp;Anna Pinto,&nbsp;Sanda Alexandrescu,&nbsp;Harry Kozakewich,&nbsp;Joyce Bischoff","doi":"10.1007/s10456-024-09950-8","DOIUrl":"10.1007/s10456-024-09950-8","url":null,"abstract":"<div><p>Capillary malformations (CM) are congenital vascular irregularities of capillary and venous blood vessels that appear in the skin, leptomeninges of the brain, and the choroid of the eye in the disorder known as Sturge Weber Syndrome (SWS). More common are non-syndromic CM found only in the skin, without brain or ocular involvement. A somatic activating mutation in <i>GNAQ</i> (p.R183Q) is found in ~ 90% of syndromic and non-syndromic CM specimens and is present in CD31^pos endothelial cells isolated from brain and skin CM specimens. Endothelial expression of the <i>GNAQ</i> p.R183Q variant is sufficient to form CM-like vessels in mice. Given the distinct features and functions of blood vessels in the brain versus the skin, we examined the features of CM vessels in both tissues to gain insights into the pathogenesis of CM. Herein, we present morphologic characteristics of CM observed in specimens from brain and skin. The <i>GNAQ</i> p.R183Q variant allelic frequency in each specimen was determined by droplet digital PCR. Sections were stained for endothelial cells, tight junctions, mural cells, and macrophages to assess the endothelium as well as perivascular constituents. CM blood vessels in brain and skin were enlarged, exhibited fibrin leakage and reduced zona occludin-1 and claudin-5, and were surrounded by MRC1^pos/LYVE1^pos macrophages. In contrast, the CMs from brain and skin differ in endothelial sprouting activity and localization of mural cells. These characteristics might be helpful in the development of targeted and/or tissue specific therapies to prevent or reverse non-syndromic and syndromic CM.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"931 - 941"},"PeriodicalIF":9.2,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammasome activation aggravates choroidal neovascularization","authors":"Ryan D. Makin,&nbsp;Ivana Apicella,&nbsp;Roshni Dholkawala,&nbsp;Shinichi Fukuda,&nbsp;Shuichiro Hirahara,&nbsp;Yoshio Hirano,&nbsp;Younghee Kim,&nbsp;Ayami Nagasaka,&nbsp;Yosuke Nagasaka,&nbsp;Siddharth Narendran,&nbsp;Felipe Pereira,&nbsp;Akhil Varshney,&nbsp;Shao-bin Wang,&nbsp;Jayakrishna Ambati,&nbsp;Bradley D. Gelfand","doi":"10.1007/s10456-024-09949-1","DOIUrl":"10.1007/s10456-024-09949-1","url":null,"abstract":"<div><p>Inflammasome activation is implicated in diseases of aberrant angiogenesis such as age-related macular degeneration (AMD), though its precise role in choroidal neovascularization (CNV), a characteristic pathology of advanced AMD, is ill-defined. Reports on inhibition of inflammasome constituents on CNV are variable and the precise role of inflammasome in mediating pathological angiogenesis is unclear. Historically, subretinal injection of inflammasome agonists alone has been used to investigate retinal pigmented epithelium (RPE) degeneration, while the laser photocoagulation model has been used to study pathological angiogenesis in a model of CNV. Here, we report that the simultaneous introduction of any of several disease-relevant inflammasome agonists (<i>Alu</i> or B2 RNA, <i>Alu</i> cDNA, or oligomerized amyloid β (1–40)) exacerbates laser-induced CNV. These activities were diminished or abrogated by genetic or pharmacological targeting of inflammasome signaling constituents including P2rx7, Nlrp3, caspase-1, caspase-11, and Myd88, as well as in myeloid-specific caspase-1 knockout mice. <i>Alu</i> RNA treatment induced inflammasome activation in macrophages within the CNV lesion, and increased accumulation of macrophages in an inflammasome-dependent manner. Finally, IL-1β neutralization prevented inflammasome agonist-induced chemotaxis, macrophage trafficking, and angiogenesis. Collectively, these observations support a model wherein inflammasome stimulation promotes and exacerbates CNV and may be a therapeutic target for diseases of angiogenesis such as neovascular AMD.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"919 - 929"},"PeriodicalIF":9.2,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09949-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306973","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}

{"title":"Timed topical dexamethasone eye drops improve mitochondrial function to prevent severe retinopathy of prematurity","authors":"Hitomi Yagi,&nbsp;Myriam Boeck,&nbsp;Mariya Petrishka-Lozenska,&nbsp;Pia Lundgren,&nbsp;Taku Kasai,&nbsp;Gael Cagnone,&nbsp;Katherine Neilsen,&nbsp;Chaomei Wang,&nbsp;Jeff Lee,&nbsp;Yohei Tomita,&nbsp;Sasha A. Singh,&nbsp;Jean-Sébastien Joyal,&nbsp;Masanori Aikawa,&nbsp;Kazuno Negishi,&nbsp;Zhongjie Fu,&nbsp;Ann Hellström,&nbsp;Lois E.H. Smith","doi":"10.1007/s10456-024-09948-2","DOIUrl":"10.1007/s10456-024-09948-2","url":null,"abstract":"<div><p>Pathological neovascularization in retinopathy of prematurity (ROP) can cause visual impairment in preterm infants. Current ROP treatments which are not preventative and only address late neovascular ROP, are costly and can lead to severe complications. We showed that topical 0.1% dexamethasone eye drops administered prior to peak neovessel formation prevented neovascularization in five extremely preterm infants at high risk for ROP and suppressed neovascularization by 30% in mouse oxygen-induced retinopathy (OIR) modeling ROP. In contrast, in OIR, topical dexamethasone treatment before any neovessel formation had limited efficacy in preventing later neovascularization, while treatment after peak neovessel formation had a non-statistically significant trend to exacerbating disease. Optimally timed topical dexamethasone suppression of neovascularization in OIR was associated with increased retinal mitochondrial gene expression and decreased inflammatory marker expression, predominantly found in immune cells. Blocking mitochondrial ATP synthetase reversed the inhibitory effect of dexamethasone on neovascularization in OIR. This study provides new insights into topical steroid effects in retinal neovascularization and into mitochondrial function in phase II ROP, and suggests a simple clinical approach to prevent severe ROP.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"903 - 917"},"PeriodicalIF":9.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09948-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249609","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}

{"title":"The influences of ApoE isoforms on endothelial adherens junctions and actin cytoskeleton responding to mCRP","authors":"Zhengrong Zhang,&nbsp;Weiwei Lin,&nbsp;Qini Gan,&nbsp;Maohua Lei,&nbsp;Bin Gong,&nbsp;Chao Zhang,&nbsp;Jessica Salles Henrique,&nbsp;Jingyan Han,&nbsp;Hua Tian,&nbsp;Qiushan Tao,&nbsp;Lawrence A. Potempa,&nbsp;Thor D. Stein,&nbsp;Andrew Emili,&nbsp;Wei Qiao Qiu","doi":"10.1007/s10456-024-09946-4","DOIUrl":"10.1007/s10456-024-09946-4","url":null,"abstract":"<div><p>Apolipoprotein E4 (<i>ApoE</i>4) plays an important role responding to monomeric C-reactive protein (mCRP) via binding to CD31 leading to cerebrovascular damage and Alzheimer’s disease (AD). Using phosphor-proteomic profiling, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures linked with CD31 in brain endothelia in <i>ApoE</i>4 carriers, <i>ApoE</i>4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP increased the expressions of phosphorylated CD31 (pCD31) and LIMA1, and facilitate the binding of pCD31 to LIMA1. mCRP combined with recombinant <i>APOE</i>4 protein decreased interaction of CD31 and VE-Cadherin at adherens junctions (AJs), along with altered the expression of various actin cytoskeleton proteins, causing microvasculature damage. Notably, the <i>APOE</i>2 protein attenuated these changes. Overall, our study demonstrates that <i>ApoE</i>4 responds to mCRP to disrupt the endothelial AJs which link with the actin cytoskeleton and this pathway could play a key role in the barrier dysfunction leading to AD risk.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"861 - 881"},"PeriodicalIF":9.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09946-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249445","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}

{"title":"Oscillatory contractile forces refine endothelial cell-cell interactions for continuous lumen formation governed by Heg1/Ccm1","authors":"Jianmin Yin,&nbsp;Ludovico Maggi,&nbsp;Cora Wiesner,&nbsp;Markus Affolter,&nbsp;Heinz-Georg Belting","doi":"10.1007/s10456-024-09945-5","DOIUrl":"10.1007/s10456-024-09945-5","url":null,"abstract":"<div><p>The formation and organization of complex blood vessel networks rely on various biophysical forces, yet the mechanisms governing endothelial cell-cell interactions under different mechanical inputs are not well understood. Using the dorsal longitudinal anastomotic vessel (DLAV) in zebrafish as a model, we studied the roles of multiple biophysical inputs and cerebral cavernous malformation (CCM)-related genes in angiogenesis. Our research identifies <i>heg1</i> and <i>krit1</i> (<i>ccm1</i>) as crucial for the formation of endothelial cell-cell interfaces during anastomosis. In mutants of these genes, cell-cell interfaces are entangled with fragmented apical domains. A Heg1 live reporter demonstrated that Heg1 is dynamically involved in the oscillatory constrictions along cell-cell junctions, whilst a Myosin live reporter indicated that <i>heg1</i> and <i>krit1</i> mutants lack actomyosin contractility along these junctions. In wild-type embryos, the oscillatory contractile forces at junctions refine endothelial cell-cell interactions by straightening junctions and eliminating excessive cell-cell interfaces. Conversely, in the absence of junctional contractility, the cell-cell interfaces become entangled and prone to collapse in both mutants, preventing the formation of a continuous luminal space. By restoring junctional contractility via optogenetic activation of RhoA, contorted junctions are straightened and disentangled. Additionally, haemodynamic forces complement actomyosin contractile forces in resolving entangled cell-cell interfaces in both wild-type and mutant embryos. Overall, our study reveals that oscillatory contractile forces governed by Heg1 and Krit1 are essential for maintaining proper endothelial cell-cell interfaces and thus for the formation of a continuous luminal space, which is essential to generate a functional vasculature.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"845 - 860"},"PeriodicalIF":9.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09945-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152990","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}

{"title":"Sialyl Lewis X decorated integrin α3 on small extracellular vesicles promotes metastasis of bladder cancer via enhancing vascular permeability","authors":"Hui Feng,&nbsp;Liang Liang,&nbsp;Wenli Deng,&nbsp;Jiaojiao Gao,&nbsp;Xiang Li,&nbsp;Feng Guan","doi":"10.1007/s10456-024-09947-3","DOIUrl":"10.1007/s10456-024-09947-3","url":null,"abstract":"<div><p>The permeability of blood vessels plays a crucial role in the spread of cancer cells, facilitating their metastasis at distant sites. Small extracellular vesicles (sEVs) are known to contribute to the metastasis of various cancers by crossing the blood vessel wall. However, the role of abnormal glycoconjugates on sEVs in tumor blood vessels remains unclear. Our study found elevated levels of fucosyltransferase VII (FUT7) and its product sialyl Lewis X (sLeX) in muscle-invasive bladder cancer (BLCA), with high levels of sLeX promoting the growth and invasion of BLCA cells. Further investigation revealed that sLeX was enriched in sEVs derived from BLCA. sLeX-decorated sEVs increased blood vessel permeability by disrupting the tight junctions of human umbilical vein endothelial cells (HUVECs). Using the glycoproteomics approach, we identified integrin α3 (ITGA3) as a sLeX-bearing glycoprotein in BLCA cells and their sEVs. Mechanically, sLeX modification stabilized ITGA3 by preventing its degradation in lysosomes. sEVs carrying sLeX-modified ITGA3 can be effectively internalized by HUVECs, leading to a decrease in the expression of tight junction protein. Conversely, silencing ITGA3 in sLeX-decorated sEVs restored tight junction proteins and reduced blood vessel permeability by inhibiting the MAPK pathway. Moreover, sLeX-modification of ITGA3 at Asn 265 in HUVECs promoted occludin dephosphorylation at Ser/Thr residues, followed by inducing its importin α1-mediated nuclear translocation, which resulted in the disruption of tight junctions. Our findings suggest a potential strategy for disrupting the formation of a metastatic microenvironment and preventing the spread of malignant bladder cancer.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"883 - 901"},"PeriodicalIF":9.2,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senescent endothelial cells: a potential target for diabetic retinopathy","authors":"Ying-Lu Liao,&nbsp;Yi-Fan Fang,&nbsp;Jia-Xing Sun,&nbsp;Guo-Rui Dou","doi":"10.1007/s10456-024-09943-7","DOIUrl":"10.1007/s10456-024-09943-7","url":null,"abstract":"<div><p>Diabetic retinopathy (DR) is a diabetic complication that results in visual impairment and relevant retinal diseases. Current therapeutic strategies on DR primarily focus on antiangiogenic therapies, which particularly target vascular endothelial growth factor and its related signaling transduction. However, these therapies still have limitations due to the intricate pathogenesis of DR. Emerging studies have shown that premature senescence of endothelial cells (ECs) in a hyperglycemic environment is involved in the disease process of DR and plays multiple roles at different stages. Moreover, these surprising discoveries have driven the development of senotherapeutics and strategies targeting senescent endothelial cells (SECs), which present challenging but promising prospects in DR treatment. In this review, we focus on the inducers and mechanisms of EC senescence in the pathogenesis of DR and summarize the current research advances in the development of senotherapeutics and strategies that target SECs for DR treatment. Herein, we highlight the role played by key factors at different stages of EC senescence, which will be critical for facilitating the development of future innovative treatment strategies that target the different stages of senescence in DR.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"663 - 679"},"PeriodicalIF":9.2,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-024-09943-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103708","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}

{"title":"Soluble FLT-1 in angiogenesis: pathophysiological roles and therapeutic implications","authors":"Layal EI Wazan,&nbsp;Ariel Widhibrata,&nbsp;Guei-Sheung Liu","doi":"10.1007/s10456-024-09942-8","DOIUrl":"10.1007/s10456-024-09942-8","url":null,"abstract":"<div><p>Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"641 - 661"},"PeriodicalIF":9.2,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The angiogenic role of the alpha 9-nicotinic acetylcholine receptor in triple-negative breast cancers","authors":"Sonjid Ochirbat,&nbsp;Tzu-Chun Kan,&nbsp;Chun-Chun Hsu,&nbsp;Tzu-Hsuan Huang,&nbsp;Kuo-Hsiang Chuang,&nbsp;Michael Chen,&nbsp;Chun-Chia Cheng,&nbsp;Chun-Chao Chang,&nbsp;Sri Rahayu,&nbsp;Jungshan Chang","doi":"10.1007/s10456-024-09944-6","DOIUrl":"10.1007/s10456-024-09944-6","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"27 4","pages":"827 - 843"},"PeriodicalIF":9.2,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}