Angiogenesis最新文献

VEGFR2-dependent VEGFR3 expression leads to CXCL1/2 and CXCR2 induction in the development of retinal neovascularization. vegfr2依赖性VEGFR3表达导致CXCL1/2和CXCR2诱导视网膜新生血管的形成。

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-25 DOI: 10.1007/s10456-026-10104-1

Chandra Sekhar Yadavalli, Raj Kumar, Suresh Govatati, Gadiparthi N Rao

{"title":"VEGFR2-dependent VEGFR3 expression leads to CXCL1/2 and CXCR2 induction in the development of retinal neovascularization.","authors":"Chandra Sekhar Yadavalli, Raj Kumar, Suresh Govatati, Gadiparthi N Rao","doi":"10.1007/s10456-026-10104-1","DOIUrl":"https://doi.org/10.1007/s10456-026-10104-1","url":null,"abstract":"<p><p>Elevated levels of IL-8 have been detected in the vitreous samples of patients with diabetic retinopathy. However, its role in retinal neovascularization remains unknown. We hypothesized that IL-8 and its murine orthologues, CXCL1/2, are key mediators of oxygen-induced retinopathy (OIR)-driven retinal angiogenesis. To this end, we found that VEGFA stimulates CXCL1/2 and their receptor CXCR2 expression in mouse retinal microvascular endothelial cells (MRMVECs) in a time-dependent manner. Recombinant CXCL1/2 induced MRMVEC migration, proliferation, sprouting, and tube formation alone and in combination. Neutralizing CXCL1/2 or CXCR2 antibodies (Abs) attenuated the angiogenic effects of CXCL1/2 as well as VEGFA. In line with these observations in mice, VEGFA induced IL-8 and its receptor CXCR2 expression in human retinal microvascular endothelial cells (HRMVECs), and neutralizing IL-8 or CXCR2 Abs suppressed their angiogenic effects. Furthermore, OIR induced CXCL1/2 and CXCR2 expression in the mouse retina in vivo, and blockade of their function using their neutralizing Abs reduced retinal neovascularization. Mechanistically, depletion of ATF6 or GRP78 levels abrogated VEGFA-induced CXCL1/2 and CXCR2 expression in MRMVECs and IL-8 and CXCR2 expression in HRMVECs in vitro and OIR-induced CXCL1/2 and CXCR2 expression in vivo in mice. Furthermore, silencing VEGFR2 or VEGFR3 levels inhibited VEGFA/OIR-induced ATF6-GRP78 activation and their downstream CXCL1/2, IL-8 and CXCR2 expression both in vitro and in vivo. Together, these findings identify IL-8 as potential therapeutic target for treating retinal neovascular diseases.</p>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260823","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}

引用次数: 0

Targeting the epigenetic landscape of ECFCs: a new opportunity to enhance vascular repair. 靶向ecfc的表观遗传景观：增强血管修复的新机会。

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-25 DOI: 10.1007/s10456-026-10103-2

Yaqiong Liu, Caomhán John Lyons, Christine Ayu Lagonda, Yingquan Luo, Lin Cheng, Zhenfei Fang

{"title":"Targeting the epigenetic landscape of ECFCs: a new opportunity to enhance vascular repair.","authors":"Yaqiong Liu, Caomhán John Lyons, Christine Ayu Lagonda, Yingquan Luo, Lin Cheng, Zhenfei Fang","doi":"10.1007/s10456-026-10103-2","DOIUrl":"https://doi.org/10.1007/s10456-026-10103-2","url":null,"abstract":"<p><p>Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells characterized by robust proliferative and vasculogenic capacities, making them promising candidates for therapeutic tissue revascularization. However, the clinical application of ECFCs is hindered by their functional impairment under pathological conditions, such as diabetes and cardiovascular disease. Accumulating evidence indicates that aberrant epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, have been implicated in disease-associated ECFC dysfunction. In this review, we summarize current insights into the epigenetic regulation of ECFCs in pathological contexts, discuss epigenetic intervention strategies aimed at restoring ECFC function, and further highlight the therapeutic potential of ECFC-derived extracellular vesicles (EVs) as carriers of epigenetic cargo that promotes vascular repair. Collectively, a deeper understanding of the epigenetic landscape of ECFCs and ECFC-derived EVs may facilitate the development of novel therapeutic approaches for vascular regeneration and accelerate the clinical translation of ECFC- and EV-based therapies.</p>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260859","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}

引用次数: 0

From persistent biomarker signatures to vascular pathophysiology in post-COVID-19 syndrome 从持续的生物标志物特征到covid -19综合征后的血管病理生理

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-23 DOI: 10.1007/s10456-026-10099-9

Güney Sarıoğlu, Oğuz Kaan Kaya

引用次数: 0

Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity 女性对内皮fox01的特异性依赖控制着血管弹性和对肥胖的代谢适应

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-22 DOI: 10.1007/s10456-026-10093-1

Alexandra Pislaru, Emilie Roudier, Omid Rezvan, Connor Breadmore, Minoosh Fathi, George Nader, Ibrahim AlZaim, Emmanuel Nwadozi, Gisang Lee, Ehsan Yavari, Aly Fawzy, Eric Rullman, Joanna Kalucka, Thomas Gustafsson, Martina Rudnicki, Tara L. Haas

{"title":"Female-specific reliance on endothelial FoxO1 governs vascular resilience and metabolic adaptation to obesity","authors":"Alexandra Pislaru, Emilie Roudier, Omid Rezvan, Connor Breadmore, Minoosh Fathi, George Nader, Ibrahim AlZaim, Emmanuel Nwadozi, Gisang Lee, Ehsan Yavari, Aly Fawzy, Eric Rullman, Joanna Kalucka, Thomas Gustafsson, Martina Rudnicki, Tara L. Haas","doi":"10.1007/s10456-026-10093-1","DOIUrl":"10.1007/s10456-026-10093-1","url":null,"abstract":"<div><p>Sex differences in adipose tissue vascular remodeling critically influence susceptibility to obesity-associated metabolic disease, yet the underlying mechanisms remain unclear. Here we identify Forkhead box O1 (FoxO1) as a sex-dependent regulator of endothelial function, with female endothelial cells (EC) expressing higher levels of FoxO1 and depending on it to maintain vascular remodeling and metabolic homeostasis. Accordingly, FoxO1 loss in females disrupted angiogenesis, and promoted adipocyte hypertrophy, weight gain and glucose dysregulation, whereas opposite effects have been reported in males. This phenotype was associated with a shift in the endothelial transcriptome toward a male-like state, consistent with loss of female protection against diet-induced metabolic dysfunction. Mechanistically, FoxO1 inhibition exerted time-dependent effects, with short-term suppression promoting proliferation and sustained inhibition reducing proliferation and inducing metabolic dysfunction. Although also observed in males, these effects were more pronounced in female EC, which also selectively exhibited mitochondrial dysfunction, increased oxidative stress and DNA damage accumulation, culminating in a senescence-like arrest. Antioxidant treatment partially rescued this phenotype, implicating oxidative stress as a driver of female-specific vulnerability. These findings reveal a sex-dependent divergence in FoxO1 function and identify endothelial FoxO1 as a determinant of opposing vascular and metabolic responses to obesogenic stress.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-026-10093-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234962","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

Nuclear SUN2 coordinates endothelial cell-matrix interactions to regulate blood vessel homeostasis and barrier function 核SUN2协调内皮细胞-基质相互作用，调节血管稳态和屏障功能

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-15 DOI: 10.1007/s10456-026-10098-w

Pauline Bougaran, Danielle B. Buglak, Alexandra Neal, Mitesh Rathod, Michaelanthony Gore, Max A. Hockenberry, Aryan A. Amin, Natalie Tanke, Morgan Oatley, Wesley R. Legant, Ziqing Liu, James E. Bear, William J. Polacheck, Victoria L. Bautch

{"title":"Nuclear SUN2 coordinates endothelial cell-matrix interactions to regulate blood vessel homeostasis and barrier function","authors":"Pauline Bougaran, Danielle B. Buglak, Alexandra Neal, Mitesh Rathod, Michaelanthony Gore, Max A. Hockenberry, Aryan A. Amin, Natalie Tanke, Morgan Oatley, Wesley R. Legant, Ziqing Liu, James E. Bear, William J. Polacheck, Victoria L. Bautch","doi":"10.1007/s10456-026-10098-w","DOIUrl":"10.1007/s10456-026-10098-w","url":null,"abstract":"<div><p>Vascular endothelial cells respond to environmental forces to remodel vessels during development and to achieve homeostasis, and mis-regulated responses lead to vascular dysfunction and disease. The nucleus participates in transmitting signals to cell–matrix junctions via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that resides in the nuclear envelope, but how this information is regulated and relayed is incompletely understood. We found that the LINC complex protein SUN2 is required for proper endothelial cell–matrix interactions that occur far from the nucleus and affect angiogenic expansion, vascular responses to flow, and barrier integrity. Endothelial cells lacking SUN2 had inappropriate responses to environmental cues generated under both non-flow and flow conditions as well as reduced expression of flow-mediated transcription factors in vitro and in vivo. Expression of several matrix and adhesion genes was reduced in SUN2-depleted cells and associated with defective extracellular matrix, dysmorphic focal adhesions resistant to dynamic turnover, and disturbed cell–matrix force distribution. Mechanistically, nuclear SUN2 regulated cytoskeletal microtubule dynamics upstream of effects on cell and focal adhesion morphology, barrier integrity, and flow-mediated endothelial quiescence. These findings indicate that nuclear SUN2 establishes and maintains blood vessel homeostasis by controlling microtubule-mediated effects on focal adhesion and extracellular matrix properties, with implications for cardiovascular aging and diseases such as Marfan syndrome that affect vessel wall integrity.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-026-10098-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149189571","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

A novel approach for reliable differentiation of lymphatic endothelial precursor cells in vitro 淋巴内皮前体细胞体外可靠分化的新方法。

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-13 DOI: 10.1007/s10456-026-10097-x

Inazio Arriola-Alvarez, María Rodríguez-Hidalgo, Luca Melotti, Ainhoa Irastorza-Lorenzo, Héctor Lafuente, Sonia Alonso-Martín, Ander Izeta

{"title":"A novel approach for reliable differentiation of lymphatic endothelial precursor cells in vitro","authors":"Inazio Arriola-Alvarez, María Rodríguez-Hidalgo, Luca Melotti, Ainhoa Irastorza-Lorenzo, Héctor Lafuente, Sonia Alonso-Martín, Ander Izeta","doi":"10.1007/s10456-026-10097-x","DOIUrl":"10.1007/s10456-026-10097-x","url":null,"abstract":"<div><p>The lymphatic system plays critical roles in fluid homeostasis, immune regulation, and lipid transport, making its dysfunction a contributor to numerous pathological conditions. Lymphatic tissue engineering aims to develop therapeutic strategies for lymphatic regeneration and repair, depending on the availability of suitable cell sources for lymphatic endothelial cell generation. Key cell sources explored for lymphatic tissue engineering include the dermis, bone marrow (BM) and stromal vascular fraction (SVF). To our knowledge, no existing differentiation protocols can accurately generate lymphatic endothelial precursor cells (LEPCs). This study presents a novel in vitro differentiation protocol for generating murine LEPCs from stromal SVF, dermis and BM-derived mesenchymal stem cells (MSCs). The feasibility of using them as tissue sources was first evaluated leading to dermal cells exclusion due to low yield post-isolation, and highlighting the limited differentiation efficiency of BM-MSCs. SVF-derived LEPCs showed the most prominent results, exhibiting robust LEPCs differentiation and superior scalability. In vitro characterization confirmed that LEPCs maintain a distinct lymphatic endothelial phenotype, exhibiting high migratory capacity, robust capillary-like network formation, and consistent expression of key lymphatic markers across 2D and 3D cultures, supported by strong transcriptomic alignment as validated by RNA-Seq. Furthermore, in vivo modelling demonstrated their preclinical efficacy, as transplanted LEPCs integrated seamlessly into pre-existing lymphatic vessels within a wound-healing model. The protocol provides a consistent platform for studying lymphatic endothelial biology and potential applications in regenerative medicine and therapeutic angiogenesis.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-026-10097-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178934","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

Angiogenesis: a research field in full bloom 血管生成：一个蓬勃发展的研究领域。

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-10 DOI: 10.1007/s10456-026-10077-1

Andrew C. Dudley, Arjan W. Griffioen

引用次数: 0

VEGF165b attenuates LPS-induced acute lung injury via antagonizing the VEGF165a/VEGFR2 signaling pathway VEGF165b通过拮抗VEGF165a/VEGFR2信号通路减轻lps诱导的急性肺损伤。

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-10-04 DOI: 10.1007/s10456-026-10090-4

Jia Deng, Xilong Wang, Zhixiong Wu, Qianwen Bai, Qiao Luo, Liang Zhou, Yao Yao, Hongquan Wang, Kai Zhong, Haoyu Liu, Xin Chen, Tao Wang

{"title":"VEGF165b attenuates LPS-induced acute lung injury via antagonizing the VEGF165a/VEGFR2 signaling pathway","authors":"Jia Deng, Xilong Wang, Zhixiong Wu, Qianwen Bai, Qiao Luo, Liang Zhou, Yao Yao, Hongquan Wang, Kai Zhong, Haoyu Liu, Xin Chen, Tao Wang","doi":"10.1007/s10456-026-10090-4","DOIUrl":"10.1007/s10456-026-10090-4","url":null,"abstract":"<div><p>Vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), yet targeted therapies for these conditions remain elusive. This study identified the VEGF-A splice variant VEGF<sub>165</sub>b as a crucial endogenous protector against ALI/ARDS. In patients, the circulating ratio of VEGF<sub>165</sub>b to total VEGF-A was significantly reduced and correlated inversely with disease severity. In murine models of LPS-induced ALI, administration of exogenous VEGF<sub>165</sub>b alleviated pulmonary edema, inflammation, and injury, whereas its neutralization exacerbated damage. Mechanistically, VEGF<sub>165</sub>b functioned as a competitive antagonist, selectively inhibiting VEGF<sub>165</sub>a-induced phosphorylation of VEGFR2 at tyrosine 1175. This blockade suppressed the downstream PI3K/AKT/eNOS permeability pathway, reducing SRC-mediated VE-cadherin phosphorylation and thereby enhancing endothelial barrier integrity. Additionally, VEGF<sub>165</sub>b downregulated the chemokine CCL2, limiting monocyte–endothelial adhesion through a distinct anti-inflammatory mechanism. Our findings established VEGF<sub>165</sub>b as a key endogenous stabilizer of the vascular barrier, acting via dual pathways—direct junctional reinforcement and anti-inflammatory activity—and highlighted its potential as both a biomarker and a therapeutic agent for ALI/ARDS. This work revealed the critical balance of VEGF splicing variants in vascular homeostasis and offers a novel strategy for treating vascular barrier dysfunction in critical lung diseases.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103126","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}

引用次数: 0

Lysed erythrocyte membranes metabolically prime endothelial cells for angiogenesis 裂解的红细胞膜代谢为血管生成的内皮细胞

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-09-25 DOI: 10.1007/s10456-026-10096-y

Rajinikanth Gogiraju, Kateryna Moiko, Magdalena L. Bochenek, Franziska Greulich, Claudius Witzler, Werner Schmitz, Konstantinos Zifkos, Cécile Derieux, Iman Ghasemi, Payal Guliani, Beichen Sun, Christine Espinola-Klein, Henriette N. Uhlenhaut, Andreas Bock, Wolfram Ruf, Thati Madhusudhan, Philipp Lurz, Katrin Schäfer

{"title":"Lysed erythrocyte membranes metabolically prime endothelial cells for angiogenesis","authors":"Rajinikanth Gogiraju, Kateryna Moiko, Magdalena L. Bochenek, Franziska Greulich, Claudius Witzler, Werner Schmitz, Konstantinos Zifkos, Cécile Derieux, Iman Ghasemi, Payal Guliani, Beichen Sun, Christine Espinola-Klein, Henriette N. Uhlenhaut, Andreas Bock, Wolfram Ruf, Thati Madhusudhan, Philipp Lurz, Katrin Schäfer","doi":"10.1007/s10456-026-10096-y","DOIUrl":"10.1007/s10456-026-10096-y","url":null,"abstract":"<div><p>Endothelial dysfunction is a hallmark of pathological angiogenesis and associated with erythrocyte extravasation and lysis. Whether mediators released from lysed erythrocytes instruct endothelial cells (ECs) for new vessel formation is unknown. Here, we show that the membrane fraction of lysed erythrocytes activates inflammatory endothelial gene transcription and metabolically reprograms ECs to promote angiogenic sprout formation. Alterations in endothelial glucose metabolism occurred downstream of NFκB p65 activation by extracellular ATP via fast-acting endothelial P2X7 receptors and also involved ATP-mediated adenylyl cyclase activation and cyclic AMP generation via P2RY11. Overexpression and acetylation of histone 3 at lysine 27 of NR4A1 was identified as anti-inflammatory control mechanism and angio-metabolic switch activating <i>VEGF</i>, <i>PFKFB3</i> and other AP-1 dependent gene transcription programs. The angiogenic potential of lysed erythrocyte membranes from patients with peripheral artery disease was impaired and could be restored by inhibiting endothelial phosphodiesterase 4 to prevent endothelial cAMP degradation. Our findings uncover that erythrolysis metabolically primes ECs for angiogenesis and that targeting endothelial cAMP generation may be a promising strategy to restore endothelial angiogenic functions.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-026-10096-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035238","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

Myeloid deficiency of RORα exacerbates lipid dysregulation and laser-induced choroidal neovascularization 髓系RORα缺乏加剧脂质失调和激光诱导的脉络膜新生血管

IF 11.2 1区医学

Angiogenesis Pub Date : 2026-09-25 DOI: 10.1007/s10456-026-10092-2

Neetu Kushwah, Chi-Hsiu Liu, Kiran Bora, Meenakshi Maurya, Madeline C. Pavlovich, Zhongjie Fu, Theodore M. Kamenecka, Ye Sun, Laura A. Solt, Jing Chen

{"title":"Myeloid deficiency of RORα exacerbates lipid dysregulation and laser-induced choroidal neovascularization","authors":"Neetu Kushwah, Chi-Hsiu Liu, Kiran Bora, Meenakshi Maurya, Madeline C. Pavlovich, Zhongjie Fu, Theodore M. Kamenecka, Ye Sun, Laura A. Solt, Jing Chen","doi":"10.1007/s10456-026-10092-2","DOIUrl":"10.1007/s10456-026-10092-2","url":null,"abstract":"<div><p>Dysregulated lipid and cholesterol metabolism is implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of vision loss. Retinoic acid receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor genetically associated with neovascular AMD. We investigated the role of RORα in regulating AMD-like pathologies and laser-induced choroidal neovascularization (CNV) through mediating myeloid cell lipid homeostasis and function. Both systemic (<i>Rora</i><sup><i>sg/sg</i></sup>) and myeloid-specific (<i>Rora</i><sup><i>fl/fl</i></sup><i>;LysMCre</i>) RORα deficient mice exhibited fundus lesions with aging, and exacerbated CNV with chronic subretinal inflammation, with subretinal accumulation of lipid-laden activated microglia/macrophages, and increased levels of pro-inflammatory cytokines. RORα-deficient macrophages showed enhanced lipid droplet formation and upregulation of peroxisome proliferator-activated receptor gamma (PPARγ), a lipogenic RORα target gene. Pharmacological inhibition of RORα in cultured macrophage recapitulated the effects of RORα deficiency on lipid enrichment and inflammation, whereas PPARγ inhibition in RORα deficient mice partially reversed the effects on laser-induced CNV, lipid accumulation and inflammation. Additionally, migratory chemokine receptors, including CX3CR1 and CD47, were downregulated in RORα-deficient myeloid cells, contributing to impaired elimination of inflammatory cells from the subretinal space. These findings identify RORα as a critical transcriptional regulator that links lipid dysregulation to persistent subretinal inflammation and pathological CNV highly relevant in AMD.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"29 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-026-10092-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035236","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