{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:43:47Z","timestamp":1791607427126,"version":"4.3.4"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Although multiple evidences suggest that angiogenesis is associated with the pathophysiology of rosacea, its role is still in debate. Here, we showed that angiogenesis was enhanced in skin lesions of both rosacea patients and LL37-induced rosacea-like mice. Inhibition of angiogenesis alleviated LL37-induced rosacea-like features in mice. Mechanistically, we showed that mTORC1 was activated in the endothelial cells of the lesional skin from rosacea patients and LL37-induced rosacea-like mouse model. Inhibition of mTORC1 decreased angiogenesis and blocked the development of rosacea in mice. On the contrary, hyperactivation of mTORC1 increased angiogenesis and exacerbated rosacea-like phenotypes. Our <jats:italic>in vitro<\/jats:italic> results further demonstrated that inhibition of mTORC1 signaling significantly declined LL37-induced tube formation of human endothelial cells. Taken together, our findings revealed that mTORC1-mediated angiogenesis responding to LL37 might be essential for the development of rosacea and targeting angiogenesis might be a novel potential therapy.<\/jats:p>","DOI":"10.3389\/fcell.2021.751785","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T05:43:12Z","timestamp":1640065392000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["mTORC1-Mediated Angiogenesis is Required for the Development of Rosacea"],"prefix":"10.3389","volume":"9","author":[{"given":"Qinqin","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Sha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"San","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfu","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhili","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.cmet.2017.11.004","article-title":"mTORC1 Signaling: A Double-Edged Sword in Diabetic \u03b2 Cells","volume":"27","author":"Ardestani","year":"2018","journal-title":"Cel Metab."},{"key":"B2","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/s00403-007-0816-z","article-title":"A Study of the Pathogenesis of Rosacea: How Angiogenesis and Mast Cells May Participate in a Complex Multifactorial Process","volume":"300","author":"Aroni","year":"2008","journal-title":"Arch. Dermatol. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1016\/j.cmet.2018.07.019","article-title":"Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation","volume":"28","author":"Bruning","year":"2018","journal-title":"Cel Metab."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2786","DOI":"10.3389\/fimmu.2018.02786","article-title":"Epidermal mTORC1 Signaling Contributes to the Pathogenesis of Psoriasis and Could Serve as a Therapeutic Target","volume":"9","author":"Buerger","year":"2018","journal-title":"Front. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"109011","DOI":"10.1016\/j.biopha.2019.109011","article-title":"Thalidomide Ameliorates Rosacea-like Skin Inflammation and Suppresses NF-\u039ab Activation in Keratinocytes","volume":"116","author":"Chen","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B6","first-page":"38","article-title":"Rosacea: a Review","volume":"34","author":"Culp","year":"2009","journal-title":"P T"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e13560","DOI":"10.15252\/emmm.202013560","article-title":"A Positive Feedback Loop between mTORC1 and Cathelicidin Promotes Skin Inflammation in Rosacea","volume":"13","author":"Deng","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1159\/000488619","article-title":"DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis","volume":"46","author":"Ding","year":"2018","journal-title":"Cell Physiol Biochem"},{"key":"B9","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.bcp.2011.11.027","article-title":"Identification of Dual mTORC1 and mTORC2 Inhibitors in Melanoma Cells: Prodigiosin vs. Obatoclax","volume":"83","author":"Espona-Fiedler","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.jaad.2017.08.037","article-title":"Standard Classification and Pathophysiology of Rosacea: The 2017 Update by the National Rosacea Society Expert Committee","volume":"78","author":"Gallo","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1111\/j.1600-0560.2006.00695.x","article-title":"Lymphangiogenesis and Angiogenesis in Non-phymatous Rosacea","volume":"34","author":"Gomaa","year":"2007","journal-title":"J. Cutan. Pathol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/j.jaad.2007.06.009","article-title":"Enhanced Skin Blood Flow and Sensitivity to Noxious Heat Stimuli in Papulopustular Rosacea","volume":"57","author":"Guzman-Sanchez","year":"2007","journal-title":"J. Am. Acad. Dermatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1164\/rccm.201911-2137OC","article-title":"Loss of DP1 Aggravates Vascular Remodeling in Pulmonary Arterial Hypertension via mTORC1 Signaling","volume":"201","author":"He","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/jidsymp.2011.5","article-title":"The Cutaneous Vascular System in Chronic Skin Inflammation","volume":"15","author":"Huggenberger","year":"2011","journal-title":"J. Invest. Dermatol. Symp. Proc."},{"key":"B15","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1111\/exd.12745","article-title":"Recombinant Erythroid Differentiation Regulator 1 Inhibits Both Inflammation and Angiogenesis in a Mouse Model of Rosacea","volume":"24","author":"Kim","year":"2015","journal-title":"Exp. Dermatol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR Signaling in Growth Control and Disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/ni.3655","article-title":"Chronic Signaling via the Metabolic Checkpoint Kinase mTORC1 Induces Macrophage Granuloma Formation and marks Sarcoidosis Progression","volume":"18","author":"Linke","year":"2017","journal-title":"Nat. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e1600611","DOI":"10.1126\/sciadv.1600611","article-title":"Discovery of Pan-VEGF Inhibitory Peptides Directed to the Extracellular Ligand-Binding Domains of the VEGF Receptors","volume":"2","author":"Michaloski","year":"2016","journal-title":"Sci. Adv."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1007\/s40265-014-0281-x","article-title":"Rosacea: New and Emerging Treatments","volume":"74","author":"Moustafa","year":"2014","journal-title":"Drugs"},{"key":"B20","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1158\/1078-0432.CCR-08-1019","article-title":"Inhibition of mTOR Radiosensitizes Soft Tissue Sarcoma and Tumor Vasculature","volume":"15","author":"Murphy","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1016\/j.jaci.2016.09.052","article-title":"A Mechanistic Target of Rapamycin Complex 1\/2 (mTORC1)\/V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT1)\/cathepsin H axis Controls Filaggrin Expression and Processing in Skin, a Novel Mechanism for Skin Barrier Disruption in Patients with Atopic Dermatitis","volume":"139","author":"Naeem","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/0955-2235(94)90019-1","article-title":"Vascular Endothelial Growth Factor and its Receptors","volume":"5","author":"Neufeld","year":"1994","journal-title":"Prog. Growth Factor. Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1161\/HYPERTENSIONAHA.120.14708","article-title":"mTORC1 (Mechanistic Target of Rapamycin Complex 1) Signaling in Endothelial and Smooth Muscle Cells Is Required for Vascular Function","volume":"77","author":"Reho","year":"2021","journal-title":"Hypertension"},{"key":"B24","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.cell.2017.03.035","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"169","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/jidsymp.2011.6","article-title":"Neurovascular and Neuroimmune Aspects in the Pathophysiology of Rosacea","volume":"15","author":"Schwab","year":"2011","journal-title":"J. Invest. Dermatol. Symp. Proc."},{"key":"B26","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/0190-9622(92)70086-u","article-title":"Rosacea: a Study of Clinical Patterns, Blood Flow, and the Role of Demodex Folliculorum","volume":"26","author":"Sibenge","year":"1992","journal-title":"J. Am. Acad. Dermatol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1136\/bjo.2006.101121","article-title":"Expression of Vascular Endothelial Growth Factor and its Receptors in Rosacea","volume":"91","author":"Smith","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/jidsymp.2011.7","article-title":"Clinical, Cellular, and Molecular Aspects in the Pathophysiology of Rosacea","volume":"15","author":"Steinhoff","year":"2011","journal-title":"J. Invest. Dermatol. Symp. Proc."},{"key":"B29","doi-asserted-by":"publisher","first-page":"S15","DOI":"10.1016\/j.jaad.2013.04.045","article-title":"New Insights into Rosacea Pathophysiology: a Review of Recent Findings","volume":"69","author":"Steinhoff","year":"2013","journal-title":"J. Am. Acad. Dermatol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"S27","DOI":"10.1016\/j.jaad.2013.04.043","article-title":"Rosacea: Current State of Epidemiology","volume":"69","author":"Tan","year":"2013","journal-title":"J. Am. Acad. Dermatol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.jaad.2014.08.028","article-title":"Rosacea","volume":"72","author":"Two","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e139237","DOI":"10.1172\/jci.insight.139237","article-title":"Selective Inhibition of mTORC1 in Tumor Vessels Increases Antitumor Immunity","volume":"5","author":"Wang","year":"2020","journal-title":"JCI Insight"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1172\/JCI97426","article-title":"MicroRNA-210 Overexpression Promotes Psoriasis-like Inflammation by Inducing Th1 and Th17 Cell Differentiation","volume":"128","author":"Wu","year":"2018","journal-title":"J. Clin. Invest."},{"key":"B34","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1038\/nm1616","article-title":"Increased Serine Protease Activity and Cathelicidin Promotes Skin Inflammation in Rosacea","volume":"13","author":"Yamasaki","year":"2007","journal-title":"Nat. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/jid.2010.351","article-title":"TLR2 Expression Is Increased in Rosacea and Stimulates Enhanced Serine Protease Production by Keratinocytes","volume":"131","author":"Yamasaki","year":"2011","journal-title":"J. Invest. Dermatol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41467-018-02890-0","article-title":"IL-6\/STAT3 Pathway Induced Deficiency of RFX1 Contributes to Th17-dependent Autoimmune Diseases via Epigenetic Regulation","volume":"9","author":"Zhao","year":"2018","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.751785\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T05:43:16Z","timestamp":1640065396000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.751785\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":36,"alternative-id":["10.3389\/fcell.2021.751785"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.751785","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,21]]},"article-number":"751785"}}