{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:53:27Z","timestamp":1791363207508,"version":"4.3.1"},"reference-count":52,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Lipedema is a chronic, predominantly female disorder characterized by disproportionate regional expansion of subcutaneous adipose tissue, pain, tenderness, and easy bruising. Reported abnormalities involve adipocytes, stromal\/progenitor cells, microvascular and immune compartments, extracellular matrix (ECM), and, variably, lymphatic function, but their causal and temporal relationships remain unresolved. Here, we propose the adipovascular unit (AVU) as a systems-level framework that links these compartments within a spatially organized regenerative niche. The conceptual advance is not the identification of a new anatomical structure, but the prediction that regional disease expression depends on reciprocal interactions among adipose stem and progenitor cells (ASPCs), endothelial and mural cells, immune populations, ECM, and mature adipocytes, rather than on a universal defect in any single cell type. We hypothesize that physiological female reproductive signals may expose a regionally susceptible AVU in which regenerative responses are inadequately constrained in space, magnitude, or duration. This framework also distinguishes lipedema from obesity-associated adipose dysfunction: lipedema is regionally patterned and may coexist with relatively preserved systemic metabolic function, whereas obesity-related adipose dysfunction is more closely linked to whole-body energy excess, ectopic fat, insulin resistance and cardiometabolic risk. Evidence demonstrated directly in lipedema is separated throughout from general adipose-tissue biology used to establish plausibility and from mechanisms that remain hypothetical. We derive falsifiable predictions involving depot-specific molecular states, endocrine context, multicellular cross-talk, extracellular-vesicle cargo and transfer, spatial biological boundaries, and persistence after stimulus withdrawal. Testing these predictions in paired-depot, spatially resolved and multicellular systems will determine whether AVU dysregulation is a causal organizing principle of lipedema or a descriptive consequence of established disease.<\/jats:p>","DOI":"10.3390\/cells15191820","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:28:57Z","timestamp":1791361737000},"page":"1820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Adipovascular Unit in Lipedema: A Framework for Regional Adipose Tissue Dysregulation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9203-4958","authenticated-orcid":false,"given":"J\u00f6rg","family":"Faulhaber","sequence":"first","affiliation":[{"name":"Clinic for Dermatology, Venerology, and Allergology, University Medical Center Mannheim, Ruprecht-Karls-University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3254-0330","authenticated-orcid":false,"given":"C. William","family":"Hanke","sequence":"additional","affiliation":[{"name":"Laser and Skin Surgery Center of Indiana, Indianapolis, IN 46260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Barsch","sequence":"additional","affiliation":[{"name":"Lipedema Center Linz, Starhembergstrasse 12\/3, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Sandhofer","sequence":"additional","affiliation":[{"name":"Lipedema Center Vienna, Sch\u00f6nbrunnerstrasse 153\/6\/21, 1120 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.7326\/0003-4819-34-5-1243","article-title":"Lipedema of the legs: A syndrome characterized by fat legs and edema","volume":"34","author":"Wold","year":"1951","journal-title":"Ann. Intern. Med."},{"key":"ref_2","first-page":"1303","article-title":"S2k guideline lipedema","volume":"22","author":"Faerber","year":"2024","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41467-025-68232-z","article-title":"Lipedema World Alliance Delphi Consensus-Based Position Paper on the Definition and Management of Lipedema: Results from the 2023 Lipedema World Congress in Potsdam","volume":"17","author":"Kruppa","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nature06902","article-title":"Dynamics of fat cell turnover in humans","volume":"453","author":"Spalding","year":"2008","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7643","DOI":"10.1038\/s41467-024-51867-9","article-title":"Adipose stem cells are sexually dimorphic cells with dual roles as preadipocytes and resident fibroblasts","volume":"15","author":"Uhrbom","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.2337\/db25-0773","article-title":"Estrogen Mediates Capacity for Hyperplastic Adipose Expansion and Preserves Adipose Progenitor Cell Availability in Subcutaneous Depots of Female Mice","volume":"75","author":"Scheidl","year":"2026","journal-title":"Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/2042-6410-3-13","article-title":"Sex differences in human adipose tissues\u2014The biology of pear shape","volume":"3","author":"Karastergiou","year":"2012","journal-title":"Biol. Sex Differ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.molmet.2013.05.006","article-title":"The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis","volume":"2","author":"Davis","year":"2013","journal-title":"Mol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.jcyt.2017.03.073","article-title":"The adipose tissue-derived stromal vascular fraction cells from lipedema patients: Are they different?","volume":"19","author":"Priglinger","year":"2017","journal-title":"Cytotherapy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/PRS.0000000000005918","article-title":"Adipose Stem Cells from Lipedema and Control Adipose Tissue Respond Differently to Adipogenic Stimulation In Vitro","volume":"144","author":"Bauer","year":"2019","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Al-Ghadban, S., Pursell, I.A., Diaz, Z.T., Herbst, K.L., and Bunnell, B.A. (2020). 3D Spheroids Derived from Human Lipedema ASCs Demonstrated Similar Adipogenic Differentiation Potential and ECM Remodeling to Non-Lipedema ASCs In Vitro. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218350"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Al-Ghadban, S., Isern, S.U., Herbst, K.L., and Bunnell, B.A. (2024). The Expression of Adipogenic Marker Is Significantly Increased in Estrogen-Treated Lipedema Adipocytes Differentiated from Adipose Stem Cells In Vitro. Biomedicines, 12.","DOI":"10.3390\/biomedicines12051042"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7211","DOI":"10.1038\/s41598-020-64215-w","article-title":"SVF-derived extracellular vesicles carry characteristic miRNAs in lipedema","volume":"10","author":"Priglinger","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Strohmeier, K., Hofmann, M., Jacak, J., Narzt, M.S., Wahlmueller, M., Mairhofer, M., Schaedl, B., Holnthoner, W., Barsch, M., and Sandhofer, M. (2022). Multi-Level Analysis of Adipose Tissue Reveals the Relevance of Perivascular Subpopulations and an Increased Endothelial Permeability in Early-Stage Lipedema. Biomedicines, 10.","DOI":"10.1101\/2022.04.27.22274309"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wolf, S., Rannikko, J.H., Virtakoivu, R., Cinelli, P., Felmerer, G., Burger, A., Giovanoli, P., Detmar, M., Lindenblatt, N., and Hollm\u00e9n, M. (2022). A distinct M2 macrophage infiltrate and transcriptomic profile decisively influence adipocyte differentiation in lipedema. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1004609"},{"key":"ref_16","first-page":"8747461","article-title":"Dilated Blood and Lymphatic Microvessels, Angiogenesis, Increased Macrophages, and Adipocyte Hypertrophy in Lipedema Thigh Skin and Fat Tissue","volume":"2019","author":"Cromer","year":"2019","journal-title":"J. Obes."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"bnaa004","DOI":"10.1210\/endrev\/bnaa004","article-title":"Metabolically Healthy Obesity","volume":"41","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/s41586-022-04518-2","article-title":"A single-cell atlas of human and mouse white adipose tissue","volume":"603","author":"Emont","year":"2022","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eaav2501","DOI":"10.1126\/science.aav2501","article-title":"Identification of a mesenchymal progenitor cell hierarchy in adipose tissue","volume":"364","author":"Merrick","year":"2019","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/s42255-026-01475-2","article-title":"Defining the vascular niche of human adipose tissue across metabolic states","volume":"8","author":"AlZaim","year":"2026","journal-title":"Nat. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sandhofer, M., Hanke, C.W., Barsch, M., and Faulhaber, J. (2026). Pathogenesis of lipedema: A hypothesis-generating model of regenerative imbalance in adipose tissue. J. Aesthetic Med., 2.","DOI":"10.20944\/preprints202605.0074.v1"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kruppa, P., Gohlke, S., \u0141api\u0144ski, K., Garcia-Carrizo, F., Soultoukis, G.A., Infanger, M., Schulz, T.J., and Ghods, M. (2023). Lipedema stage affects adipocyte hypertrophy, subcutaneous adipose tissue inflammation and interstitial fibrosis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1223264"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10947","DOI":"10.1038\/s41598-020-67987-3","article-title":"Increased levels of VEGF-C and macrophage infiltration in lipedema patients without changes in lymphatic vascular morphology","volume":"10","author":"Felmerer","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_24","first-page":"480","article-title":"Interstitial Fluid in Lipedema and Control Skin","volume":"1","author":"Allen","year":"2020","journal-title":"Womens Health Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1177\/000331979504600408","article-title":"Functional lymphatic alterations in patients suffering from lipedema","volume":"46","author":"Bilancini","year":"1995","journal-title":"Angiology"},{"key":"ref_26","first-page":"170","article-title":"Microlymphatic aneurysms in patients with lipedema","volume":"34","author":"Franzeck","year":"2001","journal-title":"Lymphology"},{"key":"ref_27","unstructured":"F\u00f6ldi, E., and Mannheimer, E. (1986). Indirekte Lymphographie bei Lip\u00f6dem. \u00d6dem, Perimed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104298","DOI":"10.1016\/j.mvr.2021.104298","article-title":"Indocyanine green lymphography as novel tool to assess lymphatics in patients with lipedema","volume":"140","author":"Buso","year":"2022","journal-title":"Microvasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1002\/oby.22778","article-title":"Upper and Lower Extremity Measurement of Tissue Sodium and Fat Content in Patients with Lipedema","volume":"28","author":"Crescenzi","year":"2020","journal-title":"Obesity"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/jmri.28281","article-title":"Subcutaneous Adipose Tissue Edema in Lipedema Revealed by Noninvasive 3T MR Lymphangiography","volume":"57","author":"Crescenzi","year":"2023","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1002\/ajmg.a.33313","article-title":"Lipedema: An inherited condition","volume":"152A","author":"Child","year":"2010","journal-title":"Am. J. Med. Genet A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41431-022-01231-6","article-title":"Genome-wide association study of a lipedema phenotype among women in the UK Biobank identifies multiple genetic risk factors","volume":"31","author":"Klimentidis","year":"2023","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Katzer, K., Hill, J.L., McIver, K.B., and Foster, M.T. (2021). Lipedema and the Potential Role of Estrogen in Excessive Adipose Tissue Accumulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111720"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0960-0760(03)00360-1","article-title":"Sources of estrogen and their importance","volume":"86","author":"Simpson","year":"2003","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1210\/jcem-60-1-174","article-title":"Effects of aging and obesity on aromatase activity of human adipose cells","volume":"60","author":"Cleland","year":"1985","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S116","DOI":"10.1067\/mjd.2001.117432","article-title":"Estrogen production and action","volume":"45","author":"Nelson","year":"2001","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/s41366-021-01002-1","article-title":"Key signaling networks are dysregulated in patients with the adipose tissue disorder, lipedema","volume":"46","author":"Ishaq","year":"2022","journal-title":"Int. J. Obes."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"156191","DOI":"10.1016\/j.metabol.2025.156191","article-title":"Defining lipedema\u2019s molecular hallmarks by multi-omics approach for disease prediction in women","volume":"168","author":"Straub","year":"2025","journal-title":"Metabolism"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1111\/j.1600-0560.2009.01256.x","article-title":"Adipose tissue remodeling in lipedema: Adipocyte death and concurrent regeneration","volume":"36","author":"Suga","year":"2009","journal-title":"J. Cutan. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1177\/1358863X231202769","article-title":"National survey of patient symptoms and therapies among 707 women with a lipedema phenotype in the United States","volume":"29","author":"Aday","year":"2024","journal-title":"Vasc. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00105-023-05189-4","article-title":"Lip\u00f6demschmerz\u2014Das vernachl\u00e4ssigte Symptom [Lipedema pain-the neglected symptom]","volume":"74","author":"Hucho","year":"2023","journal-title":"Die Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chakraborty, A., Crescenzi, R., Usman, T.A., Reyna, A.J., Garza, M.E., Al-Ghadban, S., Herbst, K.L., Donahue, P.M.C., and Rutkowski, J.M. (2022). Indications of Peripheral Pain, Dermal Hypersensitivity, and Neurogenic Inflammation in Patients with Lipedema. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810313"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1155","DOI":"10.1097\/PR9.0000000000001155","article-title":"Non-obese lipedema patients show a distinctly altered quantitative sensory testing profile with high diagnostic potential","volume":"9","author":"Dinnendahl","year":"2024","journal-title":"Pain Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"308","DOI":"10.2337\/db24-0890","article-title":"Adipose Tissue Biology and Effect of Weight Loss in Women with Lipedema","volume":"74","author":"Cifarelli","year":"2025","journal-title":"Diabetes"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Jeziorek, M., Wuczy\u0144ski, M., Sowicz, M., Adaszy\u0144ska, A., Szuba, A., and Chachaj, A. (2025). Metabolic Alterations in Women with Lipedema Compared to Women with Lifestyle-Induced Overweight\/Obesity. Biomedicines, 13.","DOI":"10.3390\/biomedicines13040867"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e5436","DOI":"10.1097\/GOX.0000000000005436","article-title":"Lipedema Reduction Surgery Improves Pain, Mobility, Physical Function, and Quality of Life: Case Series Report","volume":"11","author":"Wright","year":"2023","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"326","DOI":"10.36849\/JDD.5828","article-title":"High Volume Liposuction in Tumescence Anesthesia in Lipedema Patients: A Retrospective Analysis","volume":"20","author":"Sandhofer","year":"2021","journal-title":"J. Drugs Dermatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1177\/0268355520949775","article-title":"Improvements in patients with lipedema 4, 8 and 12 years after liposuction","volume":"36","author":"Baumgartner","year":"2021","journal-title":"Phlebology"},{"key":"ref_49","unstructured":"Stecco, C., Driscoll, M., Huijing, P., and Schleip, R. (2021). Fascia: The Tensional Network of the Human Body: The Science and Clinical Applications in Manual and Movement Therapy, Elsevier. [2nd ed.]."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1097\/DSS.0000000000002019","article-title":"Prevention of Progression of Lipedema with Liposuction Using Tumescent Local Anesthesia: Results of an International Consensus Conference","volume":"46","author":"Sandhofer","year":"2020","journal-title":"Dermatol. Surg."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s12631-017-0087-2","article-title":"Das Lip\u00f6dem: Anatomische Studie, Diagnostik und perioperatives Umfeld","volume":"10","author":"Sandhofer","year":"2017","journal-title":"J. \u00c4sthet Chir."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s12631-018-0168-x","article-title":"Anatomie des Lymphsystems","volume":"12","author":"Pilsl","year":"2019","journal-title":"J. \u00c4sthet Chir."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1820\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:36:49Z","timestamp":1791362209000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":52,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cells15191820"],"URL":"https:\/\/doi.org\/10.3390\/cells15191820","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]}}}