Increased levels of VEGF-C and macrophage infiltration in lipedema patients without changes in lymphatic vascular morphology

Abstract

Lipedema is a chronic adipose tissue disorder characterized by the disproportional subcutaneous deposition of fat and is commonly misdiagnosed as lymphedema or obesity. The molecular determinants of the lipedema remain largely unknown and only speculations exist regarding the lymphatic system involvement. The aim of the present study is to characterize the lymphatic vascular involvement in established lipedema. The histological and molecular characterization was conducted on anatomically-matched skin and fat biopsies as well as serum samples from eleven lipedema and ten BMI-matched healthy patients. Increased systemic levels of vascular endothelial growth factor (VEGF)-C (P = 0.02) were identified in the serum of lipedema patients. Surprisingly, despite the increased VEGF-C levels no morphological changes of the lymphatic vessels were observed. Importantly, expression analysis of lymphatic and blood vessel-related genes revealed a marked downregulation of Tie2 (P < 0.0001) and FLT4 (VEGFR-3) (P = 0.02) consistent with an increased macrophage infiltration (P = 0.009), without changes in the expression of other lymphatic markers. Interestingly, a distinct local cytokine milieu, with decreased VEGF-A (P = 0.04) and VEGF-D (P = 0.02) expression was identified. No apparent lymphatic anomaly underlies lipedema, providing evidence for the different disease nature in comparison to lymphedema. The changes in the lymphatic-related cytokine milieu might be related to a modified vascular permeability developed secondarily to lipedema progression. Lipedema is a distinct adipose tissue disorder, affecting primarily women 1. Epidemiological data of large studies are still not available but the prevalence of lipedema is estimated between 7 and 9.7%. Interestingly the prevalence of lipedema in patients referred to lymphatic clinics is increased, estimated as 10-15% 2,3. The mechanisms involved in lipedema development are largely unknown and despite the distinct clinical features the disease is commonly misdiagnosed as obesity or lymphedema. Clinically, lipedema is characterized by the bilateral and symmetrical adipose tissue deposition, mostly of the lower extremities, sparing the feet. The Stemmer sign is negative and the edematous appearance is resistant to diet restrictions, elevation of the extremities or lymphatic drainage 4 .

A Distinct Cytokine Profile and Stromal Vascular Fraction Metabolic Status without Significant Changes in the Lipid Composition Characterizes Lipedema

“…As a second hallmark, lipedema is associated with a state of low-grade inflammation. Our previous research showed that a distinct immune cell infiltration occurs in lipedema, characterized by the infiltration of M2 polarized macrophages [ 8 ]. The presence of such an immune signature is associated with systemic changes reflected in circulating cytokines’ levels.…”

“…Recent studies conducted by multiple research groups, including ours, have revealed a distinct immune cell composition in lipedema characterized by increased macrophage infiltration whereas the T-cell compartment remains unchanged [ 7 , 8 ]. Interestingly, an M2 macrophage polarization phenotype was identified, attributed to CD163 overexpression [ 8 ]. The presence of such an immune signature is commonly associated with changes in cytokine levels.…”

“…Initial investigations showed increased systemic levels of vascular endothelial growth factor (VEGF)-C which might be related to the increased macrophage infiltrate. In addition, downregulation of lymphatic-related cytokines such as Tie2, VEGF-A and VEGF-D which could be linked to a modified vascular permeability, developed secondarily to lipedema progression [ 8 ].…”

Potential Effects of a Modified Mediterranean Diet on Body Composition in Lipoedema

“…Most of the patients report onset of lipoedema at menarche, with progression of the disease dependent on family history and lifestyle. Lipoedema is a disease characterized by an inflammatory condition [ 6 , 7 ]. From a pathophysiological point of view, the progression of lipoedema is caused by dilation and lengthening of the lymphatic channels with the development of microaneurysms.…”

3D Spheroids Derived from Human Lipedema ASCs Demonstrated Similar Adipogenic Differentiation Potential and ECM Remodeling to Non-Lipedema ASCs In Vitro

“…Lipedema is a connective tissue disorder that affects~11% of women worldwide [28][29][30]. The disease is characterized by hypertrophic adipocytes, inflammation, leaky blood and lymphatic vessels and fibrosis, all of which contributed to increased proliferation and adipogenic differentiation of ASCs/preadipocytes as well as tissue remodeling [31][32][33][34]. We and others have shown that SVF, a heterogeneous population of cells, isolated from lipedema AT and expanded in monolayer cultures, is composed of significantly higher levels of the mesenchymal stem marker (CD90; cluster of differentiation 90) and endothelial markers (CD31 and CD146) as compared to individuals unaffected with lipedema [35,36], which may be a contributing factor to the leaky blood and lymphatic vessels detected in lipedema tissues.…”