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Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence
- Source :
- International Journal of Molecular Sciences, Volume 20, Issue 24
- Publication Year :
- 2019
- Publisher :
- MDPI AG, 2019.
-
Abstract
- In systemic sclerosis (SSc), the possible involvement of lymphatic microcirculation and lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on dysfunctional blood vascular system and angiogenesis. In the present in vitro study, we explore for the first time whether the SSc microenvironment may interfere with lymphangiogenesis, a complex, multi-step process in which lymphatic microvascular endothelial cells (LMVECs) sprout, migrate, and proliferate to generate new lymphatic capillaries. Normal human adult dermal LMVECs from three donors were treated with serum from SSc patients (n = 8), serum from healthy individuals (n = 8), or recombinant human vascular endothelial growth factor (VEGF)-C as a positive control for lymphangiogenesis. Cell proliferation, Boyden chamber Matrigel chemoinvasion, wound healing capacity, and lymphatic capillary morphogenesis on Geltrex were assayed. VEGF-C serum levels were measured by enzyme-linked immunosorbent assay. Gene and protein expression levels of the lymphangiogenic orchestrators VEGF receptor-3 (VEGFR-3)/Flt-4 and neuropilin-2 (NRP-2) were determined by real-time PCR and Western blotting, respectively. Conditioning with SSc serum significantly inhibited LMVEC proliferation, Matrigel invasion, and wound healing capacity with respect to healthy serum. The ability of LMVECs to form lymphatic tubes on Geltrex was also severely compromised in the presence of SSc serum. VEGF-C levels were comparable in SSc and healthy sera. Treatment with SSc serum resulted in a significant downregulation of both VEGFR-3/Flt-4 and NRP-2 mRNA and protein levels. In SSc, the pathologic environment severely hampers every lymphangiogenesis step, likely through the reduction of pro-lymphangiogenic VEGFR-3/NRP-2 co-receptor signaling. The impairment of the lymphangiogenic process opens a new scenario underlying SSc vascular pathophysiology, which is worth investigating further.
- Subjects :
- Male
0301 basic medicine
systemic sclerosis
Angiogenesis
Apoptosis
chemistry.chemical_compound
0302 clinical medicine
Cell Movement
Tumor Microenvironment
Medicine
scleroderma
Cells, Cultured
Spectroscopy
dermal lymphatic microvascular endothelial cells
VEGFR-3/Flt-4
Neovascularization, Pathologic
integumentary system
General Medicine
Middle Aged
Lymphatic Capillary
Computer Science Applications
Lymphangiogenesis
lymphangiogenesis
Vascular endothelial growth factor
Lymphatic system
Female
Adult
In Vitro Techniques
Article
Catalysis
Microcirculation
Inorganic Chemistry
Young Adult
03 medical and health sciences
NRP-2
Humans
Physical and Theoretical Chemistry
Molecular Biology
Cell Proliferation
030203 arthritis & rheumatology
Matrigel
Scleroderma, Systemic
business.industry
Organic Chemistry
Endothelial Cells
Vascular Endothelial Growth Factor Receptor-3
Neuropilin-2
030104 developmental biology
chemistry
Case-Control Studies
Culture Media, Conditioned
Cancer research
business
Wound healing
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....c80fee73cf971e9445a326c33acac06d