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Cited by 310Systemic Sclerosis and Related DiseasesAngiogenesis and VEGF in CancerVascular Tumors and Angiosarcomas

Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis

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Distler, Oliver, Distler, Jörg H. W., Scheid, Annette, Acker, Till, Hirth, Astrid, Rethage, Janine, Michel, Beat A., Gay, Renate E. +5 more·2004·Circulation Research
DOI 10.1161/01.res.0000134644.89917.96
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Abstract

Systemic sclerosis (SSc) skin lesions are characterized by disturbed vessel morphology with enlarged capillaries and an overall reduction in capillary density, suggesting a deregulated, insufficient angiogenic response. It has been postulated that this phenomenon is due to reduced expression of the potent angiogenic factor vascular endothelial growth factor (VEGF). In contrast to this hypothesis, we demonstrate that the expression of both VEGF and its receptors VEGFR-1 and VEGFR-2 is dramatically upregulated in skin specimens of SSc patients throughout different disease stages. Interestingly, upregulation of VEGF was not mediated by hypoxia-inducible transcription factor-1 (HIF-1) as indicated by only a weak expression of the oxygen-sensitive α-subunit of HIF-1 in the skin of SSc patients. This was unexpected on measuring low P o 2 values in the SSc skin by using a polarographic oxygen microelectrode system. Considering our observation that PDGF and IL-1β costimulated VEGF expression, we propose that chronic and uncontrolled VEGF upregulation that is mediated by an orchestrated expression of cytokines rather than VEGF downregulation is the cause of the disturbed vessel morphology in the skin of SSc patients. Consequently, for therapeutic approaches aiming to improve tissue perfusion in these patients, a controlled expression and timely termination of VEGF signaling appears to be crucial for success of proangiogenic therapies.

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  • Myofibroblasts produce VEGF and can express angiopoietin 1 and 2, both of which stimulate the formation of new blood vessels.

    “Furthermore, myofibroblasts also produce VEGF (154), e.g., during wound healing, and can also express angiopoietin 1 and 2, both of which stimulate the formation of new blood vessels (155).”

    From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [154]

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Research works printed but not linked: 5

  1. Furst DE, Clements PJ. Pathogenesis, Fusion (Summary). In: Furst DE, Clements PJ, eds. Systemic Sclerosis. Baltimore, Md: Williams & Wilkins;1996:275-284.
  2. Hofer T, Wenger H, Gassmann M. Oxygen sensing, HIF-1alpha stabili- zation and potential therapeutic strategies. Pflugers Arch. 2002;443: 503-507.
  3. Kowal-Bielecka O, Distler O, Neidhart M, Kunzler P, Rethage J, Nawrath M, Carossino A, Pap T, Muller-Ladner U, Michel BA, Sierakowski S, Matucci-Cerinic M, Gay RE, Gay S. Evidence of 5-lipoxygenase over- expression in the skin of patients with systemic sclerosis: a newly iden- tified pathway to skin inflammation in systemic sclerosis. Arthritis Rheum. 2001;44:1865-1875.
  4. Hebbar M, Peyrat JP, Hornez L, Hatron PY, Hachulla E, Devulder B. Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum. 2000;43: 889 -893.
  5. Distler J, Hirth A, Scheid A, Del Rosso A, Gay RE, Lorenz HM, Kalden JR, Matucci-Cerinic M, Gassmann M, Gay S, Distler O. Expression profile of SSc fibroblasts reveals extracellular matrix proteins as down- stream molecules of hypoxia induced pathways. Arthritis Rheum. 2002; 46:S203. Abstract.

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Authors
Distler, O., Distler, J. H. W., Scheid, A., Acker, T., Hirth, A., Rethage, J., Michel, B. A., Gay, R. E., Müller-Ladner, U., Matucci-Cerinic, M., Plate, K. H., Gassmann, M., & Gay, S.
Affiliations
  • Goethe University Frankfurt (DE)
  • From the Center of Experimental Rheumatology, Department of Rheumatology (O.D., J.H.W.D., A.H., J.R., B.A.M., R.E.G., S.G.), University Hospital Zurich, Switzerland; Institute of Physiology (A.S.), University of Zurich, Switzerland; Karolinska Institute (T.A.), Stockholm, Sweden; Institute of Neurology (Edinger Institute) (T.A., K.H.P.), Johann-Wolfgang Goethe University, Frankfurt, Germany; Department of Internal Medicine I (U.M.-L.), University of Regensburg, Germany; Department of Medicine (M.M....
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2004-07-09
Volume
95
Issue
1
Pages
109-116
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.0000134644.89917.96
OpenAlex
W2143222045
Cited by
310
References
38
Citations by year
2026: 2 · 2025: 8 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 11 · 2020: 9 · 2019: 11 · 2018: 15 · 2017: 19 · 2016: 28 · 2015: 19 · 2014: 12 · 2013: 17 · 2012: 16
FWCI
8.26
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
Funders
  • Bundesministerium für Bildung und Forschung
  • Universität Zürich (560031)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Vascular Tumors and Angiosarcomas
Keywords
systemic sclerosis, vascular endothelial growth factor, VEGFR1, VEGFR2, HIF-1, tissue oxygen tension, platelet-derived growth factor, IL-1β, tissue perfusion
MeSH terms
DNA-Binding Proteins, Fibroblasts, Humans, Nuclear Proteins, Scleroderma, Systemic, Skin, Transcription Factors, Cell Hypoxia, Up-Regulation, Cytokines, Neovascularization, Physiologic, Dermis, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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