Published online before print June 3, 2004, doi: 10.1161/01.RES.0000134644.89917.96
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Submitted on December 1, 2003
Revised on May 21, 2004
Accepted on May 24, 2004
Uncontrolled Expression of Vascular Endothelial Growth Factor and Its Receptors Leads to Insufficient Skin Angiogenesis in Patients With Systemic Sclerosis
Oliver Distler *;
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.-C.), Section of Rheumatology, University of Florence, Italy; and the Institute of Veterinary Physiology (M.G.), University of Zurich, Switzerland.
* To whom correspondence should be addressed. E-mail: Oliver.Distler{at}usz.ch.
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 
-subunit of HIF-1 in the skin of SSc patients. This was unexpected on measuring low PO2 values in the SSc skin by using a polarographic oxygen microelectrode system. Considering our observation that PDGF and IL-1
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.
Key words: angiogenesis • vascular endothelial growth factor • hypoxia-inducible transcription factor-1
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