Uncontrolled Expression of Vascular Endothelial Growth Factor and Its Receptors Leads to Insufficient Skin Angiogenesis in Patients With Systemic Sclerosis

Abstract

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 ␣-subunit of HIF-1 in the skin of SSc patients. This was unexpected on measuring low PO 2 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.

Evolution of serum cytokine profile after hematopoietic stem cell transplantation in systemic sclerosis patients

“…A slight decrease in VEGF serum levels was observed after aHSCT, which merits further exploration, as chronic and uncontrolled VEGF upregulation has been related to abnormal vessel morphology and endothelium in SSc. 15 Despite the increased levels of IL-6, IL-8, IL-10 and IFN-γ at baseline, these cytokines levels were not clinically meaningful and did not fall after transplant. Apart from changes in serum MCP-1 levels, the other serum cytokine levels analyzed herein did not appear as relevant markers of SSc clinical evolution.…”

Mechanisms of vascular damage in systemic sclerosis

“…After forming primary small new vessels, the following lumenation of these primary sprouts results in capillary loops, followed by synthesis of a new basement membrane and subsequently in blood vessel maturation. In SSc, a number of these sequential steps have revealed to been altered and contribute to its pathophysiology (14)(15)(16). In addition, the expression of the angiogenic inhibitor endostatin has been suggested to be associated with the presence of giant capillaries in nailfold capillaroscopy.…”

“…Although persisting hypoxia, should be a major stimulus for angiogenesis, sufficient angiogenesis does not occur in SSc patients despite severe tissue hypoxia (15,16) Scleroderma serum-induced EPC apoptosis was demonstrated in a recent study, and this may account, at least in part, for the decreased circulating EPC levels in scleroderma patients (24).…”

T cells expressing allograft inflammatory factor 1 display increased chemotaxis and induce a profibrotic phenotype in normal fibroblasts in vitro

“…Therefore, a generally accepted hypothesis regarding the pathogenesis of tissue fibrosis in SSc is that activated T cells specifically infiltrate target organs and, once in the tissue, they release cytokines and growth factors, which in turn initiate and/or perpetuate the fibrotic process as well as the endothelial and vascular alterations (8,9,14,23). Immunohistochemistry and gene expression studies have identified numerous cytokines, growth factors, and other polypeptides that are selectively expressed in affected tissue in SSc and are therefore believed to participate in its pathogenesis (21,22,(24)(25)(26). Allograft inflammatory factor 1 (AIF-1) is one of the most recently identified candidates (27,28).…”