Background Systemic sclerosis (SSc) is an autoimmune disorder characterized by microangiopathy and immunological abnormalities evolving into fibrosis. Endothelial damage occurs early in the disease. EGFL7, is a recently identified molecule expresses in vascular endothelial cells (ECs) and their mesodermal progenitors. EGFL7 controls blood vessel development by promoting ECs migration, proliferation, sprouting, adhesion (1,2). Its alteration results in abnormal vessel formation.
Objectives We hypothesized that EGFL7 might play an important role in regulating SSc angiogenesis/vasculogenesis.
Methods EGFL7 expression was investigated in the involved skin of 33 SSc patients, according to the different subsets (16 diffuse and 17 limited SSc) and stages (16 early and 17 late) of the disease and 27 healthy controls (HC), by using immunohistochemistry, immunofluorescence, RT-PCR analyses and Western Blot (WB). Furthermore, placenta biopsies from 4 healthy uncomplicated pregnancies were used as physiological angiogenesis controls. Microvascular endothelial cells (MVECs) and fibroblasts (FBs) both from patients and HC were also analyzed for EGFL7, by confocal laser scanning microscopy, RT-PCR analysis and WB.
Results EGFL7 expression is clearly up-regulated in the placenta, that represents the physiological model of angiogenesis as observed by immunohistochemistry, immunofluorescence, RT-PCR and WB analyses, when compared to skin of HC and patients. Moreover, patients in the early stage and diffuse form display lesser expression of EGFL7 when compared to patients with limited subset, late stage, and HC, respectively. Cultured SSc-MVECs express a significantly higher amounts of EGFL7 mRNA in the early stage and lowest expression in the later stages of the disease, not mirroring the skin findings and suggesting a post transcriptional modification. Furthermore, cultured SSc-FBs express lower mRNA and protein levels of EGFL7. Interestingly, in cultured SSc and HC FBs only SSc myofibroblasts (a-SMA +) showed a strong immunopositivity for EGFL7, suggesting a role of this factor in the EndMT (endothelial-mesenchymal transition) transition.
Conclusions We report the first observation of an abnormal expression of EGFL7 in the skin and in the myofibroblasts of the SSc patients, compared to controls which is generally considered a specific endothelial molecule. The alteration of EGFL7, seems to be involved in defective angiogenesis of SSc and in the modulation of EndMT, that leads to the fibroproliferative vasculopathy.
Campagnolo L et al. EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. Am J Pathol. 2005 Jul;167(1):275-84
Schmidt M, et al. EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development 2007 Aug;134(16):2913-23. Epub 2007 Jul 11.
Disclosure of Interest None Declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.