Table 1 Evidence for endothelial cell dysfunction and defective angiogenic pathways in systemic sclerosis

In vitro studies on peripheral blood mononuclear cells suggest a defective contribution of immune cells to angiogenesis [1]. Greater up-regulation of angiostatic than pro-angiogenic mediators [1, 2]. Microarray studies of microvascular EC gene expression have shown an overexpression of either several pro-angiogenic transcripts or many genes that have a negative effect on angiogenesis [1]

Circulating endothelial progenitor cells, involved in postnatal vasculogenesis, are decreased and functionally impaired [1, 5]. Moreover, these cells show mesenchymal properties that may indicate that they potentially contribute to the accumulation of connective tissue and to vascular malfunction [6]

Bone marrow-derived CD14+ monocytic pro-angiogenic hematopoietic cells (promoting vascular formation and repair and differentiation into mural cells) are significantly increased. They can differentiate into fibroblast-like cells producing extracellular matrix proteins contributing to the fibrotic process [7]

Platelet activation contributes to the pro-angiogenic/angiostatic imbalance by release of bioactive factors and aggregation [8]

A change in the endothelial phenotype of residual microvessels is also present in the skin, favoring anti-angiogenic mechanisms [9]

The endothelial-to-mesenchymal transition process is now clarified and is a novel concept in understanding the significant contribution that ECs may play also in the pathogensis of fibrosis [10]