The Role of Endothelial Progenitors in the Repair of Vascular Damage in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a connective tissue disease characterized by a complex pathological process where the main scenario is represented by progressive loss of microvascular bed, with the consequent progressive fibrotic changes in involved organ and tissues. Although most aspects of vascular injury in scleroderma are poorly understood, recent data suggest that the scleroderma impairment of neovascularization could be related to both angiogenesis and vasculogenesis failure. Particularly, compensatory angiogenesis does not occur normally in spite of an important increase in many angiogenic factors either in SSc skin or serum. Besides insufficient angiogenesis, the contribution of defective vasculogenesis to SSc vasculopathy has been extensively studied. Over the last decades, our understanding of the processes responsible for the formation of new vessels after tissue ischemia has increased. In the past, adult neovascularization was thought to depend mainly on angiogenesis (a process by which new vessels are formed by the proliferation and migration of mature endothelial cells). More recently, increased evidence suggests that stem cells mobilize from the bone marrow into the peripheral blood (PB), differentiate in circulating endothelial progenitors (EPCs), and home to site of ischemia to contribute to de novo vessel formation. Significant advances have been made in understanding the biology of EPCs, and molecular mechanisms regulating EPC function. Autologous EPCs now are becoming a novel treatment option for therapeutic vascularization and vascular repair, mainly in ischemic diseases. However, different diseases, such as cardiovascular diseases, diabetes, and peripheral artery ischemia are related to EPC dysfunction. Several studies have shown that EPCs can be detected in the PB of patients with SSc and are impaired in their function. Based on an online literature search (PubMed, EMBASE, and Web of Science, last updated December 2017) using keywords related to “endothelial progenitor cells” and “Systemic Sclerosis,” “scleroderma vasculopathy,” “angiogenesis,” “vasculogenesis,” this review gives an overview on the large body of data of current research in this issue, including controversies over the identity and functions of EPCs, their meaning as biomarker of SSc microangiopathy and their clinical potency.

HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association

“…Consistent with our findings, endothelial progenitor cells (EPC) with impaired angiogenic function have been detected in peripheral blood of SSc subjects [68], and the regression of capillaries and small vessels during SSc strongly suggests an impairment in the angiogenetic abilities of endothelial cells, although the specific mechanisms have not yet been elucidated.…”

Decreased circulating lymphatic endothelial progenitor cells in digital ulcer-complicated systemic sclerosis

“…In systemic sclerosis (SSc), the main pathogenic scenario is represented by early endothelial cell injury and microvascular desertification culminating into skin and internal organ fibrosis 1. Growing evidence suggests that impaired vascular repair and neovascularisation could be related to failure of both angiogenesis and endothelial progenitor cell (EPC)-driven vasculogenesis 2…”

“…In SSc, the majority of studies are focused on the role of blood vessel dysfunction,1 2 while the involvement of the lymphatic microcirculation has attracted much less attention. Nevertheless, clinical and histological findings have shown that lesional SSc skin displays lymphatic circulatory abnormalities 3–5.…”

“…Interestingly, an expansion of circulating LEPC has been recently shown in rheumatic diseases such as spondyloarthritis and primary Sjögren’s syndrome 7 8. As far as SSc is concerned, heterogeneous data have been reported on the numbers and functions of EPC,2 but no data are currently available on LEPC. Therefore, we investigated for the first time circulating levels of LEPC and their possible association with markers of disease severity in patients with SSc.…”

Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence

“…In SSc, great emphasis has traditionally been placed on blood vessel dysfunction and defective angiogenesis and vascular repair, while the involvement of the lymphatic vascular counterpart has been mostly overlooked [5][6][7][8]. Nonetheless, a few clinical and histopathologic studies have demonstrated that clinically-affected SSc skin displays lymphatic microvascular abnormalities, including a severe reduction in both superficial and deep dermal microlymphatic networks that has been correlated with the presence of fingertip ulcers and linked to cutaneous disease progression from an early edematous stage toward overt fibrotic remodeling [9][10][11][12].…”