Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed?

Abstract

The early phase of systemic sclerosis (SSc) presents edema as one of the main features: this is clinically evident in the digital swelling (puffy fingers) as well as in the edematous skin infiltration of the early active diffuse subset. Other organs could be affected by this same disease process, such as the lung (with the appearance of ground glass opacities) and the heart (with edematous changes on cardiac magnetic resonance imaging). The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor β, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc. This condition has an alteration in the glycocalyx thickness, reducing the protection of the vessel wall and causing non-fibrotic interstitial edema, a marker of vascular leak. Moreover, changes in the junctional adhesion molecule family and other adhesion molecules, such as ICAM and VCAM, are associated with an increased myeloid cells' extravasation in the skin and increased myofibroblasts transformation with further vascular leak and cellular migration. This mini-review examines current knowledge on determinants of vascular leak in SSc, shedding light on the role of vascular protection. This could enhance further studies in the light of drug development for early treatment, suggesting that the control of vascular leakage should be considered in the same way that vasodilation and inflammation reduction, as potential therapeutic targets.

Keywords: capillary leak; edema; endothelial dysfunction; extravasation; permeability; systemic sclerosis; vasculopathy.

Figure 1

Perivascular edema and inflammatory cell infiltration are prominent in skin of early diffuse cutaneous systemic sclerosis (SSc). Representative microphotographs of paraffin-embedded skin sections from patients with early diffuse cutaneous SSc subjected to hematoxylin and eosin staining (A, a1, a2, B) or double immunofluorescence staining for CD45/leukocyte common antigen (green) and CD31/pan-endothelial cell marker (red) with 4′,6-diamidino-2-phenylindole (DAPI, blue) counterstain for nuclei (C) are shown. (a1) and (a2) represent higher magnifications of the boxed areas in (A). (a1) Infiltrating inflammatory cells are observed around small dermal blood vessels (arrows). (a2) A dermal lymphatic vessel with an enlarged lumen (asterisk) is surrounded by edematous extracellular matrix. (B) Edema is prominent around blood capillaries. The inset depicts a higher magnification view of the boxed area from the respective panel. (C) CD45-positive inflammatory cells are widely found in the perivascular area. (D,E) Representative transmission electron microscopy microphotographs of ultrathin skin sections from patients with early diffuse cutaneous SSc. (D) A blood capillary displays hypertrophic endothelial cells and is surrounded by edema and inflammatory cells. (E) A lymphatic vessel surrounded by edema shows an enlarged lumen (asterisk). EC, endothelial cell; MC, mast cell; MO, mononuclear cell; P, pericyte; RBC, red blood cell.

Figure 2

Schematic representation of the mechanisms leading to endothelial injury and capillary sufferance, evolving into vascular leaking.