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.
Highlights
Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed?
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 systemic sclerosis (SSc)
Capillary leak may take place in several diseases due to local pathological conditions and the following are prototypes arising from different origins: 1) Anti-angiogenic and potential permeability inhibitors have been demonstrated in neoplasms [16], 2) Hypoxia-induced vascular endothelial growth factor (VEGF) production can determine vascular leak and local edema in ischemic diseases such as stroke and myocardial infarction [17], 3) Pathological or mechanical endothelial stretch induces increased vascular permeability in pulmonary diseases including asthma [18], acute and ventilator-induced lung injury [19], 4) Hypoxia-induced VEGF production has been demonstrated in ocular conditions such as diabetic retinopathy or age-related macular degeneration [20]
Summary
Systemic sclerosis (SSc) is characterized, in its early phase, by the prominent interplay between the microvasculature and the immune system [1]. The aim of this review is to examine the characteristics and mechanisms of vascular leaking in SSc. The vessel structure depends on its size and function: while larger arteries, arterioles, veins and venules have an endothelial layer plus varying amounts of surrounding muscular cells, capillaries and post-capillary venules have an inner surface coat overlying the endothelium called the glycocalyx, a negatively charged glycosaminoglycan (GAG) layer, and are usually surrounded by pericytes [3]. Endothelial cells (ECs) are anchored via integrins to a basement membrane (BM) which can be fenestrated or continuous. An intercellular vascular leak can be a physiological reparative event, such as during neovascularization following wound healing. This is consecutively characterized by BM degradation, pericyte detachment, endothelial thinning and increase in lumen size, mostly at a post-capillary venule level [5]
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