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.

Inflammation without Vascular Leakage. Science Fiction No Longer?

“…In the brain, cerebral edema can raise intracranial pressure and induce cerebral ischemia and frank herniation; its avoidance or amelioration has long been a therapeutic goal (17). There are also emerging data to suggest that vascular leakage may predispose to tissue fibrosis, making it relevant not only to acute syndromes like ARDS but also to more chronic diseases like systemic sclerosis (18) and chronic kidney disease (19).…”

Altered serum level of metabolic and endothelial factors in patients with systemic sclerosis

“…Both exhibit a potent chemotactic activity for lymphocytes T, monocytes and natural killer cells [11]. Furthermore, membrane-linked form mediates immune cells adhesion and migration through the vessel wall resulting in perivascular infiltration of inflammatory cells, which is an event preceding the development of fibrosis [12]. Structural changes of blood vessels are mediated also by galectin-3-a carbohydrate-binding protein expressed and secreted to the circulation by the variety of cells, mostly endothelial and immune cells.…”

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

“…The pathogenic scenario of systemic sclerosis (SSc, scleroderma) is dominated by peripheral microvascular damage and immune system disturbances, culminating in progressive fibrosis of the skin and internal organs [1,2]. Early endothelial cell activation/injury and failure in vascular recovery are considered the hallmarks of the disease, and may lead to a variety of clinical manifestations, ranging from Raynaud's phenomenon and digital painless swelling ("puffy fingers") to digital ulcers or even gangrene of the extremities in the most severe cases [3][4][5].…”

“…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].…”

“…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]. Indeed, it has been suggested that dermal lymphatic microangiopathy may take place as a consequence of blood capillary leaking in very early SSc, when "puffy fingers" are a clinical hallmark [5]. Specifically, dermal blood capillary leaks result in greater amounts of fluid and macromolecules in the interstitium, followed by maximal increase in lymph flow, which provokes microlymphatic vessel overload/insufficiency and consequent tissue accumulation of protein-rich interstitial fluid, immune cells, chemokines, and growth factors, clinically manifesting as skin edema [5].…”