New mechanism-based approaches to treating and evaluating the vasculopathy of scleroderma

Abstract

Purpose of reviewUtilizing recent insight into the vasculopathy of scleroderma (SSc), the review will highlight new opportunities for evaluating and treating the disease by promoting stabilization and protection of the microvasculature.Recent findingsEndothelial junctional signaling initiated by vascular endothelial-cadherin (VE-cadherin) and Tie2 receptors, which are fundamental to promoting vascular health and stability, are disrupted in SSc. This would be expected to not only diminish their protective activity, but also increase pathological processes that are normally restrained by these signaling mediators, resulting in pathological changes in vascular function and structure. Indeed, key features of SSc vasculopathy, from the earliest signs of edema and puffy fingers to pathological disruption of hemodynamics, nutritional blood flow, capillary structure and angiogenesis are all consistent with this altered endothelial signaling. It also likely contributes to further progression of the disease including tissue fibrosis, and organ and tissue injury.SummaryRestoring protective endothelial junctional signaling should combat the vasculopathy of SSc and prevent further deterioration in vascular and organ function. Indeed, this type of targeted approach has achieved remarkable results in preclinical models for other diseases. Furthermore, tracking this endothelial junctional signaling, for example by assessing vascular permeability, should facilitate insight into disease progression and its response to therapy.

Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis

“…The inner layer of blood vessels is lined with endothelial cells that interact with the circulation and are vulnerable to attack by various intrinsic and environmental stimuli. Microbial infection, autoantibodies against endothelial cells, shear stress, oxidative stress, and ischemia/reperfusion injury have been reported as potential contributors to elucidating vascular injury in SSc patients [9]. In this regard, cytomegalovirus infects endothelial cells and monocytes/macrophages, leading to endothelial cell apoptosis and immune system dysregulation, although direct evidence supporting its role in the pathogenesis of SSc is lacking [10].…”

Biomarkers in Systemic Sclerosis: An Overview

“…The exact processes of SSc pathogenesis are not clear. However, the pathogenic processes can be summarized in three main events: the endothelial injury with a consequent microvasculopathy, followed by the autoimmune response and inflammation and finally a diffuse fibrosis of skin and internal organs [1][2][3][4][5][6][7][8][9][10][109][110][111][112][113][114][115][116][117][118]. Several studies confirmed the role of each of these three events and their interaction in SSc pathogenesis.…”

“…The SSc vascular damage is characterized by the presence of a characteristic processes with a vasomotor instability with an imbalance of vasoactive factors: overproduction of vasoconstrictors (ET-1) and underproduction of vasodilators (NO and prostacyclin) [6][7][8][9][10][11][12][13][22][23][24][25][106][107][108][109]. The free radical nitric oxide (NO) is a potent vasodilator and is synthesized from L-arginine by NO synthase (NOS) [10][11][12][13][14][15][16][17][18][19][22][23][24][25][40][41][42][43][44][45][46][47][48][106][107][108][109][110][111][112][113]. Endothelial isoforms of NOS (eNOS or NOS 3) has been identified with a constitutive expression, other isoforms are shown...…”

“…Endothelial isoforms of NOS (eNOS or NOS 3) has been identified with a constitutive expression, other isoforms are shown in other cell types. Furthermore, an inducible expression (iNOS or NOS 2) in response to a variety of stimuli is possible, with NO-mediated signalling apparent in the skin [10][11][12][13][14][15][16][17][18][19][40][41][42][43][44][45][46][47][48][106][107][108][109][110][111][112][113]. Several studies reported that NO have a biphasic effect in physiological and pathological conditions, being both beneficial and detrimental depending on the concentration and local environment [10][11][12][13][14][15][16][17][18][19][40][41][42][43][44][45][46][47][48].…”

“…Several studies reported that NO have a biphasic effect in physiological and pathological conditions, being both beneficial and detrimental depending on the concentration and local environment [10][11][12][13][14][15][16][17][18][19][40][41][42][43][44][45][46][47][48]. Recently observation proposed the regulation of NO by endogenous levels of the NOS inhibitor asymmetric dimethylarginine (ADMA) [10][11][12][13][14][15][16][17][18][19][22][23][24][25][40][41][42][43][44][45][46][47][48][106][107][108][109][110][111][112]…”