Vascular Disease in Scleroderma: Mechanisms of Vascular Injury

doi:10.1016/j.rdc.2007.12.004

Rheumatic Disease Clinics of North America

Volume 34, Issue 1, February 2008, Pages 57-71

https://doi.org/10.1016/j.rdc.2007.12.004 Get rights and content

Vascular endothelial injury in systemic sclerosis (SSc) includes a spectrum of changes that involve predominantly the microcirculation and arterioles. The pathologic changes in the blood vessels adversely impact the physiology of many organ systems, with a reduction in the size of microvascular beds leading to decreased organ blood flow and ultimately to a state of chronic ischemia. Current hypotheses in SSc vascular disease suggest a possible chemical or infectious trigger.

Section snippets

Vascular disease in scleroderma

Vascular involvement in SSc includes a spectrum of changes that involve predominantly the microcirculation and arterioles [1], [2]. The microvascular changes include a reduction in the number of capillaries and the presence of avascular areas. The most marked abnormalities appear in the arteriolar segments of capillary beds. Morphologic capillary changes can be visualized in the nail fold when examined with the dissecting stereomicroscope. Specific capillary patterns in SSc were initially

Endothelial injury and apoptosis

Endothelial cell injury is identified as an early and central event in the pathogenesis of SSc vasculopathy. An apoptotic alteration in endothelial cells was first described on ultrastructural examination of SSc biopsy specimens in the early stages of the disease in association with the inflammatory stage, suggesting a causal association [2]. It was later noted in the University of California at Davis lines 200/206 chickens that spontaneously develop disease resembling SSc [8]. Endothelial cell

Vascular dysfunction

The earliest signs of vascular dysfunction in SSc include enhanced vascular permeability and dysregulated control of vascular tone. The propensity for vasospasm in SSc is well known and best illustrated by Raynaud's phenomenon, which results from digital arterial closure after cold exposure. The arterial closure is believed to be the end result of an imbalance in endothelial signals (increased endothelin release and an impaired endothelial-dependent vasodilatory mechanism, NO). Although

Circulating markers of vascular disease

An increase in the circulating level of von Willebrand factor was the first proposed marker for endothelial cell injury in SSc. A decrease in the level of angiotensin-converting enzyme (ACE) was later identified as another marker that correlates inversely with von Willebrand factor levels. Other markers were later suggested (Table 1).

Summary

The etiology and pathogenesis of SSc remain unknown. Nonetheless, signs of vascular injury and devascularization of involved organs in association with evidence of profound endothelial dysfunction are well documented. Countless central issues in the pathogenic process of SSc remain poorly understood. Issues related to the initial trigger in the disease, the nature of immune activation, mechanisms of intimal proliferation, and the relationship of vascular injury to tissue fibrosis are some of

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Cited by (101)

Serum netrin-1 levels in systemic sclerosis patients with capillary abnormalities
2023, Egyptian Rheumatologist
Citation Excerpt :
Systemic sclerosis (SSc) is a progressive disease that begins in pathophysiological terms with microvascular damage, followed by extensive fibrosis due to increased autoimmune response and inflammation [21]. Dysregulations in vasodilators (nitric oxide and prostacyclins), cell adhesion molecules (selectins and integrins), and vasoconstrictors (ET-1, platelet-activating factor) are thought to be responsible for the microvascular abnormalities and endothelial dysfunction seen in SSc [22,23]. A limited number of studies evaluated the relationship of netrin-1 with SSc.
Systemic sclerosis (SSc) is a rare, potentially destructive systemic autoimmune disease characterized by organ fibrosis and vasculopathy. Netrin-1 is associated with angiogenesis, inflammation, and apoptosis.
To assess the level of serum netrin-1 in SSc patients with capillary abnormalities and to evaluate its relation to disease manifestations.
This study investigated the relationship between netrin-1 and fibrosis in 56 SSc patients and 58 matched control. The modified Rodnan skin score (mRss) was used to assess skin thickness. Serum netrin-1 level was quantitatively measured using an enzyme-linked immunosorbent assay.
The study included 56 patients; 53 females and 3 males (F:M 17.7:1) with a mean age of 48·1 ± 13·6 years and disease duration of 13.01 ± 8·7 years. They were 43 (76.7 %) diffuse and 13 (23.3 %) limited subtypes. The median mRss was 6.58 ± 2.2. Raynaud’s disease was present in 50 % and interstitial lung disease in 57.1 %. The median netrin-1 level was significantly higher in SSc patients (268·8 pg/mL; 82·8-1006·6 pg/mL) than in the controls (108·6 pg/mL;21·02-351·5 pg/mL, p < 0·0001). There was no significant difference in the serum netrin-1 levels in SSc patients with and without Raynaud’s disease (p = 0.55), interstitial lung disease (p = 0.18), anti-Scl70 positive antibodies (p = 0·78), and anti-centromere antibody (p = 0·493). Netrin-1 was significantly related to SSc (OR = 1·02, 95 %CI: 1·01 − 1·03, p < 0·0001). At a cut-off value 126·3 pg/mL, netrin-1 would diagnose SSc (sensitivity 60·3%, specificity 94·6%, 95 %CI: 0·83 − 0·95, p < 0·0001).
SSc patients had significantly high levels of serum netrin-1 with a potential role in the pathophysiology of the disease.
Asymmetric dimethylarginine correlates with worsening peripheral microangiopathy in systemic sclerosis
2023, Microvascular Research
Systemic sclerosis (SSc) is a connective tissue disease characterized primarily by micro-angiopathy and endothelial dysfunction which stimulate a fibrotic process. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor and represents a novel biomarker for vascular dysfunction. Nailfold video capillaroscopy (NVC) represents a non-invasive and reliable technique for the evaluation of microvasculopathy in SSc.
The aim of this study was to examine the possible association between ADMA and microvascular involvement in patients with SSc.
This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA was measured in serum samples using a commercial enzyme immunoassay. Participants underwent NVC with qualitative and semi-quantitative assessment and all NVC parameters were measured in the distal row of each finger. The findings were classified in one of the three qualitative NVC patterns: early, active, and late.
Eighty-one (92,6 % women) SSc individuals with mean age 55.44 ± 13.4 years were included in this analysis. Within-groups comparisons revealed a trend between higher ADMA levels and progressive micro-vasculopathy (1,29 [2,1] vs 1,57 [1,95] vs 2,41 [3,87]; for early, active and late patterns respectively, p = 0.039). Furthermore, ADMA concentration was significantly associated with the number of capillaries/mm (r = −0.235; p = 0.035).
Serum ADMA levels were significantly associated with advancing stages of microcirculatory abnormalities suggesting that ADMA may have a role in promoting microvascular endothelial dysfunction in SSc individuals.
Acute Myocardial Infarction in Autoimmune Rheumatologic Disease: A Nationwide Analysis of Clinical Outcomes and Predictors of Management Strategy
2021, Mayo Clinic Proceedings
To examine national-level differences in management strategies and outcomes in patients with autoimmune rheumatic disease (AIRD) with acute myocardial infarction (AMI) from 2004 through 2014.
All AMI hospitalizations were analyzed from the National Inpatient Sample, stratified according to AIRD diagnosis into 4 groups: no AIRD, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSC). The associations between AIRD subtypes and (1) receipt of coronary angiography and percutaneous coronary intervention (PCI) and (2) clinical outcomes were examined compared with patients without AIRD.
Of 6,747,797 AMI hospitalizations, 109,983 patients (1.6%) had an AIRD diagnosis (RA: 1.3%, SLE: 0.3%, and SSC: 0.1%). The prevalence of RA rose from 1.0% (2004) to 1.5% (2014), and SLE and SSC remained stable. Patients with SLE were less likely to receive invasive management (odds ratio [OR] [95% CI]: coronary angiography—0.87; 0.84 to 0.91; PCI—0.93; 0.90 to 0.96), whereas no statistically significant differences were found in the RA and SSC groups. Subsequently, the ORs (95% CIs) of mortality (1.15; 1.07 to 1.23) and bleeding (1.24; 1.16 to 1.31) were increased in patients with SLE; SSC was associated with increased ORs (95% CIs) of major adverse cardiovascular and cerebrovascular events (1.52; 1.38 to 1.68) and mortality (1.81; 1.62 to 2.02) but not bleeding or stroke; the RA group was at no increased risk for any complication.
In a nationwide cohort of AMI hospitalizations we found lower use of invasive management in patients with SLE and worse outcomes after AMI in patients with SLE and SSC compared with those without AIRD.
Chemical exposure-induced systemic fibrosing disorders: Novel insights into systemic sclerosis etiology and pathogenesis
2020, Seminars in Arthritis and Rheumatism
Citation Excerpt :
However, it was not until Campbell and LeRoy postulated the hypothesis that vascular alterations played a crucial role in the global pathogenesis of SSc [165] that a large number of studies were initiated to examine the essential involvement of vascular abnormalities in SSc including the exaggerated and persistent activation of cells mediating the fibrotic process. The role of vascular alterations in the development of the SSc pathologic manifestations has been subsequently explored in a large number of publications [Reviewed in 166-172]. More recently, the focus of investigation has been shifted to emphasize that alterations in EC are at the center of SSc pathogenesis [173-178].
Numerous drugs and chemical substances are capable of inducing exaggerated tissue fibrotic responses. The vast majority of these agents cause localized fibrotic tissue reactions or fibrosis confined to specific organs. Although much less frequent, chemically-induced systemic fibrotic disorders have been described, sometimes occurring as temporally confined outbreaks. These include the Toxic Oil Syndrome (TOS), the Eosinophilia-Myalgia Syndrome (EMS), and Nephrogenic Systemic Fibrosis (NSF). Although each of these disorders displays some unique characteristics, they all share crucial features with Systemic Sclerosis (SSc), the prototypic idiopathic systemic fibrotic disease, including vasculopathy, chronic inflammatory cell infiltration of affected tissues, and cutaneous and visceral tissue fibrosis. The study of the mechanisms and molecular alterations involved in the development of the chemically-induced systemic fibrotic disorders has provided valuable clues that may allow elucidation of SSc etiology and pathogenesis. Here, we review relevant aspects of the TOS, EMS, and NSF epidemic outbreaks of chemically-induced systemic fibrosing disorders that provide strong support to the hypothesis that SSc is caused by a toxic or biological agent that following its internalization by endothelial cells induces in genetically predisposed individuals a series of molecular alterations that result in the development of SSc clinical and pathological alterations.
Imbalanced serum levels of Ang1, Ang2 and VEGF in systemic sclerosis: Integrated effects on microvascular reactivity
2019, Microvascular Research
Microangiopathy is a hallmark of systemic sclerosis (SSc). It is a progressive process from an early inflammatory and proangiogenic environment to insufficient microvascular repair with loss of microvessels. The exact underlying mechanisms remain ill-defined. Aim of the study was to investigate whether imbalanced angiopoietins/VEGF serum profile should be related in SSc to the altered microvascular reactivity characterized by aberrant angiogenesis and avascularity.
Serum levels of Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and VEGF were measured by ELISA in 47 SSc patients and 27 healthy controls. Microvascular alterations were assessed by nailfold videocapillaroscopy (NVC).
Serum concentrations of Ang1 were significantly lower [mean (S.D.): 21516.04 (11,441.035) pg/ml], and Ang2 significantly increased [25,89.55 (934.225) pg/ml] in SSc as compared with the control group [Ang1: 28,457.08 (10,431.905) pg/ml; Ang2: 1556.23 (481.255) pg/ml, p < 0.01, respectively], whereas VEGF did not differ significantly. The ratios of Ang1/Ang2 and Ang1/VEGF were significantly lower in SSc patients (8.346 ± 4.523 and 95.17 ± 75.0, respectively) than in healthy subjects (17.612 ± 6.731 p < 0.000001 and 183.11 ± 137.73; p = 0.004]. Formation of giant capillaries with vascular leakage and collapse was associated with significant increase in VEGF and concomitant Ang1 deficiency. Capillary loss was related to significant increase in VEGF with respect to those with preserved capillary number (395.12 ± 256.27 pg/mL vs. 254.80 ± 213.61 pg/mL) whereas elevated Ang2 levels induced more advanced capillary damage as indicated by the presence of the “Late” NVC pattern.
We found that serum levels of Ang1, Ang2 and VEGF are differentially expressed in SSc and altered Ang1/Ang2 profile might underlay the aberrant angiogenesis in SSc despite increase in VEGF. For the first time we identified that significant deficiency of Ang1 might be involved in early capillary enlargement, followed by collapse and lack of stable newly-formed vessels in VEGF-enriched environment, whereas Ang2 levels seem to increase later in disease progression and advanced microvascular damage (“Late” NVC pattern).
Endothelial-mesenchymal transition in skeletal muscle: Opportunities and challenges from 3D microphysiological systems
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Vascular Disease in Scleroderma: Mechanisms of Vascular Injury

Section snippets

Vascular disease in scleroderma

Endothelial injury and apoptosis

Vascular dysfunction

Circulating markers of vascular disease

Summary

J Am Acad Dermatol

Trends Immunol

J Biol Chem

Clin Immunol Immunopathol

Clin Immunol

Clin Immunol

Free Radic Biol Med

Immunopharmacology

Surgery

Clin Immunol Immunopathol

Biochem Biophys Res Commun

Respir Med

Clin Immunol Immunopathol

Vascular disease in progressive systemic sclerosis (scleroderma)

Ann Intern Med

The skin capillaries in Raynaud's disease

Arch Intern Med

Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders

Arthritis Rheum

Skin capillary changes in early systemic scleroderma: electron microscopy and “in vitro” autoradiography with tritiated thymidine

Arch Dermatol

Studies of the microvascular endothelium in uninvolved skin of patients with systemic sclerosis: direct evidence for a generalized microangiopathy

Br J Dermatol

Labial capillary microscopy in systemic sclerosis

Ann Rheum Dis

Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma

J Clin Invest

Apoptosis and angiogenesis are induced in the unstable coronary atherosclerotic plaque

Coron Artery Dis

Plasma from patients with idiopathic and human immunodeficiency virus-associated thrombotic thrombocytopenic purpura induces apoptosis in microvascular endothelial cells

Blood

Immature dendritic cells phagocytose apoptotic T lymphocytes

J Exp Med

Apoptosis is associated with increased cell surface tissue factor procoagulant activity

Lab Invest

Activation of the alternative pathway of human complement by apoptotic human umbilical vein endothelial cells

J Biochem

Human cytomegalovirus and the vasculopathies of autoimmune diseases (especially scleroderma), allograft rejection, and coronary restenosis

Arthritis Rheum

Epidemiology and pathogenesis of cytomegalovirus disease

Semin Hematol

Cytolytic activity against allogeneic human endothelia: resistance of cytomegalovirus-infected cells and virally activated lysis of uninfected cells

Transplantation

Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95

Arthritis Rheum

The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis

Am J Clin Pathol

Antiendothelial cell antibodies in vasculitis and connective tissue disease

Ann Rheum Dis

Anti-endothelial cell antibodies in systemic sclerosis: significant association with vascular involvement and alveolo-capillary impairment

Clin Exp Rheumatol

Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension

J Rheumatol

IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro: induction of adhesion molecule expression and involvement of endothelium-derived cytokines

J Clin Invest