Macro- and microvascular disease in systemic sclerosis

VPH-06203; No of Pages 8 Vascular Pharmacology xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph

Review

Macro- and microvascular disease in systemic sclerosis Niloufar Kavian a,b,⁎, Frédéric Batteux a,b a b

Faculté de Médecine Paris Descartes, Sorbonne Paris Cité, INSERM U 1016, Institut Cochin, Paris, France Laboratoire d'immunologie biologique, Hôpital Cochin, Groupe Hospitalier Paris Centre, AP-HP, 75679 Paris cedex 14, France

a r t i c l e

i n f o

Article history: Received 4 February 2015 Received in revised form 4 May 2015 Accepted 30 May 2015 Available online xxxx Keywords: Vasculopathy Systemic sclerosis Endothelial cells Pericytes Angiogenesis Vasculogenesis Reactive oxygen species Endo-mesenchymal transistion

a b s t r a c t Vasculopathy is common in patients with connective tissue disease and can be directly implicated in the pathogenesis of the disease. Systemic sclerosis is an auto-immune multiorgan connective tissue disorder characterized by fibrosis of the skin and visceral organs and vascular disease. Micro- and macro-vessels are a direct target of the disease. In this review, we present the various clinical manifestations of the vasculopathy that can be present in SSc patients, and then discuss the various aspects of the pathophysiology of the vascular disorders. © 2015 Elsevier Inc. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Manifestations of the microvascular and macrovascular diseases in SSc 2.1. SSc microvascular manifestations . . . . . . . . . . . . . . 2.2. SSc macrovascular manifestations . . . . . . . . . . . . . . 3. Pathophysiology of SSc vasculopathy . . . . . . . . . . . . . . . 3.1. Microvasculature changes . . . . . . . . . . . . . . . . . 3.2. Endothelial cell injury . . . . . . . . . . . . . . . . . . . 3.3. Pericytes . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Role of Endo-mesenchymal transition (EMT) . . . . . . . . . 3.5. Defective angiogenesis and vasculogenesis . . . . . . . . . . 3.6. Activation of the coagulation system . . . . . . . . . . . . 3.7. Microparticles . . . . . . . . . . . . . . . . . . . . . . 3.8. Autoantibodies . . . . . . . . . . . . . . . . . . . . . . 3.9. Atherogenesis . . . . . . . . . . . . . . . . . . . . . . . 3.10. Dysregulation of transcriptional factors . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

⁎ Corresponding author at: Laboratoire d'Immunologie, Hôpital Cochin, 27 Rue du faubourg St Jacques, 75679 Paris cedex 14, France. E-mail address: [email protected] (N. Kavian).

Vascular involvement is frequent in patients with connective tissue disorders and can represent an important cause of death in established disease. Vasculopathy can be directly implicated in the pathogenesis of the disease, representing an acute manifestation of

http://dx.doi.org/10.1016/j.vph.2015.05.015 1537-1891/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: N. Kavian, F. Batteux, Macro- and microvascular disease in systemic sclerosis, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.015

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lupus (e.g., antiphospholipid syndrome (APS), lupus vasculitis), rheumatoid arthritis (e.g., vasculitis), or systemic sclerosis (SSc) (e.g., pulmonary arterial hypertension, digital ulcers). Vasculitis is common to various connective tissue disorders and is triggered by a vascular inflammatory process of the vessel walls that may take many clinical forms due to its capacity to affect vessels of different sizes (arteries, veins, and/or capillaries) and sites (involving either skin or internal organs), with a prognosis that may range from mild to life-threatening [1]. Besides vasculitis, auto-immune connective diseases can also be associated with a large spectrum of cardiovascular manifestations affecting myocardium, cardiac valves, the pericardium, the conduction system, [2]. These cardiovascular manifestations can have various impacts on the patients' condition: from clinically silent to increasing considerably the co-morbidity and mortality. In SSc, the vascular disease is fundamental to the physiopathology of the disease all along its development from early onset to late complications. Indeed, vasculopathy represents one of the three key features that characterize the connective tissue disorder SSc, along with fibrosis and auto-immunity. Two clinical forms of the disease are distinguished on the basis of skin involvement, that both display symptoms of vasculopathy [3–5]. On one hand, patients with limited SSc (lSSc) display a skin involvement that is confined to the face, neck, and areas distal to elbow and knees. On the other hand, in patients with diffuse SSc (dSSc) the skin involvement extends proximally to involve upper arms, thighs and/or trunk. Blood vessels are a direct target in this disease, as shown by the various clinical manifestations that occur from the initiation to the propagation of the disease, and have an important effect on the quality of life of the patients. These typical features of the vascular disease in SSc can differ when SSc co-exist with Antineutrophil cytoplasmic antibody (ANCA)associated vasculitis. ANCA-associated vasculitis is a multi-organ autoimmune disease associated with ANCA production and inflammation of small vessels. Any organ can be affected but more particularly the respiratory tract, skin, heart, nervous system and kidneys. The incidence of ANCA auto-antibodies in patients with SSc has been evaluated to be about 7% [6–8]. Though, there are only few case reports of ANCAassociated vasculitis in SSc [9,10]. In the case of ANCA-associated vasculitis occurring in overlap with SSc, patients can present with ANCAassociated necrotizing glomerulonephritis, that can be confused with scleroderma renal crisis, making the diagnosis challenging. DerrettSmith et al. interestingly reported in a small cohort that shared HLA haplotypes may be present in patients who develop both scleroderma and ANCA-associated vasculitis [10]. In this review, we will briefly present the clinical manifestations directly linked to the micro- and macro-vascular involvement of the disease and then focus on the cellular and molecular aspects defining the pathophysiology of the vascular disease in SSc, including the modifications of the microvasculature, the endothelium, the pericytes, the impaired angiogenesis and vasculogenesis, the activation of the coagulation system, the role of auto-antibodies and atherogenesis, and the dysfunction of recently involved transcription factors. 2. Manifestations of the microvascular and macrovascular diseases in SSc Several organs can be affected by the vascular disease in SSc including the lungs, kidneys, heart and digital arteries, leading to various clinical manifestations in SSc patients. 2.1. SSc microvascular manifestations Raynaud's phenomenon is one of the first clinical manifestations observed in SSc. This microvasculature disorder affects mostly the fingers and toes but can also affect other extremities. Over 95% of SSc patients display evidence of Raynaud's phenomenon, that can begin many

years before any other clinical symptoms of SSc. Raynaud's phenomenon is due to hypoxia in the extremities in response to cold and is characterized by a triphasic color pattern: pallor (constricted blood-flow), cyanosis (tissue hypoxia) and rubor (reperfusion) [11]. Evidence suggests that Raynaud's phenomenon is triggered by endothelial injuries in association with dysregulations in the production of nitric oxide and vasoactive factors [12]. Raynaud's phenomenon can lead to the formation of digital ulcers that is also one of the earliest complications of the disease. Healing of digital ulcers is often difficult and the most threatening complication is the loss of digits that is secondary to infections. Telangiectasias are also frequent in SSc patients, reflecting the systemic microvascular involvement of the disease. They are caused by a dilatation of postcapillary venules [13]. They are localized on the hands, face, lips and oral cavity, reflecting the systemic microvascular disease in SSc. Pulmonary vascular involvement in the form of pulmonary arterial hypertension (PAH), diagnosed by right-heart catheterization, occurs in approximately 12% of patients with SSc, and is seen in both lcSSc and dcSSc [14,15]. SSc-PAH occurs as a consequence of progressive remodeling of the small- to medium-sized pulmonary vasculature leading to pulmonary artery vasoconstriction and cellular proliferation. Hypoxemia and ischemia–reperfusion injury in the pulmonary vasculature maintain the vascular remodeling, fibrosis, and intraluminal microthrombosis [16]. These phenomena result in a progressive increase in pulmonary vascular resistance, pulmonary arterial pressure, and right ventricular pressure overload. Compensatory mechanisms in the right ventricle eventually lead to cardiac failure, making PAH life-threatening. The vascular disease can also affect renal vessels and cause scleroderma renal crisis that affects approximately 10% of patients with diffuse scleroderma and 2% of patients with limited scleroderma. This vascular complication is frequently associated with the presence of anti-RNA polymerase III antibodies [17]. Scleroderma renal crisis typically presents as an acute onset of severe hypertension and renal failure, caused by a proliferative obliterative vasculopathy of arterioles leading to a glomerular ischemia, as shown by histopathological studies of renal biopsies. Likewise, vascular malformations of the gastro-intestinal mucosa closely resembling telangiectasias (Gastric Antral Vascular Ectasia) can induce gastro-intestinal manifestations in SSc patients [18]. GAVE or watermelon stomach has a typical microscopic aspect characterized by dilatation of mucosal capillaries, focal fibrin thrombosis, fibromuscular hyperplasia, and fibrohyalinosis. This typical gastrointestinal feature can be observed in autoimmune connective tissue disorders including SSc, but is also associated with liver diseases. Various reports estimate its prevalence in SSc population between 1 and 20% [18–22]. 2.2. SSc macrovascular manifestations Macrovascular disease is considered very rare in SSc and the prevalence of vascular abnormalities in SSc is inversely proportional to the size of the blood vessels [23]. The heart is one of the major organs involved in SSc macrovascular disease [24], but histology examinations or coronary angiography show that coronary arteries are rarely involved [25–28]. Vasospasm of the coronary arteries with or without the presence of structural vascular abnormalities could be observed in patients with SSc [13,14]. This phenomenon is due to a transient nonperfusion because of arrythmias or Raynaud's phenomenon of the coronary arteries. Improvement of myocardial perfusion after oral nifedipine administration supports the hypothesis of myocardial RP in SSc [77,78]. Endothelial dysfunction and local hyperreactivity are involved in its pathogenesis [79]. Contradicting data have been reported regarding the prevalence of cerebrovascular involvement in SSc, but the current opinion is that it is very low [29,30].

Please cite this article as: N. Kavian, F. Batteux, Macro- and microvascular disease in systemic sclerosis, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.015

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Patients with systemic sclerosis might have an increased risk of atherosclerosis secondary to changes in the vascular wall. Several studies are available regarding peripheral atherosclerotic vascular disease showing an increased prevalence of distal peripheral vascular disease in SSc patients compared to healthy controls [31]. Results on early signs of atherosclerosis are conflicting certainly because of methodological differences, ie type of patients included, comorbidity, and non-invasive techniques used. Traditional risk factors are not different between controls and SSc patients. Therefore, other factors beyond traditional cardiovascular risk factors may contribute to any putatively increased prevalence of cardiovascular, cerebrovascular and peripheral vascular disease in SSc. Among them, the inflammatory process, that is a typical feature of systemic sclerosis, contributes to the development of atherosclerosis [74]. 3. Pathophysiology of SSc vasculopathy SSc vasculopathy affects primarily small and medium-size arteries that display intimal hyperplasia and media thickening. Perivascular inflammation can be associated with these vasculopathy manifestations in the skin and in the lungs of patients with PAH. Beside arteries, capillaries can also be affected by the vascular disease observed in SSc [32]. This particular involvement is highlighted in nailfold capillaroscopy that reveals dilatation of the capillaries in early stages of the disease, and loss of the capillaries in the later stages [33]. Impaired vascular permeability and

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tone are the earliest symptoms of vascular pathology in SSc. A dysregulation in the balance of vasoconstrictor molecules including ET-1 and the vasodilator nitric oxide (NO) contributes to the vascular dysfunction. The etiology of vascular pathology in SSc is unknown but several events could lead to the vascular injury in SSc, including infectious agents, free radicals, cytotoxic T cells and auto-antibodies directed against endothelial cells (Fig. 1). 3.1. Microvasculature changes As previously mentioned, abnormalities of arterioles and capillaries are an early and major sign of SSc. The first clinical manifestation of these abnormalities is the Raynaud's phenomenon that affects mostly the fingers and toes. Several reports have evidenced the structural modifications of the microvasculature in SSc, using capillary microscopy in the nailfold of the fingers [34]. Indeed, nailfold capillaroscopy allows the distinction of early and late microvascular disease [33]. Few giant capillaries with no loss of capillaries are characteristic of an early stage of the disease. A greater number of giant capillaries with capillary microhemorrhages without important loss of capillaries are typical of an active disease. The late pattern characteristic of a late microvascular disease associates an absence of giant capillaries along with an important loss of capillaries with avascular areas and marked disorganization of the normal capillary array. As previously mentioned, vascular changes not only affect skin but also the lungs, kidneys and other organs. The

Fig. 1. Sequence of events that could take part in the pathogenic process leading to vasculopathy in SSc. Various causative agents (ischemia–reperfusion injury, reactive oxygen species, microbial agents) could induce immune activation in predisposed subjects leading to chronic inflammation. Activated immune cells and auto-antibodies along with altered NO release cause EC activation. Altered production of several chemokines, cytokines and growth factors also contribute to an impaired angiogenesis and vasculogenesis, particularly VEGF, PDGF, CXCL-4, CXCL-9, and CXCL-10. Several markers of EC injury can be investigated in SSc patients, among them ET-1, vWF, NO, microparticles. The EC injury along with EMT process contribute to the activation of myofibroblasts and the production of exaggerated amounts of ECM resulting in tissue fibrosis. EC: endothelial cells, ET-1: endothelin-1, vWF : von Willebrand Factor, EMT: endo-mesenchymal transition, and ECM: Extra-cellular matrix.

Please cite this article as: N. Kavian, F. Batteux, Macro- and microvascular disease in systemic sclerosis, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.015

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lungs of SSc-patients with PAH show vascular lesions in small- and medium-sized vessels that are characterized by concentric intimal proliferation, marked luminal obstruction and the presence of infiltrating immune cells [16]. Renal vessels of SSc patients can also display signs of intimal proliferation, media-hyperplasia and obliteration of the lumen [35]. 3.2. Endothelial cell injury Elevated levels of von Willebrand factor (vWF) and endothelin-1 (ET-1) are present in the serum of patients with SSc, reflecting the endothelial cells dysfunctions and the active vascular disease [36]. The presence of large gaps between endothelial cells associated to the vacuolization of the cytoplasm and the cytoskeletal rearrangement of these cells attest for the endothelial suffering [32,37]. Several observations suggest that endothelial cell apoptosis is elevated in SSc. These apoptotic cells could activate the innate immunity and cause tissue injury as well as coagulation activation. The endothelial damage could originate from infections, cytotoxic T cells, auto-antibodies against endothelial cells or an ischemia–reperfusion phenomenon involving reactive oxygen species production. Indeed, endothelial cell apoptosis results from the interaction of endothelial cells with cytotoxic T cells either by Fas or granzyme/perforin pathway mechanisms. A viral infection of the endothelium could trigger cytotoxic endothelial cell apoptosis either directly or through recognition of infected cells by cytotoxic T cells. CMV has been suspected to be involved in this process since SSc patients display increased levels of anti-CMV antibodies [38]. CMV-infected endothelial cells can detach and circulate to distant capillary beds, thus disseminating the virus and leading to systemic endothelial cell apoptosis and potentially to autoimmunity through the production of anti-endothelial cell antibodies. This hypothesis has not been confirmed and further studies are required to define the exact role of CMV infection in endothelial injury and SSc pathophysiology. Endothelin-1 (ET-1) has vasoconstrictive effects and its expression is increased in the blood vessels, lungs, kidneys and skin of patients with SSc [39]. ET-1 is mostly produced by endothelial cells and mediates vascular wall cell proliferation along with inflammation and fibrosis. This molecule seems to play a key role in the maintenance of the endothelial damage. Higher levels of ET-1 are correlated with digital ulcers in SSc [40], and several clinical manifestations suggest that ET-1 is involved in the progression of microvascular damage in SSc [41]. Two types of ET-1 receptors have been described: ET-1 type-A receptors (ETAR) are expressed by vascular smooth muscle cells and can mediate vasoconstriction, smooth muscle cell proliferation, fibrosis and inflammation. ET-1 type-B receptors are mostly expressed on endothelial cells and mediate vasodilation via the release of nitric oxide. The ETB receptors are down-regulated on endothelial cells in SSc patients. This phenomenon could contribute to the reduction of their vasodilatory properties [42]. Molecules that blocks ETA and ETB receptors (like bosentan) are commonly used for the treatment of PAH and the prevention of new digital ulcers related to SSc. Targeting the endothelial damage and ET-1 appears as a key therapeutic element in the management of patients with SSc. The expression of endothelial NO synthase (eNOS) is decreased along with the NO release from vascular endothelium in SSc [43]. TGF-β that is involved in the fibrotic process of SSc seems to play a key role in the metabolism of NO through the regulation of both inducible- and endothelial-NO synthase [44,45]. The alteration of NO production leads to the alteration of vascular tone and platelet aggregation. NO also has a negative regulatory effect on cytokineinduced endothelial cell activation, and limits the endothelial release of pro-inflammatory cytokines such as IL-6 and IL-8. Therefore, the impaired production of NO in SSc has a major role in the vascular disease. Furthermore, several reports bring evidence that oxidative stress is elevated in SSc and that it contributes to endothelial injury

by the peroxidation of cell membrane lipids and by activating the inflammatory process [46–50]. A therapeutic increasing the sensitivity to endogenously produced NO could have beneficial effects in SSc [51,52]. Indeed, riociguat, a molecule that acts by targeting and stimulating the soluble guanylate cyclase, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension by improving exercise capacity (6-minute walk distance) as well as pulmonary vascular resistance [52]. In addition, phosphodiesterase 5 (PDE5) inhibitors have recently shown beneficial effects in SSc vasculopathy. Indeed, in the last decade, clinical trials have reported a successful treatment of Raynaud's phenomenon with two PDE5 inhibitors (sildenafil or tadalafil), that have been initially developed for erectile dysfunction [53]. A meta-analysis of the available randomized controlled trials showed that PDE-5 inhibitors significantly improve RCS and frequency and duration of RP attacks compared with placebo in secondary RP [54]. Endothelial cell adhesion molecules are involved in both cell–cell and cell–ECM interactions. They play a pivotal role in angiogenesis along with angiogenic factors, and are involved in the early steps of SSc vasculopathy [1,2]. Indeed, the activation of endothelial cells in the early onset of the disease is linked to increased levels of soluble molecules such as E-selectin, soluble Vascular cell Adhesion Molecule-1 (sVCAM-1) and soluble Intercellular Adhesion Molecule-1 (sICAM-1) [55]. SSc patients with digital ulcers have elevated levels of sICAM-1 in the plasma, compared to those that do not present any digital manifestations [3,4]. Furthermore, sE-selectin appears to be a promising biomarker of disease activity, as its circulating levels are correlated with the presence of avascular areas in nailfold capillaroscopy [5]. 3.3. Pericytes In capillaries, a layer of pericytes covers endothelial cells. They are able to differentiate into vascular smooth muscle cells, fibroblasts and myofibroblasts and synthesize ECM components, which are then deposited perivascularly [56]. These cells have a key role during angiogenesis as they contribute to vascular maturation. The PDGF-receptor beta and high-molecular-weight melanoma-associated antigen is overexpressed on pericytes from microvascular lesions of SSc patients with active Raynaud's phenomenon [56,57]. The signal mediated by the PDGFreceptor beta in pericytes seems to activate their proliferation and thus participates to the increase of the vascular wall thickness while its inhibition prevents the development of the disease (Yuen Yee Ho, David Lagares, Andrew M. Tager and Mohit Kapoor Fibrosis—a lethal component of systemic sclerosis 2014) [58]. In a mouse model of kidney fibrosis, pericytes and fibroblasts were the main sources of collagen production [59]. Likewise, pericytes have been shown to be an important source of myofibroblasts during renal fibrogenesis [60]. 3.4. Role of Endo-mesenchymal transition (EMT) Histopathologic studies of SSc micro- and macro-vasculature reveal that the proliferation of cells from fibroblastic origin also plays a key role in the development of SSc vasculopathy [61]. First, smooth muscle cells proliferate in the media of small and medium arterioles. Activated fibroblasts can proliferate in the subendothelium of small arterioles of lungs and kidneys, and produce extracellular matrix. The endomesenchymal transition (EMT) leads to the differentiation of endothelial cells into fibroblastic cells through the effects of cytokines and growth factors. Endothelial cells loose their specific line markers (VE Cadherin, vWF) and acquire a mesenchymal or myofibroblastic phenotype and express the associated markers α-SMA, vimentin and type-1 collagen [62]. These cells also acquire motility, and can therefore migrate to surrounding tissues. TGF-β, Notch, Wnt and ET-1 are molecular pathways that have been involved in the EMT process and implicated in the development of SSc [62–64].

Please cite this article as: N. Kavian, F. Batteux, Macro- and microvascular disease in systemic sclerosis, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.015

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3.5. Defective angiogenesis and vasculogenesis Angiogenesis is defined as the growth of new vessels from existing one, whereas vasculogenesis results from a de novo formation of new vessels. In SSc vasculopathy, these two phenomena are dysregulated and none of them ensure the compensation of the defects and structural abnormalities of the vasculature. • Angiogenesis relies on the activation, proliferation and migration of endothelial cells upon angiogenic signals. In SSc, tissue ischemia along with TGF-β signaling induce the expression of pro-angiogenic factors such as VEGF, leading to vasodilatation, proliferation and migration of endothelial cells to form new vessels. VEGF and its receptors are overexpressed in the skin and serum of SSc patients, despite the absence of effective neo-angiogenesis. In SSc patients, serum levels of VEGF are inversely correlated with nailfold capillary density [65]. Moreover, elevated levels of VEGF are associated with an important loss of capillaries with avascular areas and the development of digital ulcers [41]. These observations suggest that VEGF is up-regulated to activate neo-angiogenesis with insufficient effects, and that the overexpression of VEGF appears to have deleterious effects on the vascular network. Therefore, some studies report that the levels of VEGF could be used as a biomarker of vasculopathy in SSc. Two isoforms of VEGF have recently been distinguished: VEGF and its splice variant VEGF(165)b generated by alternative splicing mechanisms in the terminal exon of VEGF-A [66,67]. Surprisingly, the VEGF(165)b splice variant has anti-angiogenic effects, and a switch from the VEGF-A to the VEGF(165)b isoform may have a key role in the defective angiogenic and vascular repair processes in SSc. Levels of other proangiogenic factors such as PDGF or FGF-2 and their receptors are also increased in the skin of SSc patients and animal models as a result from tissue hypoxia [58,68,69]. In contrast, elevated levels of anti-angiogenic factors including endostatin, CXCL4, and thrombospondin-1, have also been reported in SSc patients, The latter is an activator of the TGF-Β pathway and can directly contribute to SSc vascular defects by directly blocking angiogenesis through the induction of endothelial cell apoptosis [70,71]. Chemokines may regulate angiogenesis as some of them have potent chemotactic effects on endothelial cells, whereas some others have inhibitory effects on angiogenesis. Several chemokines have been studied in SSc. On one hand, some pro-angiogenic chemokines are elevated in patients with SSc compared to healthy subjects, such as CXCL16 that is elevated in the serum from SSc patients and whose receptor CXCR6 is also overexpressed on endothelial cells in the skin [72]. On the other hand, CXCL10 and CXCL9 that are anti-angiogenic were also found elevated in the serum and skin from SSc patients [72]. Recently, plasma levels of CXCL4, a chemokine that is produced by plasmacytoid dendritic cells (pDC), were correlated with the presence and progression of complications in SSc patients, such as lung fibrosis and pulmonary arterial hypertension, suggesting that CXCL4 could be used as a biomarker in this disease [73]. Endoglin is a co-receptor for members of the TGF-Β family that is highly expressed in endothelial cells. Endoglin is crucial for the development of VEGF-induced angiogenesis [74]. Interestingly, the soluble form of endoglin has anti-angiogenic properties as it interferes with the binding of TGF to its receptor. Serum levels of soluble endoglin are elevated in patients with SSc compared to healthy subjects, and associated with the occurrence of digital ulcers in SSc patients [75]. • Vasculogenesis relies on the mobilization of bone-marrow-derived progenitor cells to form new vessels. After migrating to the sites of vascular injury, progenitor cells can differentiate into endothelial cells for the repair of the vascular wall or into vascular smooth muscle cells leading to the proliferation of the intima and vascular disease [76]. The role of circulating endothelial progenitor cells in SSc

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vasculopathy is unclear. Contradicting studies have reported their decrease or increase in the circulation of SSc patients [77]. One hypothesis is that these precursor cells may be inadequately recruited and therefore may not contribute to vascular repair. Another hypothesis is an early apoptosis of these cells induced by a circulating factor [78]. 3.6. Activation of the coagulation system A large number of data reports that coagulation and fibrinolysis are dysregulated in SSc [79,80]. Indeed, thrombosis of the microvessels and deposition of fibrin are a frequent manifestation of an imbalance between coagulation and fibrinolysis. The release of von Willebrand factor in the circulation is increased in SSc patients and in patients with Raynaud's phenomenon compared with healthy controls [36]. It has been suggested that levels of vWF and fibrinogen could be used as biomarkers of the vascular and the visceral disease in SSc [81]. The defective fibrinolysis in SSc is highlighted by the low levels of t-plasminogen activator (tPA) and the high levels of tPA inhibitor (tPAI) in the blood of patients with SSc [82]. Along with the imbalance in coagulation and fibrinolysis, the activation of platelets has been reported in SSc and could play a key role in the process of the vascular disease. Indeed, platelets are chronically activated and display enhanced aggregability in the presence of collagen, serotonin and ET-1 [83]. Activated platelets can release active molecules, thus contributing to the pathophysiology of SSc regarding fibrosis, immune activation and vasculopathy. These molecules can be inflammatory mediators (such as NO, Thromboxane-A2, prostaglandins, serotonin), chemokines (such as IL-8 or macrophage inflammatory protein 1 alpha (MIP-1alpha)), cytokines (such as IL-1beta or GMCSF), and growth factors (like PDGF, TGF or VEGF) [83]. Furthermore, platelets from SSc patients overexpress a receptor for type 1 collagen that could contribute to their enhanced aggregability, and that could be induced by cytokines produced by activated T lymphocytes [84]. 3.7. Microparticles Microparticles are a heterogeneous population of membrane-coated vesicles that are released from a variety of cells during activation and apoptosis via an exocytic budding process. They regulate inflammation, stimulate coagulation, affect vascular functions, and have also been implicated in apoptosis and cell proliferation [55,85]. High levels of microparticles are present in the plasma of SSc patients [86]. They originate from platelets, endothelial cells, monocytes, and T cells, reflecting the activation of these various cell types in SSc [86]. In the vascular pathophysiology of SSc, microparticles represent an important mediator of intercellular communication. 3.8. Autoantibodies The presence of various auto-antibodies can affect the vascular component in patients with SSc. As mentioned above, the levels of oxidized-LDL (OxLDL), a pro-atherogenic lipoprotein promoting ROS production, are increased in the circulation of patients with SSc [66]. Increased concentrations of antibodies to anti-OxLDL autoantibodies are present in patients with diffuse cutaneaous SSc and could also have deleterious effects on the vessels [74]. Also, anti-cardiolipin antibodies (aCL) and anti-beta2-glycoprotein-I antibodies (anti-beta2GPI) are found in SSc with a prevalence ranging from 0 to 40%, but no correlation between antibodies levels and clinical manifestations of the anti-phospholipid syndrome was observed [75–77]. However, some studies found an association between antiphospholipid autoantibodies and endothelial dysfunction, pulmonary hypertension and myocardial ischemia or necrosis [78], but found no association with digital ischemia [79]. Anti-endothelial cell antibodies (aECA) have been detected in 22–85% of SSc patients [80]. They are associated with digital

Please cite this article as: N. Kavian, F. Batteux, Macro- and microvascular disease in systemic sclerosis, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.015

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ischemia, nailfold capillary abnormalities and pulmonary hypertension [81,82]. In addition, auto-antibodies directed against the endothelin-1 type-A receptor (anti-ETAR) are found in SSc and are more prevalent in PAHSSc patients compared with patients presenting other forms of pulmonary hypertension. Riemekasten and coworkers have recently shown the pathogenic role of these auto-antibodies in the development of SSc [87]. They have recently described that the transfer of anti-ETAR autoantibodies from patients into healthy C57/Bl/6J mice could induce obliterative vasculopathy with perivascular lymphocyte infiltration in small pulmonary vessels [88]. 3.9. Atherogenesis SSc patients have differences in the lipoprotein profile compared to healthy subjects. Indeed, HDL levels are decrease in patients with limited cutaneous SSc compared to healthy controls [65]. No studies are available on LDL levels in SSc but oxidized-LDL (OxLDL) concentrations are increased in SSc [66]. OxLDL is a pro-atherogenic lipoprotein which promotes vascular reactive oxygen species formation, tissue remodeling, foam cell formation, endothelial dysfunction and even vasospasm [67]. The concentrations of lipoprotein-a, that is a biomarker of the development of cardiovascular disease, are increased both in limited and diffuse cutaneous SSc compared to controls [68]. Inflammation, auto-antibodies and alteration of lipoprotein profile results in endothelial cell activation that initiate atherogenesis. Expression of vascular adhesion molecules, such as P-selectin, L-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, is increased in atherosclerosis and increased levels of soluble forms of those adhesion molecules along with endothelial dysfunction has been described in SSc, but not in relation to atherosclerosis or macrovascular disease [74,75]. 3.10. Dysregulation of transcriptional factors Several transcriptional factors have recently been identified as important regulators in SSc vasculopathy. Recently developed animal models have emphasized the role of two of these factors in the development of the vascular disease in SSc: Fra-2 and Fli-1. Fos related antigen 2 (Fra-2) is a member of the activator protein 1 (AP-1) family, that is overexpressed in the skin and lungs from SSc patients [89]. Transgenic mice overexpressing Fra-2 show vascular remodeling and obliteration along with dermal and pulmonary fibrosis [90]. The vascular changes appear before the fibrosis, suggesting a connection between these two processes. The vasculopathy caused by Fra-2 overexpression resulted in the apoptosis of endothelial cells in the skin. Friend leukemia virus integration 1 (Fli1) is involved in the regulation of genes coding for ECM components [91]. Fli-1 also directly regulates a number of genes involved in the maintenance of vascular homeostasis. Several findings suggest that a reduced expression of Fli-1 in endothelial cells could contribute to a defective angiogenesis preventing both proper vessel maturation and stabilization which in turn could lead to the vascular pathology of SSc [91]. Mice with a conditional knock-out of Fli-1 in endothelial cells show abnormal vasculature with defective vessel integrity leading to increased vessel permeability [92]. 4. Conclusion Although fibrosis is the most prominent feature of SSc, the vascular tree may be the initial target-tissue in this disease. Clinical symptoms and biological signs of vascular injury in SSc patients are abundant and have been well documented for many decades, yet the understanding of the pathogenesis of SSc vasculopathy remains challenging. Indeed, digital and systemic ischemia that manifest as Raynaud's phenomenon, digital ulcers, PAH or renal crises generate vascular

complications that are important causes of morbidity and mortality in SSc patients. Even though, numerous triggers can contribute to the major endothelial dysfunction, the defective angiogenesis and vasculogenesis and the activation of coagulation and platelets, the exact chronology of the events leading to the devascularization of skin and involved visceral organs remains unknown. Key mediators produced by endothelial cells and platelets, but also fibroblasts and immune cells play major roles in the pathogenesis of the vascular disease and could represent new therapeutic targets in the treatment of digital ischemia, PAH and renal crises. The initial trigger(s) of the disease and the contribution of immune activation and fibrosis to the vascular disease are essential issues that remain to be solved. Acknowledgments We would like to thank Olivier Cerles for careful proofreading of this manuscript. The authors are funded by Faculté de Médecine Paris Descartes and Assistance Publique Hôpitaux de Paris (APHP), and declare no conflicts of interest. References [1] E. Toubi, A. Kessel, E. Bamberger, et al., Systemic lupus erythematosus vasculitis: a current therapeutic overview, Curr. Treat. Options Cardiovasc. Med. 6 (2) (Apr 2004) 87–97. [2] M. Prasad, J. Hermann, S.E. Gabriel, et al., Cardiorheumatology: cardiac involvement in systemic rheumatic disease, Nat. Rev. Cardiol. 12 (3) (2014) 168–176. [3] A.E. Koch, O. Distler, Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis, Arthritis Res. Ther. 9 (Suppl. 2) (2007) S3. [4] E.C. LeRoy, C. Black, R. Fleischmajer, et al., Scleroderma (systemic sclerosis): classification, subsets and pathogenesis, J. Rheumatol. 15 (2) (Feb 1988) 202–205. [5] A. Gabrielli, E.V. Avvedimento, T. Krieg, Scleroderma, N. Engl. J. Med. 360 (19) (May 7 2009) 1989–2003. [6] S. Akimoto, O. Ishikawa, T. Tamura, et al., Antineutrophil cytoplasmic autoantibodies in patients with systemic sclerosis, Br. J. Dermatol. 134 (3) (Mar 1996) 407–410. [7] I.C. Locke, J.G. Worrall, B. Leaker, et al., Autoantibodies to myeloperoxidase in systemic sclerosis, J. Rheumatol. 24 (1) (Jan 1997) 86–89. [8] A. Ruffatti, R.A. Sinico, A. Radice, et al., Autoantibodies to proteinase 3 and myeloperoxidase in systemic sclerosis, J. Rheumatol. 29 (5) (May 2002) 918–923. [9] U. Arad, A. Balbir-Gurman, K. Doenyas-Barak, et al., Anti-neutrophil antibody associated vasculitis in systemic sclerosis, Semin. Arthritis Rheum. 41 (2) (Oct 2011) 223–229. [10] E.C. Derrett-Smith, S.I. Nihtyanova, J. Harvey, et al., Revisiting ANCA-associated vasculitis in systemic sclerosis: clinical, serological and immunogenetic factors, Rheumatology (Oxford) 52 (10) (Oct 2013) 1824–1831. [11] J.A. Block, W. Sequeira, Raynaud's phenomenon, Lancet 357 (9273) (Jun 23 2001) 2042–2048. [12] B. Kahaleh, Progress in research into systemic sclerosis, Lancet 364 (9434) (Aug 14–20, 2004) 561–562. [13] J.G. Walker, J. Stirling, D. Beroukas, et al., Histopathological and ultrastructural features of dermal telangiectasias in systemic sclerosis, Pathology 37 (3) (Jun 2005) 220–225. [14] D. Mukerjee, D. St George, B. Coleiro, et al., Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach, Ann. Rheum. Dis. 62 (11) (Nov 2003) 1088–1093. [15] S.M. Proudman, W.M. Stevens, J. Sahhar, et al., Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment, Int. Med. J. 37 (7) (Jul 2007) 485–494. [16] H.W. Farber, J. Loscalzo, Pulmonary arterial hypertension, N. Engl. J. Med. 351 (16) (Oct 14 2004) 1655–1665. [17] V.D. Steen, T.A. Medsger Jr., T.A. Osial Jr., et al., Factors predicting development of renal involvement in progressive systemic sclerosis, Am. J. Med. 76 (5) (May 1984) 779–786. [18] E.W. Hung, M.D. Mayes, R. Sharif, et al., Gastric antral vascular ectasia and its clinical correlates in patients with early diffuse systemic sclerosis in the SCOT trial, J. Rheumatol. 40 (4) (Apr 2013) 455–460. [19] E. Ghrenassia, J. Avouac, D. Khanna, et al., Prevalence, correlates and outcomes of gastric antral vascular ectasia in systemic sclerosis: a EUSTAR case–control study, J. Rheumatol. 41 (1) (Jan 2014) 99–105. [20] I. Marie, P. Ducrotte, M. Antonietti, et al., Watermelon stomach in systemic sclerosis: its incidence and management, Aliment. Pharmacol. Ther. 28 (4) (Aug 15 2008) 412–421. [21] I. Marie, H. Levesque, P. Ducrotte, et al., Gastric involvement in systemic sclerosis: a prospective study, Am. J. Gastroenterol. 96 (1) (Jan 2001) 77–83. [22] K. Laoubi, Y. Allanore, S. Chaussade, et al., Watermelon stomach in systemic sclerosis, J. Mal. Vasc. 35 (4) (Jul 2010) 250–253. [23] W.L. Norton, J.M. Nardo, Vascular disease in progressive systemic sclerosis (scleroderma), Ann. Intern. Med. 73 (2) (Aug 1970) 317–324.

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