***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Nitric  oxide ( NO , nitrogen monoxide ) is a messenger molecule whose synthesis can be induced by proinflammatory cytokines . Increased production of NO has been reported in various inflammatory and autoimmune diseases . We studied serum nitrite and citrulline  as surrogate markers for NO production in patients with systemic sclerosis ( SSc ) and looked for correlation with extent of disease , disease duration , age , and systemic involvement . Thirty-four patients were studied against 20 controls . The nitrite levels were significantly higher in the disease group ( 1588.4 + /- 998.2 nmol/ml compared to 327.8 + /- 137.7 nmol/ml ; P < 0.001 ) . The citrulline levels of the disease group were also significantly higher ( 5490.1 + /- 2518.3 nmol/ml compared to 3264.5 + /- 2509.7 nmol/ml in the controls ; P = 0.005 ) . There was no significant difference among limited and diffuse subgroups . There was no significant difference in patients with or without arthritis or interstitial lung disease or with other systemic involvement . On multivariate analysis there was a trend toward a rising level of nitrite with worsening lung functions ( P = 0.07 ) . Hence , there is evidence of increased NO production in patients with SSc . There is no difference between NO levels in disease subgroups or those with systemic involvement Objective To evaluate the possible merit of endothelial markers for the prediction of ischaemic digital ulcers in patients with systemic sclerosis ( SSc ) . Methods  Circulating endothelial progenitor cells ( EPC ) , circulating endothelial cells and serum levels of placental growth factor ( PlGF ) , soluble vascular adhesion molecule and vascular endothelial growth factor  were measured in a prospect i ve cohort of 100 SSc patients . The primary outcome was the occurrence of one or more new ischaemic digital ulcers during a planned 3-year follow-up . Results After the follow-up period , 17 patients developed new digital ulcers . By multivariate analysis focused on biomarkers , high PlGF serum levels and low EPC counts were identified as predictors of the occurrence of at least one new digital ulcer . In a secondary model including biomarkers together with clinical SSc characteristics all predictors of digital ulcers defined by p≤0.1 in univariate analysis , high PlGF serum levels ( HR 7.26 , 95 % CI 1.92 to 27.41 ) and a history of digital ulcers ( HR 9.32 , 95 % CI 1.51 to 59.83 ) were identified as independent predictors of a new digital ulcer . In an alternative model excluding patients with a history of digital ulcers at baseline , high PlGF serum levels ( HR 13.46 , 95 % CI 1.58 to 114.73 ) and low EPC counts ( HR 7.95 , 95 % CI 2.09 to 30.09 ) remained predictive of new digital ulcer occurrence during follow-up . Conclusion This study identified high PlGF serum levels and low circulating EPC counts as predictors of new digital ulcers in SSc . It highlights the critical role of angiogenesis in this vascular outcome . These markers may improve digital ulcer risk stratification and therefore allow earlier therapeutic intervention Objective The role of complement system in the pathogenesis of systemic sclerosis ( SSc ) has been debated during the last decade but an evident implication in this disease has never been found . We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator , the Membrane Cofactor Protein ( MCP , CD46 ) on skin vascular bed as target distinctive of SSc disease . We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region . Methods  C5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay .  Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells . The expression of MCP was vali date d by immunoblot analysis with specific antibody . Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method . Results Even though circulating levels of C5b-9 did not differ between SSc and controls , C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects . MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter , which has been related to more aggressive phenotypes in other immune-mediated diseases . Conclusions Our results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients , suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation Impaired angiogenesis in systemic sclerosis has a major role in tissue injury pathogenesis . Our objective was to determine whether angiogenic biomarkers ( vascular endothelial growth factor ( VEGF ) , endoglin , and endostatin ) are related to microvascular damage and to determine their predictive value for new digital ulcers ( DU ) . The main outcome of the study was the occurrence of a new digital ulcer during 3-year follow-up . This prospect i ve longitudinal study was performed between October 2011 and December 2014 . Seventy-seven patients definitely diagnosed with systemic sclerosis where divided into two groups : those with active DU at baseline and those with no DU until enrollment . Patients were matched by sex and age with healthy controls . Serum levels of VEGF , endoglin , and endostatin  were measured at enrollment , and several nailfold videocapillaroscopies were performed during the 3-year follow-up . Serum levels of VEGF were lower ( 245.06 , 158.68–347.33 ; p < 0.001 ) and those of endoglin were higher ( 3.013 , 1.463–7.023 ; p < 0.001 ) in patients with active DU than those with no DU history ( 339.49 , 202.00–730.93/1.879 , 0.840–3.280 ) , and they were higher than those found in controls ( 178.030 , 101.267–222.102)/0.277 , 0.154–0.713 ) , respectively . No differences in endostatin levels were found between groups ( p = 0.450 ) . Endoglin was the only biomarker significantly different ( p = 0.031 ) between patients with diffuse versus limited systemic sclerosis and between early , active , and late patterns ( p = 0.020 ) . VEGF was identified as an independent predictor for the development of new DU . Our study confirmed the relationship between angiogenic vascular biomarkers and the occurrence of DU . Endoglin and VEGF serum levels are potential risk factors , and VEGF has a predictive value for the occurrence of new DU OBJECTIVE : To determine whether measurement of different markers of endothelial damage , activation of coagulation , and platelet activation might differentiate between patients with primary Raynaud 's phenomenon ( PRP ) , limited cutaneous and diffuse systemic sclerosis ( lcSSc and dSSc ) , and healthy control subjects . METHODS : Under carefully controlled conditions , fasting blood was drawn from 19 healthy control subjects , 10 patients with PRP , 17 with lcSSc and nine with dSSc  for measurement of the following : von Willebr and factor ( VWF ) and soluble thrombomodulin as markers of endothelial damage/activation , thromboxane ( as thromboxane B2 ) and beta-thromboglobulin as markers of platelet activation , and tissue plasminogen activator antigen , tissue plasminogen activator activity and plasminogen activator inhibitor-1 ( PAI-1 ) as markers of fibrinolysis . RESULTS : VWF was increased significantly in patients with SSc , and there was also a linear trend for thromboxane and tissue plasminogen activator antigen ( in addition to VWF ) to differentiate between different subgroups of patients with Raynaud 's phenomenon . Patients with dSSc had the highest values . A combined index of VWF and thromboxane showed a highly significant trend across the four groups studied . CONCLUSION : VWF , and to a lesser extent thromboxane and tissue plasminogen activator antigen , are associated with disease severity in patients with Raynaud 's phenomenon . Prospect i ve studies are now required to establish if these parameters can be used as markers of disease progression 
    Output:
    
Emerging , relatively new discovered biomarkers described in the selected articles , are VEGF165b , IL-17A and the adipocytokines .
Finally , myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition .
CONCLUSION This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival ( activation and apoptosis ) , angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy