The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem?

In systemic sclerosis (SSc), peripheral vasculopathy is characterized by a progressive and irreversible loss of capillaries following endothelial cell injury, due to defects in both vascular repair and expected increase in new vessel growth (angiogenesis). The discovery of key molecular targets may help to develop the most effective therapeutic strategy for the SSc-related vasculopathy. A pathway worth targeting in SSc may include vascular endothelial growth factor, 165b isoform, an endogenous angiogenesis inhibitor abnormally expressed and released by different cell types, including activated endothelial cells and platelets

Immunosuppression for interstitial lung disease in systemic sclerosis

The efficacy of immunosuppressors in the treatment of systemic sclerosis-interstitial lung disease is still matter of controversy. In this review we will analyse the evidence that immunosuppressors, despite not being able to reverse fibrotic changes, may help in slowing disease progression. Induction treatment with cyclophosphamide should be started as soon as possible in patients at risk for progression. Mycophenolate mofetil and rituximab have to be considered in patients who are unable to tolerate cyclophosphamide. After remission, maintenance treatment with mycophenolate mofetil or azathioprine should be started in order to preserve the benefits achieved during the induction treatment

Critical finger ischemia and myocardial fibrosis development after sudden interruption of sildenafil treatment in a systemic sclerosis patient.

Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud’s Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment

Angiotensin II type 2 receptor (AT2R) as a novel modulator of inflammation in rheumatoid arthritis synovium

Abstract Despite increasing evidence suggesting that angiotensin II type 2 receptor (AT2R) may regulate tissue inflammation, no study has yet analyzed its possible implication in rheumatoid arthritis (RA) synovitis. In this study, we investigated the expression and function of AT2R in synovial tissue and cultured fibroblast-like synoviocytes (FLS) from RA patients. AT2R expression was strongly increased in RA compared with osteoarthritis (OA) synovium, as well as in in cultured RA-FLS respect to OA-FLS and healthy FLS. Treatment with pro-inflammatory cytokines was able not only to boost AT2R expression in RA-FLS and OA-FLS, but also to induce its de novo expression in healthy FLS. The stimulation of AT2R with the specific agonist CGP42112A significantly reduced gene expression of interleukin (IL)-1β and IL-6 and activation of NF-κB in RA-FLS, while opposite effects were elicited by AT2R small interfering RNA. Moreover, AT2R agonism efficiently decreased RA-FLS proliferation and migration either at baseline or under pro-inflammatory cytokine challenge. In conclusion, AT2R is strongly expressed in key effector cells of rheumatoid synovitis, namely RA-FLS, and the activation of AT2R with a specific agonist may effectively dampen their pro-inflammatory and aggressive behavior. AT2R agonism might represent a novel therapeutic strategy for patients with RA

Does Physical Exercise Enhance the Immune Response after Vaccination? A Systematic Review for Clinical Indications of COVID-19 Vaccine

Background: Stimulating protective immunity with vaccines appears to be the most promising option for providing widespread moderate to high protection against COVID-19 in people over the age of 18. Regular exercise improves the immune response, transmitting possible benefits against virus infections. The aim of this review is to study the effects of physical activity on vaccine injections, helping to develop new recommendations for COVID-19 vaccination campaigns. Methods: A comprehensive review of the existing literature was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The internal quality of the studies was assessed according to the Physiotherapy Evidence Database (PEDro) scale. The outcomes analyzed were antibody titer, the level of lymphocytes CD4, CD8, InterLeukin 6 (IL6), leukocytes level, the visual analogue scale (VAS) for overall pain rating, arm and forearm circumferences and volume of oxygen (VO2) peak. Results: Fourteen articles were selected for the analysis. The majority of studies were randomized controlled trials (RCT) (n = 8) and controlled trials (CT) (n = 6). According to PEDro, the ‘fair’ category (n = 7) was the most represented, followed by ‘good’ (n = 6) and ‘excellent’ (n = 1). Physical training showed a positive effect on antibody titers of the vaccine; yet, different variables seem to influence antibody titers: higher new vs. old antigen in the vaccine, higher in younger vs. older individuals, and higher in females vs. males. After exercise, when analyzing variables of direct response to the vaccine, such as the amount of CD4, IL-6 and leukocytes, higher levels were observed in the patients who performed physical exercise compared to the control group. In the same way, better results were observed in physiological variables such as VO2 and limb circumferences, or subjective variables such as pain, which showed better results than the control group. [...]Funding for open access charge: Universidad de Málaga / CBUA

Systemic Sclerosis Sera Impair Angiogenic Performance of Dermal Microvascular Endothelial Cells: Therapeutic Implications of Cyclophosphamide

In systemic sclerosis (SSc), dermal capillaries are progressively lost with consequent chronic tissue hypoxia insufficiently compensated by angiogenesis. Clinical studies reported that intravenous cyclophosphamide (CYC) may improve SSc-related peripheral microvascular damage. Recently, we showed that CYC treatment may normalize SSc sera-induced abnormalities in endothelial cell-matrix interactions. Our objective was to evaluate in vitro the effects of sera from treatment-naïve or CYC-treated SSc patients on dermal blood microvascular endothelial cell (dMVEC) angiogenesis, migration, proliferation and apoptosis. dMVECs were challenged with sera from 21 SSc patients, treatment-naïve (n = 8) or under CYC treatment (n = 13), and 8 healthy controls. Capillary morphogenesis on Geltrex matrix was significantly reduced upon challenge with sera from naïve SSc patients compared with healthy controls. When dMVECs were challenged with sera from CYC-treated SSc patients, their angiogenic capacity was comparable to that of cells treated with healthy sera. Wound healing capacity and chemotaxis in Boyden chamber were both significantly decreased in the presence either of naïve or CYC-treated SSc sera compared with healthy sera. WST-1 assay revealed that cell proliferation was significantly decreased in dMVECs challenged with sera from naïve SSc patients compared with healthy sera. Conversely, dMVEC proliferation was not impaired in the presence of sera from CYC-treated SSc patients. Accordingly, the percentage of TUNEL-positive apoptotic dMVECs was significantly higher in the presence of sera from naïve SSc patients than healthy controls, while CYC-treated SSc sera did not induce dMVEC apoptosis. Levels of the angiostatic mediators endostatin, pentraxin 3, angiostatin and matrix metalloproteinase-12 were all significantly elevated in sera from naïve SSc patients compared with sera from both healthy controls and CYC-treated SSc patients. In SSc, CYC treatment might boost angiogenesis and consequently improve peripheral microangiopathy through the normalization of the endothelial cell-matrix interactions, reduction of endothelial cell apoptosis and rebalance of dysregulated angiostatic factors

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

Objective: Systemic sclerosis (SSc) features multiorgan fibrosis orchestrated predominantly by activated myofibroblasts. Endothelial-to-mesenchymal transition (EndoMT) is a transdifferentiation by which endothelial cells (ECs) lose their specific morphology/markers and acquire myofibroblast-like features. Here, we determined the possible contribution of EndoMT to the pathogenesis of dermal fibrosis in SSc and two mouse models. Methods: Skin sections were immunostained for endothelial CD31 or vascular endothelial (VE)-cadherin in combination with α-smooth muscle actin (α-SMA) myofibroblast marker. Dermal microvascular ECs (dMVECs) were prepared from SSc and healthy skin (SSc-dMVECs and H-dMVECs). H-dMVECs were treated with transforming growth factor-β1 (TGFβ1) or SSc and healthy sera. Endothelial/mesenchymal markers were assessed by real-time PCR, immunoblotting and immunofluorescence. Cell contractile phenotype was assayed by collagen gel contraction. Results: Cells in intermediate stages of EndoMT were identified in dermal vessels of either patients with SSc or bleomycin-induced and urokinase-type plasminogen activator receptor (uPAR)-deficient mouse models. At variance with H-dMVECs, SSc-dMVECs exhibited a spindle-shaped appearance, co-expression of lower levels of CD31 and VE-cadherin with myofibroblast markers (α-SMA+ stress fibres, S100A4 and type I collagen), constitutive nuclear localisation of the EndoMT driver Snail1 and an ability to effectively contract collagen gels. Treatment of H-dMVECs either with SSc sera or TGFβ1 resulted in the acquisition of a myofibroblast-like morphology and contractile phenotype and downregulation of endothelial markers in parallel with the induction of mesenchymal markers. Matrix metalloproteinase-12-dependent uPAR cleavage was implicated in the induction of EndoMT by SSc sera. Conclusions: In SSc, EndoMT may be a crucial event linking endothelial dysfunction and development of dermal fibrosis