Search tips
Search criteria 


Logo of bmriBioMed Research International
Biomed Res Int. 2017; 2017: 5345673.
Published online 2017 July 16. doi:  10.1155/2017/5345673
PMCID: PMC5534276

Angiogenesis Dysregulation in the Pathogenesis of Systemic Sclerosis


Systemic sclerosis is a chronic autoimmune connective tissue disease characterized by vascular injury and fibrosis and by an impaired angiogenesis which cannot ensure an efficient vascular recovery. Vascular injury is responsible for hypoxia and tissual ischemia which are the primary triggers for angiogenesis and are not able to induce a compensatory angiogenesis. This review article is focused on current knowledge on the mechanisms responsible for angiogenesis dysregulation in systemic sclerosis.

1. Introduction

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease characterized by multisystem involvement with inflammation, vasculopathy, fibrosis of the skin, and internal organs. Vascular injury is an early event in SSc pathogenesis and may be evident before the onset of fibrosis. It plays a central role in promoting Raynaud's phenomenon, digital ulcers, renal damage, and pulmonary arterial hypertension [16].

The interaction between autoimmunity, vascular injury, and fibrosis promotes the progressive tissue damage. Among these factors, autoimmunity and vascular injury characterize the earliest phases of the disease and contribute to the progression of fibrosis [79].

Angiogenesis, the formation of newly formed capillaries from preexisting vessels via a well-programmed cascade of events, is dysregulated in SSc and cannot ensure an efficient vascular recovery. Vascular injury induces hypoxia and tissual ischemia which are the primary triggers for angiogenesis, but are not able to induce a compensatory angiogenesis.

2. Vascular Involvement in SSc

In early stages of SSc endothelial cell injury is followed by vascular remodeling, which is characterized by capillary enlargement, intimal proliferation, telangiectasia, and accumulation of proteoglycans in the arterioles. Later, during the course of the disease, loss of capillaries and small arterioles induces the formation of avascular areas [10, 11]. In larger size vessels, there is vascular occlusion and thrombosis due to endothelial proliferation, fibrotic intimal proliferation, fibrin deposition, and smooth muscle cell hypertrophy [1012].

A typical clinical feature of SSc is the Raynaud's phenomenon, which is characterized by persistent vasospasm of digital arteries with alternation of ischemia and reperfusion and an increased expression of junctional adhesion molecules (JAMs) [11]. The increase expression of JAMs promotes neutrophils and platelets attachment to endothelial cells. Neutrophils and platelets, in turn, induce the production of superoxide radicals which are responsible for endothelial cell injury [10].

Thus, in SSc an endothelial cell damage has been observed already in early phases of the disease, which probably together with neural dysfunctions, and other intravascular alterations, is in turn involved in inducing vascular injury [3, 4, 10]. Even if etiopathogenesis of endothelial cell damage is still unclear, autoimmunity seems to be responsible for endothelial production of cytokines and adhesion molecules, leading to apoptosis of the endothelial cell [10, 1315].

Moreover, an imbalance between vasodilator agents, such as nitric oxide, and vasoconstrictor agents, such as endothelin-1 (ET-1), has been observed in SSc and is involved in altered vascular permeability [15]. In fact, increased ET-1 expression is involved in inflammation, vascular fibrosis, and increased smooth muscle cell proliferation [4]. Moreover, the expression of ET-1 receptor type B, called ETB receptor, is reduced in SSc on endothelial cell surface but overexpressed on smooth muscle cells where it is responsible for fibrosis and vasoconstriction [16, 17].

Cipriani et al. [18] have demonstrated that endothelial cells in SSc, under the synergistic effect of transforming growth factor-β (TGF-β) and ET-1, may transdifferentiate toward myofibroblasts in a process called endothelial-to-mesenchymal transition (EndoMT) by which endothelial cells change their morphological features and assume myofibroblast-like features. By using skin sections obtained by SSc patients, Manetti et al. [19] have recently observed that EndoMT has a key role in inducing endothelial dysfunction and dermal fibrosis in SSc. Macitentan, an ET-1 receptor antagonist, has demonstrated an inhibitory effect in vitro on EndoMT and on fibroblast activation, suggesting its potential role as new therapeutic strategy against fibrosis in SSc [18, 20].

Transdifferentiation of pericytes to myofibroblasts has also been hypothesized in SSc [21]. By considering that pericytes are cells that reside on the wall of the blood vessels and their primary function is to maintain the vessel integrity, their transdifferentiation to myofibroblasts may contribute to vessel instability.

Vascular damage may induce the onset of avascular areas and/or morphologic changes in vessel wall, such as fibrosis. These alterations play a central role in inducing tissual hypoxia which may induce digital ulcers, gangrene and amputation of the extremities, and dysfunction in several internal organs [2226].

3. Vascular Implications and Fibrosis

Angiogenic cytokines, responsible for vessel formation and stabilization, such as vascular endothelial growth factor (VEGF), TGF-β, and platelet derived growth factor (PDGF), are also involved in fibrosis. An impaired cross-talk between endothelial cells and perivascular cells, such as pericytes, may induce an abnormal expression of these angiogenic factors in SSc [27]. This is responsible for subsequent vessel instability and perivascular-myofibroblast phenotypic transdifferentiation, which contribute to fibrosis in the skin and internal organs and to the loss of peripheral vascularization [27].

4. The Role of Imbalance between Angiogenic and Antiangiogenic Factors

An imbalance between angiogenic and antiangiogenic factors has been observed in several autoimmune diseases [2830]. In SSc a dysregulation of some angiogenic factors, such as VEGF, fibroblast growth factor-2 (FGF-2), PDGF, TGF-β, monocyte chemoattractant protein-1 (MCP-1), stromal cell-derived factor 1 (SDF-1/CXCL12), interleukin (IL)-8, ET-1, and urokinase type plasminogen activator receptors (uPAR), and some antiangiogenic factors, such as angiostatin, thrombospondin-1 (TSP-1), endostatin, platelet factor 4 (PF4/CXCL4), IL-4, and pentraxin 3 (PTX3), has been described (Table 1) [10, 11, 3036].

Table 1
Angiogenic and antiangiogenic agents involved in SSc: imbalance between these factors is responsible for impaired angiogenesis.

High levels of VEGF have been demonstrated in SSc, in spite of an inadequate angiogenesis [37, 38]. Nevertheless, by considering that previous studies did not distinguish between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, originated by alternative splicing in the terminal exon of VEGF pre-RNA, Manetti et al. [39] have observed that a switch from proangiogenic to antiangiogenic VEGF isoforms may be responsible for the inefficient angiogenic response in SSc. Recently, increased production of VEGF(165)b has been found in platelets isolated from SSc patients, suggesting a role for platelets in insufficient angiogenesis [40].

Even if numerous angiogenic factors are overexpressed in SSc, reduced levels of Angiopoietin-1 (Ang-1) have been observed in sera of patients with SSc, whereas Ang-2, an antagonist of Ang-1, was upregulated. Moreover, reduced levels of Kallikreins 9, 11, and 12, three serine proteases with angiogenic activity, have been observed in SSc endothelial cell [41, 42].

An increased production of antiangiogenic factors, such as endostatin and angiostatin, has been observed in SSc. Recent evidence shows that endostatin levels are increased in all phases of the disease while angiostatin levels are significantly elevated in late disease and are correlated to lung disease severity [43].

5. Reduced Expression of Receptors for Angiogenic Factors

A possible role in the lack of response to angiogenic factors in SSc, despite their overexpression, has been suggested for the reduced expression of some receptors on cell membrane. In fact, a reduced expression of stromal cell-derived factor 1 (SDF1), an angiogenic factor also known as CXC motif chemokine 12 (CXCL12), and its receptor CXCR4 has been found in later stages of disease skin biopsy samples from SSc patients, while they were upregulated in the skin of patients with early SSc, playing probably a role in the inadequate angiogenic response [44]. Nevertheless, contrasting results for VEGF receptor-1 (VEGFR-1) and VEGFR-2 expression have been described in SSc endothelial cells [4549]. Moreover, overexpression of VEGFR-3 and chemokine receptors, such as CXCR2 (receptor of IL-8) and CXCR6 (receptor of CXCL6), has been found in endothelial cells and dermal fibroblasts isolated from SSc patients [44, 50, 51]. Recently, Tsou et al. [52] have found that increased expression of angiogenic chemokines, such as growth-regulated protein-γ (Gro-γ/CXCL3) and granulocyte chemotactic protein 2 (GCP-2/CXCL6) in serum and endothelial cells obtained from SSc patients, was unable to induce angiogenesis.

6. Impaired Expression of Angiogenic Transcription Factors

Another hypothesis to explain the lack of response to angiogenic factors in SSc is the impaired expression of angiogenic transcription factors, such as Friend leukemia integration-1 (Fli1) and Fos-related antigen 2 (Fra-2). Fli1 acts as a suppressor of collagen transcription in human skin as demonstrated in vivo. The persistent reduced expression of Fli1 in SSc fibroblast cultures has been correlated to abnormal matrix deposition in scleroderma skin. Low Fli1 levels have been correlated to the detachment of preexisting pericytes, extracellular matrix degradation by endothelial proteinases, enhanced migration, proliferation, and cell survival. On the contrary, Fli1 deficiency plays a role in inhibiting tube formation of endothelial cells, suggesting that Fli1 deficiency is probably a consequence of both proliferative obliterative vasculopathy, characterized by occlusion of arterioles and small arteries, and destructive vasculopathy, characterized by loss of small vessels, which are the typical alterations in SSc vasculopathy [53]. On the other hand, high levels of Fra-2 have been seen in SSc patients, and its overexpression has been correlated to increased profibrotic effects of TGF-β and PDGF [5456].

7. JAM-A

The reduced expression of JAM-A on endothelial cells surface decreases FGF-2 induced angiogenesis [57] and has been correlated to an increased cleavage of IL-8 and uPAR, two angiogenic factors which are responsible for endothelial cell proliferation, extracellular matrix degradation, and the adhesion of endothelial cells to the extracellular matrix, by MMPs overexpression in fibroblast and endothelial cell [5860].

8. Genetic Polymorphisms

Genetic polymorphisms may also be involved in SSc pathogenesis. Gene polymorphism of uPAR, called UPAR rs344781, has been associated with increased risk of vascular injury in SSc, while gene polymorphism of MMP-12, named MMP-12 rs2276109, has been correlated with diffuse cutaneous SSc and pulmonary fibrosis [61, 62]. Moreover, an increased expression of histone deacetylases-5, an enzyme involved in the control of genes associated with angiogenesis regulation, has been observed in endothelial cells from SSc patients, suggesting a potential role for epigenetic modification in impaired angiogenesis [63].

9. α-Klotho

Recently, a role for α-klotho, a pleiotropic protein, originally described as an antiaging factor, has been suggested in SSc pathogenesis by acting as a powerful proangiogenic factor. This factor plays important pleotropic effects on endothelial cells, by interacting with VEGFR-2 and transient receptor potential canonical-1 (TRPC-1) cation channel to control cellular homeostasis [64]. Mazzotta et al. [65] have found that α-klotho is significantly decreased in the microvasculature in SSc skin and that its administration may efficiently improve dermal microvascular endothelial cells from SSc patients functions in vitro.

10. A Link between Vascular and Nervous System

Emerging evidences underline the link between vascular and nervous system. In fact, factors responsible for transmitting axonal guidance cues, such members of class III semaphorin (Sema3) family, play an antiangiogenic role in physiological and pathological vascular development. These factors are involved in reducing cell adhesion by disrupting integrin-mediated adhesive structures, resulting in a filopodial retraction in endothelial cells. Recently, by using dermal microvascular endothelial cell cultures from SSc patients, Mazzotta et al. [66] have suggested that a member of Sema family, named Sema3E, by binding to its receptor Plexin-D1 plays probably a role in the dysregulation of angiogenesis and vascular tone control by inducing neurovascular mechanism alterations which are clinically evident above all in the early stage of the disease. A low expression of neuropilin-1, a receptor for both Sema3s and VEGF-A, has been observed in SSc, suggesting a further additional factor involved in impaired angiogenesis [67].

11. The Role of Mesenchymal Stem Cells (MSCs) in the Vascular Alteration during SSc: Therapeutic Implications

In SSc patients, MSCs are characterized by senescence [68]. Nevertheless, MSCs may preserve immunomodulatory ability, which might have potential therapeutic implications in SSc. In fact, Cipriani et al. [68] have found increased levels of IL-6 and TGF-β in SSc-MSCs. On one hand, increased levels of IL-6 have been considered as an adaptive mechanism to senescence and are responsible for immunosuppressive effects. On the other hand, increased levels of TGF-β may be involved in determining both immunosuppressive effect on lymphocyte proliferation and immunoregulatory effects, via inducing expression of CD69 on T cells surface [68]. Moreover, MSCs may differentiate into endothelial cells [69], suggesting a potential therapeutic role in vascular alteration during SSc.

Different sclerotic conditions, including localized scleroderma, have been effectively treated with autologous fat tissue grafting (AFTG). In patients affected by advanced SSc-related perioral thickening and mouth opening limitation, AFTG of the lips has demonstrated an improvement of mouth opening [70]. The efficacy of this treatment has been correlated to the presence of a stem cell population, called adipose-derived MSCs (ATDMSCs) in the adipose tissue. In fact, ATDMSCs may differentiate into endothelial cells and produce angiogenic factors, suggesting a potential role in promoting angiogenesis [71]. ATDMSCs exert also several immunosuppressive and anti-inflammatory effects by inhibiting both proliferation of T and B cells, and the expression of numerous proinflammatory cytokines [72]. Furthermore, adiponectin expression from adipose tissue is responsible for antifibrotic effects [73].

12. Concluding Remarks

SSc in the earliest stages is characterized by morphologic alterations in vessel walls, such as fibrosis and capillary loss. Endothelial cell injury plays a central role in promoting these changes, which are responsible for inducing hypoxia. These events lead to an increased angiogenesis. Nevertheless, in SSc patients angiogenesis is not compensatory. The reason of this inefficient angiogenesis in SSc is still unclear. Nevertheless, an imbalance between angiogenic and antiangiogenic factors and a reduced expression of some receptors or cofactors of angiogenic agents has been suggested.

Even if further studies are needed to explain the role of angiogenesis in the pathogenesis of SSc and to elucidate the mechanism responsible for angiogenesis dysregulation, endothelial cell injury and angiogenesis dysregulation seem to play a central role in the pathogenesis of SSc. This may provide a basis for a rational approach to the development of new therapeutic strategy to ensure efficient angiogenesis.

Conflicts of Interest

The authors declare that there are no conflicts of interest.


1. Asano Y., Sato S. Vasculopathy in scleroderma. Seminars in Immunopathology. 2015;37(5):489–500. doi: 10.1007/s00281-015-0505-5. [PubMed] [Cross Ref]
2. Matucci-Cerinic M., Kahaleh B., Wigley F. M. Review: evidence that systemic sclerosis is a vascular disease. Arthritis & Rheumatology. 2013;65:1953–1962. doi: 10.1002/art.37988. [PubMed] [Cross Ref]
3. Kahaleh M. B. Vascular involvement in systemic sclerosis (SSc) Clinical and Experimental Rheumatology. 2004;22:S19–S23. [PubMed]
4. Abraham D., Distler O. How does endothelial cell injury start? The role of endothelin in systemic sclerosis. Arthritis Research & Therapy. 2007;9(2, article S2) doi: 10.1186/ar2186. [PMC free article] [PubMed] [Cross Ref]
5. Gabrielli A., Avvedimento E. V., Krieg T. N. Scleroderma. The New England Journal of Medicine. 2009;360(19):1989–2003. doi: 10.1056/NEJMra0806188. [PubMed] [Cross Ref]
6. Cipriani P., Marrelli A., Liakouli V., Di Benedetto P., Giacomelli R. Cellular players in angiogenesis during the course of systemic sclerosis. Autoimmunity Reviews. 2011;10(10):641–646. doi: 10.1016/j.autrev.2011.04.016. [PubMed] [Cross Ref]
7. Abraham D. J., Varga J. Scleroderma: From cell and molecular mechanisms to disease models. Trends in Immunology. 2005;26(11):587–595. doi: 10.1016/ [PubMed] [Cross Ref]
8. Gabrielli A., Svegliati S., Moroncini G., Avvedimento E. V. Pathogenic autoantibodies in systemic sclerosis. Current Opinion in Immunology. 2007;19(6):640–645. doi: 10.1016/j.coi.2007.11.004. [PubMed] [Cross Ref]
9. Hunzelmann N., Brinckmann J. What are the new milestones in the pathogenesis of systemic sclerosis? Annals of the Rheumatic Diseases. 2010;69(1):i52–i56. doi: 10.1136/ard.2009.117119. [PubMed] [Cross Ref]
10. Pattanaik D., Brown M., Postlethwaite B. C., Postlethwaite A. E. Pathogenesis of systemic sclerosis. Frontiers in Immunology. 2015;6, article no. 272 doi: 10.3389/fimmu.2015.00272. [PMC free article] [PubMed] [Cross Ref]
11. Rabquer B. J., Koch A. E. Angiogenesis and vasculopathy in systemic sclerosis: Evolving concepts. Current Rheumatology Reports. 2012;14(1):56–63. doi: 10.1007/s11926-011-0219-1. [PubMed] [Cross Ref]
12. Jimenez S. A. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. ISRN Rheumatology. 2013;2013:15. doi: 10.1155/2013/835948.835948 [PMC free article] [PubMed] [Cross Ref]
13. Lunardi C., Bason C., Navone R., et al. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nature Medicine. 2000;6(10):1183–1186. doi: 10.1038/80533. [PubMed] [Cross Ref]
14. Ahmed S. S., Tan F. K., Arnett F. C., Jin L., Geng Y.-J. Induction of apoptosis and fibrillin 1 expression in human dermal endothelial cells by scleroderma sera containing anti-endothelial cell antibodies. Arthritis & Rheumatology. 2006;54:2250–2262. doi: 10.1002/art.21952. [PubMed] [Cross Ref]
15. Kahaleh B. Vascular disease in scleroderma: mechanisms of vascular injury. Rheumatic Disease Clinics of North America. 2008;34(1):57–71. doi: 10.1016/j.rdc.2007.12.004. [PubMed] [Cross Ref]
16. Abraham D. J., Vancheeswaran R., Dashwood M. R., et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. American Journal of Pathology. 1997;151:831–841. [PubMed]
17. Bauer M., Wilkens H., Langer F., Schneider S. O., Lausberg H., Schäfers H.-J. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation. 2002;105(9):1034–1036. doi: 10.1161/hc0902.105719. [PubMed] [Cross Ref]
18. Cipriani P., Di Benedetto P., Ruscitti P., et al. The endothelial-mesenchymal transition in systemic sclerosis is induced by endothelin-1 and transforming growth factor-β and may be blocked by Macitentan, a dual endothelin-1 receptor antagonist. Journal of Rheumatology. 2015;42(10):1808–1816. doi: 10.3899/jrheum.150088. [PubMed] [Cross Ref]
19. Manetti M., Romano E., Rosa I., et al. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Annals of the Rheumatic Diseases. 2017;76:924–934. doi: 10.1136/annrheumdis-2016-210229. [PubMed] [Cross Ref]
20. Cipriani P., Di Benedetto P., Ruscitti P., et al. Macitentan inhibits the transforming growth factor-β profibrotic action, blocking the signaling mediated by the ETR/TβRI complex in systemic sclerosis dermal fibroblasts. Arthritis Research and Therapy. 2015;17:p. 247. doi: 10.1186/s13075-015-0754-7. [PMC free article] [PubMed] [Cross Ref]
21. Cipriani P., Marrelli A., Benedetto P. D., et al. Scleroderma Mesenchymal Stem Cells display a different phenotype from healthy controls; Implications for regenerative medicine. Angiogenesis. 2013;16(3):595–607. doi: 10.1007/s10456-013-9338-9. [PubMed] [Cross Ref]
22. Humbert M., Morrell N. W., Archer S. L., et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. Journal of the American College of Cardiology. 2004;43(12):13S–24S. doi: 10.1016/j.jacc.2004.02.029. [PubMed] [Cross Ref]
23. Guiducci S., Giacomelli R., Cerinic M. M. Vascular complications of scleroderma. Autoimmunity Reviews. 2007;6(8):520–523. doi: 10.1016/j.autrev.2006.12.006. [PubMed] [Cross Ref]
24. Nihtyanova S. I., Brough G. M., Black C. M., Denton C. P. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Annals of the Rheumatic Diseases. 2008;67(1):120–123. doi: 10.1136/ard.2007.072686. [PubMed] [Cross Ref]
25. Denton C. P., Lapadula G., Mouthon L., Müller-Ladner U. Renal complications and scleroderma renal crisis. Rheumatology, Oxford. 2009;48:iii32–iii35. doi: 10.1093/rheumatology/kep716. [PubMed] [Cross Ref]
26. Hinchcliff M., Desai C. S., Varga J., Shah S. J. Prevalence, prognosis, and factors associated with left ventricular diastolic dysfunction in systemic sclerosis. Clinical and Experimental Rheumatology. 2012;30:S30–S37. [PMC free article] [PubMed]
27. Cipriani P., Di Benedetto P., Ruscitti P., et al. Impaired endothelium-mesenchymal stem cells cross-talk in systemic sclerosis: a link between vascular and fibrotic features. Arthritis research & therapy. 2014;16:p. 442. doi: 10.1186/s13075-014-0442-z. [PMC free article] [PubMed] [Cross Ref]
28. Maruotti N., Cantatore F. P., Crivellato E., Vacca A., Ribatti D. Angiogenesis in rheumatoid arthritis. Histology and Histopathology. 2006;21:557–566. [PubMed]
29. Maruotti N., Cantatore F. P., Nico B., Vacca A., Ribatti D. Angiogenesis in vasculitides. Clinical and Experimental Rheumatology. 2008;26:476–483. [PubMed]
30. Liakouli V., Cipriani P., Marrelli A., Alvaro S., Ruscitti P., Giacomelli R. Angiogenic cytokines and growth factors in systemic sclerosis. Autoimmunity Reviews. 2011;10(10):590–594. doi: 10.1016/j.autrev.2011.04.019. [PubMed] [Cross Ref]
31. Distler O., Del Rosso A., Giacomelli R. Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Research. 2002;4:p. R11. doi: 10.1186/ar596. [PMC free article] [PubMed] [Cross Ref]
32. Macko R. F., Gelber A. C., Young B. A., et al. Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation. The Journal of Rheumatology. 2002;29(12):2565–2570. [PubMed]
33. Giusti B., Fibbi G., Margheri F., et al. A model of anti-angiogenesis: Differential transcriptosome profiling of microvascular endothelial cells from diffuse systemic sclerosis patients. Arthritis Research and Therapy. 2006;8:p. R115. doi: 10.1186/ar2002. [PMC free article] [PubMed] [Cross Ref]
34. Mulligan-Kehoe M. J., Drinane M. C., Mollmark J., et al. Antiangiogenic plasma activity in patients with systemic sclerosis. Arthritis & Rheumatology. 2007;56:3448–3458. doi: 10.1002/art.22861. [PubMed] [Cross Ref]
35. Cipriani P., Di Benedetto P., Dietrich H., et al. Searching for a good model for systemic sclerosis: The molecular profile and vascular changes occurring in UCD-200 chickens strongly resemble the early phase of human systemic sclerosis. Archives of Medical Science. 2016;12(4):828–843. doi: 10.5114/aoms.2016.60970. [PMC free article] [PubMed] [Cross Ref]
36. İlgen U., Yayla M. E., Düzgün N. Low serum fibroblast growth factor 2 levels not accompanied by increased serum pentraxin 3 levels in patients with systemic sclerosis. Clinical Rheumatology. 2016:1–6. doi: 10.1007/s10067-016-3483-7. [PubMed] [Cross Ref]
37. Bielecki M., Kowal K., Lapinska A., Chwiesko-Minarowska S., Chyczewski L., Kowal-Bielecka O. Peripheral blood mononuclear cells from patients with systemic sclerosis spontaneously secrete increased amounts of vascular endothelial growth factor (VEGF) already in the early stage of the disease. Advances in Medical Sciences. 2011;56(2):255–263. doi: 10.2478/v10039-011-0025-z. [PubMed] [Cross Ref]
38. Maurer B., Distler A., Yossra A Suliman, et al. Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Annals of the Rheumatic Diseases. 2013 doi: 10.1136/annrheumdis-2013-203535. [PubMed] [Cross Ref]
39. Manetti M., Guiducci S., Romano E., et al. Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circulation Research. 2011;109(3):e14–e26. doi: 10.1161/circresaha.111.242057. [PubMed] [Cross Ref]
40. Hirigoyen D., Burgos P. I., Mezzano V., et al. Inhibition of angiogenesis by platelets in systemic sclerosis patients. Arthritis Research & Therapy. 2015;17:p. 332. doi: 10.1186/s13075-015-0848-2. [PMC free article] [PubMed] [Cross Ref]
41. Giusti B., Serrati S., Margheri F., et al. The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. Arthritis & Rheumatology. 2005;52:3618–3628. doi: 10.1002/art.21383. [PubMed] [Cross Ref]
42. Michalska-Jakubus M., Kowal-Bielecka O., Chodorowska G., Bielecki M., Krasowska D. Angiopoietins-1 and -2 are differentially expressed in the sera of patients with systemic sclerosis: High angiopoietin-2 levels are associated with greater severity and higher activity of the disease. Rheumatology. 2011;50(4):746–755. doi: 10.1093/rheumatology/keq392.keq392 [PubMed] [Cross Ref]
43. Almeida I., Gomes A. O., Lima M., Silva I., Vasconcelos C. Different contributions of angiostatin and endostatin in angiogenesis impairment in systemic sclerosis: A cohort study. Clinical and Experimental Rheumatology. 2016;34:37–42. [PubMed]
44. Cipriani P., Milia A. F., Liakouli V., et al. Differential expression of stromal cell-derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications. Arthritis and Rheumatism. 2006;54:3022–3033. doi: 10.1002/art.22047. [PubMed] [Cross Ref]
45. Mackiewicz Z., Sukura A., Povilenaité D., et al. Increased but imbalanced expression of VEGF and its receptors has no positive effect on angiogenesis in systemic sclerosis skin. Clinical and Experimental Rheumatology. 2002;20:641–646. [PubMed]
46. Distler O., Distler J. H. W., Scheid A., et al. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circulation Research. 2004;95(1):109–116. doi: 10.1161/01.RES.0000134644.89917.96. [PubMed] [Cross Ref]
47. Davies C. A., Jeziorska M., Freemont A. J., Herrick A. L. The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Human Pathology. 2006;37(2):190–197. doi: 10.1016/j.humpath.2005.10.007. [PubMed] [Cross Ref]
48. Avouac J., Wipff J., Goldman O., et al. Angiogenesis in systemic sclerosis: Impaired expression of vascular endothelial growth factor receptor 1 in endothelial progenitor-derived cells under hypoxic conditions. Arthritis & Rheumatology. 2008;58:3550–3561. doi: 10.1002/art.23968. [PubMed] [Cross Ref]
49. Higashi-Kuwata N., Makino T., Inoue Y., Ihn H. Expression pattern of VEGFR-1, -2, -3 and D2-40 protein in the skin of patients with systemic sclerosis. European Journal of Dermatology. 2011;21:490–494. doi: 10.1684/ejd.2011.1284. [PubMed] [Cross Ref]
50. Carulli M. T., Ong V. H., Ponticos M., et al. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: Evidence for autocrine regulation of myofibroblast differentiation. Arthritis & Rheumatology. 2005;52:3772–3782. doi: 10.1002/art.21396. [PubMed] [Cross Ref]
51. Rabquer B. J., Tsou P.-S., Hou Y., et al. Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis. Arthritis Research & Therapy. 2011;13:p. R18. doi: 10.1186/ar3242. [PMC free article] [PubMed] [Cross Ref]
52. Tsou P.-S., Rabquer B. J., Ohara R. A., et al. Scleroderma dermal microvascular endothelial cells exhibit defective response to pro-angiogenic chemokines. Rheumatology (Oxford, England) 2016;55(4):745–754. doi: 10.1093/rheumatology/kev399. [PMC free article] [PubMed] [Cross Ref]
53. Toyama T., Asano Y., Miyagawa T., et al. The impact of transcriptional factor Fli1 deficiency on the regulation of angiogenesis. Experimental Dermatology. 2017 doi: 10.1111/exd.13341. [PubMed] [Cross Ref]
54. Reich N., Maurer B., Akhmetshina A., et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis & Rheumatology. 2010;62:280–290. doi: 10.1002/art.25056. [PubMed] [Cross Ref]
55. Kubo M., Czuwara-Ladykowska J., Moussa O., et al. Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. American Journal of Pathology. 2003;163:571–581. doi: 10.1016/S0002-9440(10)63685-1. [PubMed] [Cross Ref]
56. Asano Y. Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis. International Journal of Biochemistry & Cell Biology. 2015;67:86–91. doi: 10.1016/j.biocel.2015.06.004. [PubMed] [Cross Ref]
57. Hou Y., Rabquer B. J., Gerber M. L., et al. Junctional adhesion molecule-A is abnormally expressed in diffuse cutaneous systemic sclerosis skin and mediates myeloid cell adhesion. Annals of the Rheumatic Diseases. 2010;69(1):249–254. doi: 10.1136/ard.2008.102624. [PMC free article] [PubMed] [Cross Ref]
58. D'Alessio S., Fibbi G., Cinelli M., et al. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis & Rheumatology. 2004;50:3275–3285. doi: 10.1002/art.20562. [PubMed] [Cross Ref]
59. Margheri F., Manetti M., Serratì S. Domain 1 of the urokinase-type plasminogen activator receptor is required for its morphologic and functional, β2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: Failure of association in systemic sclerosis endothelial cells. Arthritis and Rheumatism. 2006;54:3926–3938. doi: 10.1002/art.22263. [PubMed] [Cross Ref]
60. Dean R. A., Cox J. H., Bellac C. L., Doucet A., Starr A. E., Overall C. M. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR + CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: Potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood. 2008;112(8):3455–3464. doi: 10.1182/blood-2007-12-129080. [PubMed] [Cross Ref]
61. Manetti M., Ibba-Manneschi L., Fatini C., et al. Association of a functional polymorphism in the matrix metalloproteinase-12 promoter region with systemic sclerosis in an Italian population. Journal of Rheumatology. 2010;37(9):1852–1857. doi: 10.3899/jrheum.100237. [PubMed] [Cross Ref]
62. Manetti M., Allanore Y., Revillod L., et al. A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. Arthritis & Rheumatology. 2011;63:247–256. doi: 10.1002/art.30101. [PubMed] [Cross Ref]
63. Tsou P.-S., Wren J. D., Amin M. A., et al. Histone deacetylase 5 is overexpressed in scleroderma endothelial cells and impairs angiogenesis via repression of proangiogenic factors. Arthritis & Rheumatology. 2016;68:2975–2985. doi: 10.1002/art.39828. [PMC free article] [PubMed] [Cross Ref]
64. Kusaba T., Okigaki M., Matui A., et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+channel to maintain endothelial integrity. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(45):19308–19313. doi: 10.1073/pnas.1008544107. [PubMed] [Cross Ref]
65. Mazzotta C., Manetti M., Rosa I., et al. Proangiogenic effects of soluble a-Klotho on systemic sclerosis dermal microvascular endothelial cells. Arthritis Research & Therapy. 2017;19:p. 27. doi: 10.1186/s13075-017-1233-0. [PMC free article] [PubMed] [Cross Ref]
66. Mazzotta C., Romano E., Bruni C., et al. Plexin-D1/Semaphorin 3E pathway may contribute to dysregulation of vascular tone control and defective angiogenesis in systemic sclerosis. Arthritis Research & Therapy. 2015;17:p. 221. doi: 10.1186/s13075-015-0749-4. [PMC free article] [PubMed] [Cross Ref]
67. Romano E., Chora I., Manetti M., et al. Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis. Annals of the Rheumatic Diseases. 2015 doi: 10.1136/annrheumdis-2015-207483. [PubMed] [Cross Ref]
68. Cipriani P., Di Benedetto P., Liakouli V., et al. Mesenchymal stem cells (MSCs) from scleroderma patients (SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells (Tregs) with a functional phenotype: implications for cellular-based therapy. Clinical and Experimental Immunology. 2013;173(2):195–206. doi: 10.1111/cei.12111. [PubMed] [Cross Ref]
69. Oswald J., Boxberger S., Jørgensen B., et al. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004;22(3):377–384. doi: 10.1634/stemcells.22-3-377. [PubMed] [Cross Ref]
70. Del Papa N., Caviggioli F., Sambataro D., et al. Autologous fat grafting in the treatment of fibrotic perioral changes in patients with systemic sclerosis. Cell Transplantation. 2015;24(1):63–72. doi: 10.3727/096368914X674062. [PubMed] [Cross Ref]
71. Takahashi M. Adipose tissue: - An alternative source for therapeutic angiogenesis. Circulation Journal. 2012;76(7):1597–1598. doi: 10.1253/circj.CJ-12-0641. [PubMed] [Cross Ref]
72. Yi T., Song S. U. Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Archives of Pharmacal Research. 2012;35(2):213–221. doi: 10.1007/s12272-012-0202-z. [PubMed] [Cross Ref]
73. Fang F., Liu L., Yang Y., et al. The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy. Arthritis Research and Therapy. 2012;14, article R229 doi: 10.1186/ar4070. [PMC free article] [PubMed] [Cross Ref]

Articles from BioMed Research International are provided here courtesy of Hindawi Limited