Decreased circulating lymphatic endothelial progenitor cells in digital ulcer-complicated systemic sclerosis

Manetti, Mirko; Pratesi, Sara; Romano, Eloisa; Rosa, Irene; Bruni, Cosimo; Bellando-Randone, Silvia; Guiducci, Serena; Maggi, Enrico; Ibba‐Manneschi, Lidia; Matucci‐Cerinic, Marco

doi:10.1136/annrheumdis-2018-214240

Cited by 11 publications

(10 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Actually, we found that both mRNA and protein levels of VEGFR-3/Flt-4 were strongly downregulated in LMVECs challenged with SSc serum, compared with healthy serum-treated cells, which suggests that an impaired VEGFR-3/Flt-4-mediated signaling could be largely responsible for the observed dysfunctional lymphangiogenesis. Interestingly, a similar decrease in the expression of VEGFR-3/Flt-4 that likely contributes to a defective lymphangiogenic/lymphvasculogenic function has previously been reported in circulating lymphatic endothelial progenitor cells from SSc patients with severe peripheral vascular disease [13]. Increased VEGFR3/FLT4 transcript levels have instead been revealed in SSc skin biopsies [20], though it should be considered that in pathologic conditions the expression of this receptor is not restricted to the lymphatic endothelium, but is found also in blood vascular endothelial cells and cells of the monocyte/macrophage lineage [37][38][39][40].…”

Section: Discussionsupporting

confidence: 73%

“…The ensuing inflammatory response and fibrotic process may then aggravate microlymphatic damage in a vicious circle, similar to that occurring in chronic venous insufficiency; this further impairs skin tissue homeostasis and eventually culminates in dystrophic changes like digital ulcers [5,10,12]. In SSc, it has also recently been proposed that a deficiency in repair mechanisms might prevent lymphatic microcirculation recovery and possibly exacerbate even more lymphatic microvascular injury [13]. In particular, an impairment of lymphvasculogenesis due to a reduction in the number of circulating bone marrow-derived lymphatic endothelial progenitor cells has been reported in SSc patients with digital ulcers [13].…”

Section: Introductionmentioning

confidence: 99%

“…In SSc, it has also recently been proposed that a deficiency in repair mechanisms might prevent lymphatic microcirculation recovery and possibly exacerbate even more lymphatic microvascular injury [13]. In particular, an impairment of lymphvasculogenesis due to a reduction in the number of circulating bone marrow-derived lymphatic endothelial progenitor cells has been reported in SSc patients with digital ulcers [13].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence

Manetti

Romano

Rosa

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

In systemic sclerosis (SSc), the possible involvement of lymphatic microcirculation and lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on dysfunctional blood vascular system and angiogenesis. In the present in vitro study, we explore for the first time whether the SSc microenvironment may interfere with lymphangiogenesis, a complex, multi-step process in which lymphatic microvascular endothelial cells (LMVECs) sprout, migrate, and proliferate to generate new lymphatic capillaries. Normal human adult dermal LMVECs from three donors were treated with serum from SSc patients (n = 8), serum from healthy individuals (n = 8), or recombinant human vascular endothelial growth factor (VEGF)-C as a positive control for lymphangiogenesis. Cell proliferation, Boyden chamber Matrigel chemoinvasion, wound healing capacity, and lymphatic capillary morphogenesis on Geltrex were assayed. VEGF-C serum levels were measured by enzyme-linked immunosorbent assay. Gene and protein expression levels of the lymphangiogenic orchestrators VEGF receptor-3 (VEGFR-3)/Flt-4 and neuropilin-2 (NRP-2) were determined by real-time PCR and Western blotting, respectively. Conditioning with SSc serum significantly inhibited LMVEC proliferation, Matrigel invasion, and wound healing capacity with respect to healthy serum. The ability of LMVECs to form lymphatic tubes on Geltrex was also severely compromised in the presence of SSc serum. VEGF-C levels were comparable in SSc and healthy sera. Treatment with SSc serum resulted in a significant downregulation of both VEGFR-3/Flt-4 and NRP-2 mRNA and protein levels. In SSc, the pathologic environment severely hampers every lymphangiogenesis step, likely through the reduction of pro-lymphangiogenic VEGFR-3/NRP-2 co-receptor signaling. The impairment of the lymphangiogenic process opens a new scenario underlying SSc vascular pathophysiology, which is worth investigating further.

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence

Manetti

Romano

Rosa

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Early endothelial cell involvement in SSc, leads to the destruction of blood capillaries with reduction in microvasculature through vascular repair and defective neoangiogenesis simultaneously with impaired lymphatic circulation followed by exudative accumulation and edema formation. Associations between lymphatic microvasculature damage with digital ulcer development and accentuation of cutaneous induration were observed, an induration which must be differentiated from that which appears in other disorders with sclerodermiform skin lesions, occurring in isolation or in the context of associated autoimmune diseases (12)(13)(14).…”

Section: Introductionmentioning

confidence: 91%

Dynamics of digital ulcers in systemic sclerosis

et al. 2020

View full text Add to dashboard Cite

Systemic sclerosis (SSc) is a collagenosis with insufficiently known etiopathogenesis, characterized by microvasculopathy and excessive fibrosis in the context of an autoimmune disorder. The incompletely elucidated pathogenesis and limited therapeutic options, disabling aspects, skin lesions and pain determine important functional and psychological deficiencies which affect the quality of life. It is imperative to observe and correlate individual clinical and paraclinical data to optimize disease management. A group of 22 patients diagnosed with SSc, hospitalized in a university clinic in Bucharest was included in an observational study. The evolution of digital ulcers was evaluated as an indicator of vasculopathy and their status and dynamics were correlated with clinical elements reflecting the fibrotic aspect of the disease. The present study shows that the Raynaud phenomenon is almost always present during the course of the disease, but its presence is not always associated with digital ulcers. The existing data in the literature show that fibrosis is subsequent to vasculopathy, but this study did not reveal causality between these two aspects of pathogenesis. The presence of microstomia and digital contracture was identified in the presence of digital ulcers, but also in their absence. The etiopathogenic mechanisms with multiple unknown involved factors open the opportunity to investigate many aspects of SSc for optimal aiming of therapeutic interventions.

show abstract

“…Neoangiogenesis and a faulty vascular repair mechanism affect both blood capillaries and lymphatic vessels, leading to edema. 112 Newer studies have shown that angiogenesis is promoted by high levels of endothelin-1 (ET-1). Also, it was observed that microangiopathy is associated with a high level of vascular endothelial growth factor A (VEGF-A).…”

Section: Discussionmentioning

confidence: 99%

Interrelationship and Sequencing of Interleukins4, 13, 31, and 33 – An Integrated Systematic Review: Dermatological and Multidisciplinary Perspectives

Tatu¹,

Nadasdy²,

Arbune³

et al. 2022

JIR

View full text Add to dashboard Cite

The interrelations and sequencing of interleukins are complex (inter)actions where each interleukin can stimulate the secretion of its preceding interleukin. In this paper, we attempt to summarize the currently known roles of IL-4, IL-13, IL-31, and IL-33 from a multi-disciplinary perspective. In order to conduct a comprehensive review of the current literature, a search was conducted using PubMed, Google Scholar, Medscape, UpToDate, and Key Elsevier for keywords. The results were compiled from case reports, case series, letters, and literature review papers, and analyzed by a panel of multi-disciplinary specialist physicians for relevance. Based on 173 results, we compiled the following review of interleukin signaling and its clinical significance across a multitude of medical specialties. Interleukins are at the bed rock of a multitude of pathologies across different organ systems and understanding their role will likely lead to novel treatments and better outcomes for our patients. New interleukins are being described, and the role of this inflammatory cascade is still coming to light. We hope this multi-discipline review on the role interleukins play in current pathology assists in this scope.

show abstract

Decreased circulating lymphatic endothelial progenitor cells in digital ulcer-complicated systemic sclerosis

Cited by 11 publications

References 8 publications

Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence

Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence

Dynamics of digital ulcers in systemic sclerosis

Interrelationship and Sequencing of Interleukins4, 13, 31, and 33 – An Integrated Systematic Review: Dermatological and Multidisciplinary Perspectives

Contact Info

Product

Resources

About