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In response to: Autologous Mesenchymal Stem Cells Foster Revascularization of Ischemic Limbs in Systemic Sclerosis
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Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis
No full textSystemic sclerosis (SSc, scleroderma) is a chronic, multisystem connective tissue disorder affecting the skin and various internal organs. Although the disease is characterized by a triad of widespread microangiopathy, fibrosis, and autoimmunity, increasing evidence indicates that vascular damage is a primary event in the pathogenesis of SSc. The progressive vascular injury includes persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These profound vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration or amputation, pulmonary arterial hypertension, and scleroderma renal crisis. The resulting tissue hypoxia induces complex cellular and molecular mechanisms in the attempt to recover endothelial cell function and tissue perfusion. Nevertheless, in SSc patients there is no evidence of significant angiogenesis and the disease evolves towards chronic tissue ischemia, with progressive and irreversible structural changes in multiple vascular beds culminating in the loss of capillaries. A severe imbalance between pro-angiogenic and angiostatic factors may also lead to impaired angiogenic response during SSc. Besides insufficient angiogenesis, defective vasculogenesis with altered numbers and functional defects of bone marrow-derived endothelial progenitor cells may contribute to the vascular pathogenesis of SSc. The purpose of this article is to review the contribution of recent studies to the understanding of the complex mechanisms of impaired vascular repair in SSc. Indeed, understanding the pathophysiology of SSc-associated vascular disease may be the key in dissecting the disease pathogenesis and developing novel therapies. Either angiogenic or vasculogenic mechanisms may potentially become in the future the target of therapeutic strategies to promote capillary regeneration in SSc
Pathophysiology of Hemophilic Arthropathy
Full text linkSpontaneous joint bleeding and repeated hemarthroses lead to hemophilic arthropathy—a debilitating disease with a significant negative impact on mobility and quality of life. Iron, cytokines, and angiogenic growth factors play a pivotal role in the onset of the inflammatory process that involves the synovial tissue, articular cartilage, and subchondral bone, with early damages and molecular changes determining the perpetuation of a chronic inflammatory condition. Synovitis is one of the earliest complications of hemarthrosis, and is characterized by synovial hypertrophy, migration of inflammatory cells, and a high degree of neo-angiogenesis with subsequent bleeding. The pathogenic mechanisms and molecular pathways by which blood in the joint cavity causes articular cartilage and subchondral bone destruction have yet to be fully elucidated. Both cytokines and matrix metalloproteinases and hydroxyl radicals may induce chondrocyte apoptosis. Members of the tumor necrosis factor receptor superfamily (such as the molecular triad: osteoprotegerin—OPG; receptor activator of nuclear factor κB—RANK; RANK ligand—RANKL) seem instead to play a major role in the inflammatory process. These pathogenic processes interact with each other and ultimately lead to a fibrotic joint and the disabling condition characteristic of hemophilic arthropathy
The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem?
Full text linkIn 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
The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?
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Adipose-derived stem cells: Pathophysiologic implications vs therapeutic potential in systemic sclerosis
Full text linkAdipose-derived stem cells (ADSCs) residing in the stromal vascular fraction (SVF) of white adipose tissue are recently emerging as an alternative tool for stem cell-based therapy in systemic sclerosis (SSc), a complex connective tissue disorder affecting the skin and internal organs with fibrotic and vascular lesions. Several preclinical and clinical studies have reported promising therapeutic effects of fat grafting and autologous SVF/ADSC-based local treatment for facial and hand cutaneous manifestations of SSc patients. However, currently available data indicate that ADSCs may represent a double-edged sword in SSc, as they may exhibit a pro-fibrotic and anti-adipogenic phenotype, possibly behaving as an additional pathogenic source of pro-fibrotic myofibroblasts through the adipocyte-to-myofibroblast transition process. Thus, in the perspective of a larger employ of SSc-ADSCs for further therapeutic applications, it is important to definitely unravel whether these cells present a comparable phenotype and similar immunosuppressive, anti-inflammatory, anti-fibrotic and pro-angiogenic properties in respect to healthy ADSCs. In light of the dual role that ADSCs seem to play in SSc, this review will provide a summary of the most recent insights into the preclinical and clinical studies employing SVF and ADSCs for the treatment of the disease and, at the same time, will focus on the main findings highlighting the possible involvement of these stem cells in SSc-related fibrosis pathogenesis
A new avenue in the pathogenesis of systemic sclerosis: the molecular interface between the endothelial and the nervous systems
No full textSystemic sclerosis (SSc) is a connective tissue disorder characterised by immune dysregulation, endothelial cell dysfunction followed by defective vascular repair and neovascularization and progressive tissue fibrosis of the skin and internal organs, whose pathophysiology remains to be fully elucidated. Perturbed neuroendothelial control mechanisms comprising either endothelial cell or peripheral nerve fiber impairment are supposed to play an important role in the onset of Raynaud's phenomenon and development of microvascular abnormalities which are the earliest events and key features of SSc. Such pathogenic neuroendothelial mechanisms may trigger both the early endothelial cell damage and the subsequent loss of peripheral microvascular integrity characterised by the lack of compensatory angiogenesis. Of note, the vascular and nervous systems have several anatomical similarities that extend to molecular level, and the molecular mechanisms of nerve regulation are shared by the vascular system. In this context, increasing evidence demonstrated that endothelial cells express receptors for axon guidance molecules, including Ephrin family receptor tyrosine kinases, Neuropilins, Plexins, Robos, and UNC5B that are able to respond to their soluble neuroendothelial trophic ligands, such as Semaphorins and Slits, to guide the sprouting of endothelial tip cells. Here, we first provide a historical view of neuroendothelial control mechanism alterations in the pathogenesis of SSc, and then discuss the emerging role of a class of molecules sharing neurogenic and angiogenic properties, such as members of Semaphorin/Plexin/Neuropilin and Slit/Roundabout families, in SSc-related peripheral microvasculopathy
Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis
No full textDifferential expression of junctional adhesion molecules in systemic sclerosis (SSc) skin
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