Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis

Abstract

The pathogenesis of Systemic Sclerosis (SSc) is extremely complex, and despite extensive studies, the exact mechanisms involved are not well understood. Numerous recent studies of early events in SSc pathogenesis have suggested that unknown etiologic factors in a genetically receptive host trigger structural and functional microvascular endothelial cell abnormalities. These alterations result in the attraction, transmigration, and accumulation of immune and inflammatory cells in the perivascular tissues, which in turn induce the phenotypic conversion of endothelial cells and quiescent fibroblasts into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndoMT. The activated myofibroblasts are the effector cells responsible for the severe and frequently progressive fibrotic process and the fibroproliferative vasculopathy that are the hallmarks of SSc. Thus, according to this hypothesis the endothelial and vascular alterations, which include the phenotypic conversion of endothelial cells into activated myofibroblasts, play a crucial role in the development of the progressive fibrotic process affecting skin and multiple internal organs. The role of endothelial cell and vascular alterations, the potential contribution of endothelial to mesenchymal cell transition in the pathogenesis of the tissue fibrosis, and fibroproliferative vasculopathy in SSc will be reviewed here.

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

“…Consistent with this notion, IRF5 bound the promoters of the CDH5 and PDGFB genes encoding key molecules-VEcadherin and PDGF-B, respectively-regulating vascular stabilization and angiogenesis. Because of its involvement in mechanisms connecting vascular activation and tissue fibrosis, EndoMT is a critical pathological event in human and murine models of SSc (25,26). Because the loss of Irf5 decreased the number of double-positive cells for FSP1 and VE-cadherin in the perivascular region of BLM-treated skin, IRF5 is implicated as a critical regulator of EndoMT, as also was confirmed by IRF5 binding to the SNAIL1 promoter.…”

Upregulation of the N-Formyl Peptide Receptors in Scleroderma Fibroblasts Fosters the Switch to Myofibroblasts

“…Then, we investigated the expression of a-SMA, a typical marker of myofibroblast phenotype (8). Western blot analysis, using a specific Ab against a-SMA, showed an increased expression in cell lysates from SSc fibroblasts as compared with control (fold increase SSc fibroblasts vs normal cells: 2.97; p , 0.05) (Fig.…”

“…Effects of ATF-uPA, uPAR [84][85][86][87][88][89][90][91][92][93][94][95] , and WKYMVm on human skin fibroblast chemotaxis and adhesion Chemotaxis contributes to fibrosis by allowing recruitment of fibroblasts, macrophages, and PBMCs to sites of tissue injury (8). FPRs are chemotaxis receptors (11); therefore, we first tested the capability of different FPRs agonists to induce directional migration of normal and sclerotic fibroblasts to investigate a possible role of these receptors in some phases of the disease.…”

“…Consequently, fibroblasts acquire a mesenchymal or myofibroblast phenotype, expressing its typical markers, such as a-smooth muscle actin (a-SMA), vimentin, and types I and III interstitial collagens. Besides the acquisition of an activated profibrogenic phenotype, these cells also become motile and capable of migrating into surrounding tissues (8). Today, the EndoMT process is gaining increased attention in fibrotic disorders, although only few experimental evidences support the participation of EndoMT in the pathogenesis of SSc (8).…”

“…FPR2 is a promiscuous receptor activated in response to high concentration of fMLF, viral, bacterial, endogenous, and synthetic peptides (12). Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) (14), and F2L (15) are natural ligands for FPR3. The synthetic peptide WKYMVm (11) is an FPR panagonist.…”