New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Abstract

In systemic sclerosis (SSc), abnormalities in microvessel morphology occur early and evolve into a distinctive vasculopathy that relentlessly advances in parallel with the development of tissue fibrosis orchestrated by myofibroblasts in nearly all affected organs. Our knowledge of the cellular and molecular mechanisms underlying such a unique relationship between SSc-related vasculopathy and fibrosis has profoundly changed over the last few years. Indeed, increasing evidence has suggested that endothelial-to-mesenchymal transition (EndoMT), a process in which profibrotic myofibroblasts originate from endothelial cells, may take center stage in SSc pathogenesis. While in arterioles and small arteries EndoMT may lead to the accumulation of myofibroblasts within the vessel wall and development of fibroproliferative vascular lesions, in capillary vessels it may instead result in vascular destruction and formation of myofibroblasts that migrate into the perivascular space with consequent tissue fibrosis and microvessel rarefaction, which are hallmarks of SSc. Besides endothelial cells, other vascular wall-resident cells, such as pericytes and vascular smooth muscle cells, may acquire a myofibroblast-like synthetic phenotype contributing to both SSc-related vascular dysfunction and fibrosis. A deeper understanding of the mechanisms underlying the differentiation of myofibroblasts inside the vessel wall provides the rationale for novel targeted therapeutic strategies for the treatment of SSc.

Downregulation of Vascular Hemeoxygenase-1 Leads to Vasculopathy in Systemic Sclerosis

“…Saliently, the initiation of endothelial dysfunction occurring in PAH, by which a particular population of ECs undergo EndoMT and become resistant to apoptosis ( Good et al, 2015 ; Gorelova et al, 2021 ), resembles the same events described regarding ECs dysfunction in skin microvasculature in the early stages of SSc ( Manetti et al, 2017 ; Romano et al, 2021 ). This suggests that the molecular changes occurring in endothelial cells from skin vasculature in the early stages of SSc are critical to the pathogenesis of PAH associated with SSc (SSc-PAH), and potentially preventing these events could stop the subsequent development of PAH.…”

“…Endothelial cell (EC) damage is a key early process in SSc, which precedes fibrosis and involves phenotypic changes in ECs present in arterioles of skin microvasculature, where a population of ECs undergo endothelial-mesenchymal transition (EndoMT), leading to accumulation of myofibroblasts within the vessel wall and subsequent development of vasculopathy ( Pattanaik et al, 2015 ; Romano et al, 2021 ). Vasculopathy is characterised by oxidative stress (OXS), inflammation, vasoreactivity, fibrotic intima hyperplasia, impaired neoangeogenesis with a gradual obliteration of vessels, and decline in capillary density ( Abraham and Distler, 2007 ; Kahaleh, 2008 ; Ladak and Pope, 2016 ).…”

Microvasculopathy-Related Hemorrhagic Tissue Deposition of Iron May Contribute to Fibrosis in Systemic Sclerosis: Hypothesis-Generating Insights from the Literature and Preliminary Findings

“…The transformation of endothelial cells in profibrotic myofibroblasts also seems to be integral for SSc-related fibrosis [ 6 , 8 , 10 , 50 ], since cells undergoing EndoMT were detected in the skin vessels of SSc patients, as well as in animal models of SSc (bleomycin-induced fibrosis/urokinase-type plasminogen activator receptor (uPAR)-deficient mice) [ 6 ]. Similar to endothelial cells, the treatment of human lung fibroblasts with ferric ammonium citrate increased proinflammatory and extracellular matrix gene expression [ 23 ].…”

“…Moreover, vascular endothelial cells may become transformed through endothelial-to-mesenchymal transition (EndoMT) to profibrotic myofibroblasts [ 6 ], which are thought to orchestrate fibrosis [ 7 , 8 ]. Thus, the fibrotic process of the skin and internal organs, which becomes clinically evident months to years after Raynaud’s onset, is considered to be driven by the chronic vascular injury/repair process and a concomitant (auto)immune activation [ 9 , 10 ].…”

Therapeutic Options for Systemic Sclerosis: Current and Future Perspectives in Tackling Immune-Mediated Fibrosis

“…Myofibroblasts are a strongly pro-fibrotic cell type which produces large amounts of extracellular matrix (ECM) molecules and matrix-strengthening enzymes. Furthermore, these cells also excrete growth factors and cytokines that worsen inflammation [ 9 ]. IL-4, IL-6, and transforming growth factor (TGF)-β are the predominant fibrogenic cytokines that cause subendothelial accumulation of fibrous tissue, leading to aberrant vascular remodeling [ 10 ].…”