Endothelial Dysfunction in Systemic Sclerosis

Abstract

Systemic sclerosis, commonly known as scleroderma, is an autoimmune disorder characterized by vascular abnormalities, autoimmunity, and multiorgan fibrosis. The exact etiology is not known but believed to be triggered by environmental agents in a genetically susceptible host. Vascular symptoms such as the Raynaud phenomenon often precede other fibrotic manifestations such as skin thickening indicating that vascular dysfunction is the primary event. Endothelial damage and activation occur early, possibly triggered by various infectious agents and autoantibodies. Endothelial dysfunction, along with defects in endothelial progenitor cells, leads to defective angiogenesis and vasculogenesis. Endothelial to mesenchymal cell transformation is another seminal event during pathogenesis that progresses to tissue fibrosis. The goal of the review is to discuss the molecular aspect of the endothelial dysfunction that leads to the development of systemic sclerosis.

Association between systemic sclerosis and risk of cerebrovascular and cardiovascular disease: a meta-analysis

“…First, SSc is characterized by chronic inflammation, autoimmunity, and vascular injury 1 , 2 , which accelerate atherosclerosis and coronary artery disease. Second, endothelial dysfunction and impaired vascular repair, the hallmarks of SSc, also promote atherosclerosis 38 , 39 . Third, the progression of peripheral microvasculopathy, a key element in SSc pathogenesis, may further contribute to arterial stiffening and myocardial damage over time 40 .…”

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again

“…Patients with SSc experience a similar loss of microvascular ECs and EC dysfunction. In particular, defective angiogenesis, defective vasculogenesis, and EndoMT have all been implicated in the pathogenesis of SSc and SSc-PAH [91]. The specific subtypes of endothelial cells which are lost in SSc and the proliferation or persistence of other endothelial cell types is an area which is actively being studied, and analysis of single-cell RNA sequencing studies will likely highlight important endothelial subtypes and gene expression patterns which make SSc-PAH endothelium uniquely susceptible to PH.…”

Fibroblasts and Endothelial Cells in Three-Dimensional Models: A New Tool for Addressing the Pathogenesis of Systemic Sclerosis as a Prototype of Fibrotic Vasculopathies

“…They include vascular alterations, such as nail fold capillary changes, digital ulcers due to ischemic injury, cutaneous microvascular dysfunction, and progressive fibrosis, which predicts early internal organ involvement. SSc’s unique feature is that vascular dysfunctions and disease-specific autoantibodies precede fibrosis [ 18 , 19 , 20 , 21 ]. Although the pathogenic mechanisms of this complex disease are not completely understood yet, fibroblasts and endothelial cells (ECs) are deemed key players.…”