Endoglin and Systemic Sclerosis: A PRISMA-driven systematic review

Abstract

BackgroundSystemic Sclerosis (SSc) is a rare autoimmune disease whose pathogenesis is still poorly understood. The Transforming Growth Factor β superfamily is considered pivotal and a crucial role has been suggested for the type III receptor, Endoglin (ENG). The aim of this systematic review is to investigate and combine the current clinical and molecular available data, to suggest novel hints for further studies.MethodsWe followed PRISMA guidelines; the search was performed on three databases (MEDLINE, Web of Science, Embase) in date November 2nd, 2021. Subsequent to the exclusion of duplicates, we applied as inclusion criteria: 1. focus on the relationship between ENG and SSc; 2. English language. As exclusion criteria: 1. ENG exclusively as a cellular biomarker; 2. no focus on ENG-SSc relationship; 3. review articles and 4. abstracts that did not add novel data. Eligibility was assessed independently by each author to reduce biases. We divided records into clinical and molecular works and subgrouped them by their study features and aim.ResultsWe selected 25 original papers and 10 conference abstracts. Molecular studies included 6 articles and 4 abstracts, whereas clinical studies included 17 articles and 6 abstracts; 2 articles presented both characteristics. Molecular studies were focussed on ENG expression in different cell types, showing an altered ENG expression in SSc-affected cells. Clinical studies mainly suggested that different disease phenotypes can be related to peculiar disregulations in soluble ENG concentrations.DiscussionConcerning the possible limits of our search, boolean operators in our strings might have been uneffective. However, the use of different strings in different databases should have reduced this issue at a minimum. Another bias can be represented by the selection step, in which we excluded many articles based on the role of Endoglin as a histological vascular marker rather than a signaling receptor. We tried to reduce this risk by performing the selection independently by each author and discussing disagreements. Our systematic review pointed out that ENG has a pivotal role in activating different TGFβ-stimulated pathways that can be crucial in SSc pathogenesis and progression.

Biomarkers in Systemic Sclerosis: An Overview

“…Local secretion of the von Willebrand factor causes platelet aggregation, hypercoagulability, and fibrin deposition leading to terminal vascular injury [126][127][128][129][130][131][132][133]151]. The endothelialmesenchymal transition also favors the formation of myofibroblasts [128][129][130][131][132][133]152,153].…”

“…Local secretion of the von Willebrand factor causes platelet aggregation, hypercoagulability, and fibrin deposition leading to terminal vascular injury [126][127][128][129][130][131][132][133]151]. The endothelialmesenchymal transition also favors the formation of myofibroblasts [128][129][130][131][132][133]152,153]. The activated endothelium also expresses an increase in adhesion molecules and specific chemokines, recruiting immune cells and perivascular infiltrates leading to further inflammation and fibrosis [128][129][130][131][132][133]152,153].…”

“…The endothelialmesenchymal transition also favors the formation of myofibroblasts [128][129][130][131][132][133]152,153]. The activated endothelium also expresses an increase in adhesion molecules and specific chemokines, recruiting immune cells and perivascular infiltrates leading to further inflammation and fibrosis [128][129][130][131][132][133]152,153]. Specifically, the imbalance of cytokines, including endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9, endoglin, endothelin-1 (ET-1), and the angiostatic pentraxin 3 (PTX3), MMP-12, endostatin, angiostatin and semaphorin3E (Sema3E) cause dysfunction in angiogenesis and an alteration in endothelial progenitor cell (EPC) recruitment [116][117][118][119].…”

“…Specifically, the imbalance of cytokines, including endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9, endoglin, endothelin-1 (ET-1), and the angiostatic pentraxin 3 (PTX3), MMP-12, endostatin, angiostatin and semaphorin3E (Sema3E) cause dysfunction in angiogenesis and an alteration in endothelial progenitor cell (EPC) recruitment [116][117][118][119]. Endothelin-1 is secreted by endothelial cells and activated smooth muscle cells, fibroblasts, epithelial cells, and inflammatory cells [128][129][130][131][132][133]152,153]. An increase in ET-1 is present in SSc-PAH compared to SSc patients without PAH and healthy controls [116][117][118][119].…”

Unveiling Endoglin non canonical regulation: spotlight on the new role of the uPAR pathway

“…More recent works have highlighted new functions for Endoglin 7 , in particular in leukocyte adhesion and transmigration under inflammatory conditions 8 , but also in platelets biology 9 and cancer-associated fibroblasts 10 . There is then accumulating evidence that Endoglin and its soluble form (S-Endoglin) are involved in many human diseases 11 such as thrombosis 9 , coronary atherosclerosis 12 , preeclampsia 13 , hypertension 14 , autoimmune disease 15 , some cancers 16 , and beyond. Notably, elevated levels of S-Endoglin have been detected in specific conditions such as hypertension and coronary atherosclerosis 14,17,18 .…”