Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1)

Abstract

Mutations in the endoglin gene (ENG) are responsible for ∼50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-β receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF-β-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients.

The role of endoglin in post-ischemic revascularization

“…Reduced infiltration of leukocytes in HHT1 patients and in Eng +/− mice can be explained by their reduced endoglin levels and involvement of the endoglin-integrin interaction in leukocyte recruitment [27,241]. However, the previously described effects do not seem to be due only to a decrease in the number of inflammatory cells in the infarct area.…”

Endoglin: Beyond the Endothelium

“…Taken together, sol-eng might inhibit the TEM of pro-inflammatory cells and/or anti-inflammatory cells, which might be of great interest and a possible therapeutic target. An excellent review on the interaction of endoglin with integrins has been published [61].…”

Bevacizumab as a treatment option in gastrointestinal bleeding associated to hereditary hemorrhagic telangiectasia. Case Report

“…(32) In addition, endoglin gene mutations are responsible for approximately 50% of HHT cases. (33) This gen codes for a transmembrane glycoprotein mainly expressed in endothelial cells, as well as in the syncytiotrophoblast, activated monocytes and tissue macrophages. Endoglin is known for being a co-receptor of TGF-β complexes and its involvement in cell-to-cell and cell-extracellular matrix interactions, which play a critical role in vascular biology.…”

“…Also, it has been reported that human endoglin gen plays an important role in trauma induced vascular repair, which would be of great importance in unveiling HHT pathogenesis, for in patients with HHT and endoglin mutations, injured vascular tissue proper repair is hard to achieve, and as a consequence their capillary network disappears, and an arteriovenous fistula is produced. (33) On the other hand, ALK1 protein is a transmembrane receptor which is activated by its binding to BMP9 and BMP10 proteins. Once it is activated, a complex formed by ALK1, endoglin and a type II receptor is established.…”