Cellular and molecular biology of the vascular endothelium

The transforming growth factor (TGF-β) family includes subfamilies of the bone morphogenetic protein (BMP), activins, and TGF-β. The signaling of this family of factors through their membrane receptors crucially regulates various processes in the cardiovascular system, such as angiogenesis or vascular development, remodeling and homeostasis. Endoglin is a component of the TGF-β receptor complex in endothelial cells and shows high affinity for BMP9 and BMP10. Endoglin is involved in vascular pathophysiology. Thus, mutations in the endoglin gene are responsible for Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), an autosomal dominant vascular dysplasia associated with frequent epistaxis, gastrointestinal bleeding, cutaneous telangiectasia, and arteriovenous malformations in the lung, liver and brain. Endoglin plays an important role in angiogenesis and vascular homeostasis, and a pathogenic role has been described for elevated levels of a soluble form of endoglin present in pregnant women with preeclampsia. Furthermore, the release of soluble endoglin mediated by matrix metalloproteases MMP-12 and MMP-14 inhibits tumor angiogenesis, regulates vascular remodeling, and aggravates endothelial vascular wall dysfunction. On the other hand, endothelial endoglin is an adhesion receptor that interacts with integrins of leukocytes, platelets, and vascular wall cells. Despite its importance in human pathophysiology, the mechanisms by which endoglin acts in these biological processes and diseases are largely unknown. Therefore, our current line of research aims to deepen the knowledge of the expression, structure and function of endoglin, which will allow us to better understand the molecular mechanisms by which this protein is involved in vascular pathology.

Hereditary hemorrhagic telangiectasia (HHT) and the TGF-β system in endothelial cells. Heterodimers of BMP9/BMP10 bind to a protein complex composed by type I (R-I) and type II (R-II) receptors, and endoglin. Upon ligand binding, Smad proteins translocate into the nucleus. BMP9, Endoglin, ALK1, and Smad4 proteins are encoded by GDF2, ENG, ACVRL1, and MADH4 genes, whose mutations give rise to HHT5, HHT1, HHT2, and JPHT, respectively. Adapted from Bernabeu et al. [2020].