Group Leader/s

 

intro

Description

The objective of the laboratory is to study the role of endoglin in pathophysiology. Endoglin is a homodimeric membrane glycoprotein with a size of 180-kDa. It is highly expressed in endothelial cells and syncytiotrophoblasts, and at lower levels in activated monocytes/macrophages, as well as in mesenchymal stem cells, fibroblasts, and vascular smooth muscle cells. In endothelial cells, endoglin is a component of the receptor complex for the transforming growth factor (TGF-β) family, and it is also involved in integrin-mediated cell adhesion.

The TGF-β family includes the bone morphogenetic proteins (BMPs), activins, and TGF-β subfamilies. Members of the TGF-β family exert their biological functions through a receptor complex that includes serine/threonine kinases type I (TβRI) and type II (TβRII) and the auxiliary receptors endoglin or betaglycan. On endothelial cells, endoglin and ALK1 (a type of TβRI) in this complex act as receptors for BMP9, BMP10, and other family members. After ligand binding to the receptor complex, ALK1 initiates the signaling pathway by phosphorylation of the Smad family of proteins. On the other hand, endothelial endoglin is an adhesion receptor that interacts with integrins of leukocytes, platelets and vascular mural cells. The participation of endoglin in these signaling pathways is crucial for the regulation of various pathophysiological processes, including those related to the cardiovascular system. In this context, endoglin is associated with a wide range of conditions, including physiological and pathological angiogenesis, vascular pathology, preeclampsia, tumor vascularization, hemostasis or tumor malignancy.

Endoglin has important implications 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 hemorrhages, cutaneous telangiectasias, and arteriovenous malformations in the lung, liver, and brain. Endoglin plays an important role in vascular remodeling and cardiovascular development. Its expression is regulated during heart development; it is highly increased in the endocardium during valve formation and in mesenchymal cells of the atrioventricular canal during the formation of the heart septum. Its role in morphogenesis has been confirmed by the finding that mouse embryos homozygous for an endoglin mutant die at 10-10.5 days postcoitus due to vascular and cardiac anomalies. Furthermore, endoglin plays a role in vascular homeostasis by regulating nitric oxide-dependent vasodilation, and is an integrin ligand involved in endothelial cell adhesion processes during pathological inflammatory conditions and in primary hemostasis. Furthermore, a circulating form of endoglin, also called soluble endoglin, whose levels increase abnormally in different pathological conditions, such as preeclampsia, appears to act as an antagonist of membrane-bound endoglin and as a competitor of the fibrinogen-integrin interaction in platelet-dependent thrombus formation. These studies suggest that membrane-bound endoglin and circulating endoglin are important components involved in vascular homeostasis and hemostasis.

Despite its importance in human pathophysiology, the mechanisms by which endoglin acts in these biological processes and diseases are largely unknown. Our current line of research aims to deepen our knowledge on the expression, structure and function of endoglin, which will allow us to better understand the molecular mechanisms by which this protein is involved in human 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].