Description
The major goal of our laboratory is to elucidate the regulation of endoglin gene expression, as well as the function and structure of the endoglin protein in the normal physiology and in the context of human pathophysiology.
Members of the TGF-β superfamily exert their biological functions through membrane receptors known as type I (TβRI) and type II (TβRII), serine/threonine kinases. After ligand binding, TβRII recruits and phosphorylates TβRI, which initiates the signaling pathway by phosphorylating the Smad family of proteins. Endoglin is a homodimeric membrane glycoprotein of 180kDa which functions, in association with TβRI and TβRII, as an auxiliary receptor for BMP9, BMP10 and other members of the TGF-β family. It is highly expressed by endothelial cells, and at lower levels by activated monocytes/macrophages, as well as by mesenchymal cells, including fibroblasts, and vascular smooth muscle cells.
Endoglin plays an important role in vascular remodeling and cardiovascular development. Endoglin expression is regulated during heart development in humans and chicken; it is highly expressed at the level of endocardial cushion during valve formation and by the mesenchymal cells of the atrioventricular canal during heart septation. Its role in morphogenesis is further underscored by the finding that mice embryos homozygous for a mutant endoglin die at 10-10.5 days postcoitum due to vascular and cardiac anomalies. In addition, endoglin plays a role in vascular homeostasis regulating the nitric-oxide-dependent vasodilatation, and modulates the organization of the actin cytoskeleton via its interaction with the zyxin family of proteins.
Endoglin and ALK-1 (member of the TβRI family) are TGF-β receptors expressed in the endothelium. Mutations in Endoglin and ALK-1 genes are responsible for the Hereditary Hemorrhagic Telangiectasia (HHT1 and HHT2, respectively). HHT is an autosomic dominant vascular dysplasia associated with vascular telangiectases in skin and nasal mucosa, epistaxis, gastrointestinal hemorrhages and arteriovenous malformations in lung, liver and brain. Reduced levels of functional endoglin (haploinsufficiency), are widely accepted as the pathogenic mechanism of HHT1.
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