Hereditary Hemorrhagic Telangiectasia, a Vascular Dysplasia Affecting the TGF-  Signaling Pathway

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in endoglin (ENG; HHT1) or ACVRL1/ALK1 (HHT2) genes and is an autosomal dominant vascular dysplasia. Clinically, HHT is characterized by epistaxis, telangiectases and arteriovenous malformations in some internal organs such as the lung, brain or liver. Endoglin and ALK1 proteins are specific endothelial receptors of the transforming growth factor (TGF)-β superfamily that are essential for vascular integrity. Genetic studies in mice and humans have revealed the pivotal role of TGF-β signaling during angiogenesis. Through binding to the TGF-β type II receptor, TGF-β can activate two distinct type I receptors (ALK1 and ALK5) in endothelial cells, each one leading to opposite effects on endothelial cell proliferation and migration.The recent isolation and characterization of circulating endothelial cells from HHT patients has revealed a decreased endoglin expression, impaired ALK1-and ALK5-dependent TGF-β signaling, disorganized cytoskeleton and the failure to form cord-like structures which may lead to the fragility of small vessels with bleeding characteristic of HHT vascular dysplasia or to disrupted and abnormal angiogenesis after injuries and may explain the clinical symptoms associated with this disease.

Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling

“…These phenotypes are also consistent with the findings obtained on in vitro culture of endothelial cell lineages (33) and mesenchymal progenitor cells (34), which showed that pericyte maturation is promoted, and endothelial proliferation is inhibited, by TGF-␤ signaling. Vascular phenotypes due to defects in TGF-␤ signaling in vivo are also observed in two types of hereditary hemorrhagic telangiectasia (35,36), which are induced by deficiencies of endoglin or ALK-1, which are components of TGF-␤ signaling in vascular endothelium. Because of inborn and life-long abnormality of TGF-␤ signaling in vasculature, these diseases result in a tendency toward hemorrhage in capillaries that is due to vulnerability of the vascular structure.…”

BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood–brain-barrier

“…It is reported that intracellular SMAD signaling induces expression of extracellular matrix (ECM) and basement membrane components in cultured astrocytes via Type IV pro-collagens (Fuchshofer et al, 2005;Gaussin, 2002;Jackson et al, 2003). ECM components regulated by SMAD signaling direct remodeling of blood vessels in some internal organs such as the lung or liver (Ng et al, 2005;Fernandez-L A, 2006). Thus, Bmpr1a plays a role in cell adhesion capacity in these tissues.…”

Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia

“…Mutations in ENG or ALK1 genes result in a significant reduction in the level of functional endoglin and activin receptorlike kinase1 proteins, which are mediators of TGF-b signalling pathways. Such mutations lead to disrupted and abnormal angiogenesis and the formation of focal vascular lesions [10,16].…”

“…The pathophysiology of HHT has been reviewed elsewhere [10,16], and is related to impaired transforming growth factor-b (TGF-b) signalling pathways critical to angiogenesis and the regulation of vascular tone [17]. Mutations in ENG or ALK1 genes result in a significant reduction in the level of functional endoglin and activin receptorlike kinase1 proteins, which are mediators of TGF-b signalling pathways.…”