Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia

Abstract

Rendu-Osler-Weber syndrome, also known as hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant vascular disorder. Three genes are causally related to HHT: the ENG gene encoding endoglin, a co-receptor of the TGFβ family (HHT1), the ACVRL1 gene encoding ALK1 (activin receptor-like kinase 1), a type I receptor of the TGFβ family (HHT2), and the SMAD4 gene, encoding a transcription factor critical for this signaling pathway. Bone morphogenetic proteins (BMPs) are growth factors of the TGFβ family. Among them, BMP9 and BMP10 have been shown to bind directly with high affinity to ALK1 and endoglin, and BMP9 mutations have recently been linked to a vascular anomaly syndrome that has phenotypic overlap with HHT. BMP9 and BMP10 are both circulating cytokines in blood, and the current working model is that BMP9 and BMP10 maintain a quiescent endothelial state that is dependent on the level of ALK1/endoglin activation in endothelial cells. In accordance with this model, to explain the etiology of HHT we hypothesize that a deficient BMP9/BMP10/ALK1/endoglin pathway may lead to re-activation of angiogenesis or a greater sensitivity to an angiogenic stimulus. Resulting endothelial hyperproliferation and hypermigration may lead to vasodilatation and generation of an arteriovenous malformation (AVM). HHT would thus result from a defect in the angiogenic balance. This review will focus on the emerging role played by BMP9 and BMP10 in the development of this disease and the therapeutic approaches that this opens.

Keywords: ALK1; BMP10; BMP9; cell signaling; endoglin; hereditary hemorrhagic telangiectasia.

FIGURE 1

BMP9/10 are ligands of the ALK1-Endoglin receptor complex and activate the Smad pathway in endothelial cells. BMP9/10 bind to a heterotetrameric complex composed of two type I receptors (ALK1) and two type II receptors (BMPR2, ActR2A, or ActR2B). Endoglin is a co-receptor of this complex and enhances signaling. Following ligand binding, receptors are phosphorylated and propagate signal through R-Smad 1, 5, 8 phosphorylation. The R-Smads then associate with Smad4 to regulate target gene transcription in the nucleus.

FIGURE 2

(A) Schematic diagram of BMP biosynthesis and processing. BMPs are synthesized as pre-pro-proteins that are disulfide-bonded to form pro-BMPs. Pro-BMPs represent a precursor inactive form that needs to be further processed. After cleavage by pro–protein convertases, the prodomains remain non-covalently associated with the mature BMPs. BMP9 complexed form has been shown to be able to activate ALK1 signaling (modified from Bidart et al., 2012). (B) BMP9 mutations found in HHT-like vascular syndrome. Three mutations have been described, indicated by a blue star. Two of these mutations are associated in vitro with a defect in BMP9 processing (modified from Wooderchak-Donahue et al., 2013).