BMP9 and BMP10: Two close vascular quiescence partners that stand out

Abstract

Bone morphogenetic proteins (BMPs) are dimeric transforming growth factor ß (TGFß) family cytokines that were first described in bone and cartilage formation but have since been shown to be involved in many pleiotropic functions. In human, there are 15 BMP ligands, which initiate their cellular signaling by forming a complex with two copies of type I receptors and two copies of type II receptors, both of which are transmembrane receptors with an intracellular serine/threonine kinase domain. Within this receptor family, ALK1 (activin receptor-like kinase 1), which is a type I receptor mainly expressed on endothelial cells, and BMPRII (BMP Receptor type II), a type II receptor also highly expressed on endothelial cells, have been directly linked to two rare vascular diseases: hereditary hemorrhagic telangiectasia (HHT), and pulmonary arterial hypertension (PAH), respectively. BMP9 (gene name GDF2) and BMP10, two close members of the BMP family, are the only known ligands for the ALK1 receptor. This specificity gives them a unique role in physiological and pathological angiogenesis and tissue homeostasis. The aim of this current review is to present an overview of what is known about BMP9 and BMP10 on vascular regulation with a particular emphasis on recent results and the many questions that remain unanswered regarding the roles and specificities between BMP9 and BMP10.

Therapeutic Approaches for Treating Pulmonary Arterial Hypertension by Correcting Imbalanced TGF-β Superfamily Signaling

“…BMPRII pathway activity is important in both pulmonary arterial ECs and SMCs, although the two vascular cell types appear to depend on different BMPRII ligands and on different BMPRII signaling outputs. Circulating bone morphogenetic protein 9 (BMP9) and BMP10 are thought to be critical quiescence factors in the pulmonary arteries and act primarily upon ECs ( 34 ). Mice with Bmpr2 ablated selectively in ECs develop PAH-like disease, including proliferating ECs and SMCs, highlighting the importance of BMPRII signaling in the endothelium in particular ( 35 ).…”

Rethinking growth factors: the case of BMP9 during vessel maturation

“…When ALK1/BMP9 signalling is disrupted: HHT Since many years ago, it is a well-known fact that mutations that affect the ALK1 signalling cascade produce abnormal growth and wrong maturation of vessels in animals models (reviewed elsewhere 26,134,135 ) and in patients 136 . This disease, known as hereditary haemorrhagic telangiectasia (HHT) or Rendu-Olser-Weber syndrome (ORPHA774), highlights the importance of BMP9/ALK1 in the regulation of maturation.…”

“…BMPs bind to a tetrameric signalling complex formed by two homodimers, one of bone morphogenetic protein receptor 1 (BMPRI) (ALK1-3, ALK6) and one of BMPRII (BMPRII Activin receptor IIA (ActRIIA) or ActRIIB) ( 25 , 26 ). Moreover, to activate downstream messengers, a coreceptor might be needed, and depending on the complexity, different coreceptors might intervene ( 27 ).…”

The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

“…Both proteins have been demonstrated to behave as important vascular homeostasis regulators [79]. Traditionally it was believed that both proteins were redundant, but current studies using neutralizing antibodies or deficient mice are showing different functions for these proteins [113]. BMP9 is expressed in the liver, with this expression being restricted to hepatic stellate cells (HSCs) [77,[114][115][116].…”