BMP signalling in vascular biology and disease signalling

Cardiovascular diseases are worldwide the leading cause of mortality (31% of all deaths, WHO) and disability. These diseases include heart failure, coronary artery disease, hypertension, cerebrovascular and peripheral vascular diseases. Dysfunction of endothelial cells (ECs) lining the inner wall of the vasculature is a major initiator that fuels the progression of cardiovascular disease. Mutations in genes encoding different components of the bone morphogenetic protein (BMP) pathway cause various severe vascular diseases such as hereditary hemorrhagic telangiectasia (HHT), bicuspid aortic valve with thoracic aortic aneurysms (BAV/TAA) and pulmonary arterial hypertension (PAH) (Goumans et al., Cold Spring Harbor Persp. Biol. 2018). BMPs are secreted factors that belong to the larger transforming growth factor (TGF)β family. Signaling by BMPs contributes to the morphological, functional and molecular differences ('heterogeneity') among ECs in different vessel types like arteries, veins, lymphatic vessels and in different organs. Understanding how BMP signaling co-regulates EC heterogeneity in homeostasis and how its deregulation can contribute to disease is key to obtain insights in the genesis of vessel-type restricted disorders and design improved disease-tailored therapies with reduced side effects. The BMP pathway is an important therapeutic target in vascular disease, with several BMP modulators being used already in clinic. The BMP signaling output critically depends on the cellular context in the vessel wall which includes flow hemodynamics, inflammation, interplay with other "vascular" signaling cascades and the interaction of ECs with peri-endothelial cells and surrounding matrix. The BMP community – which has long remained bone-centered – is joining forces relatively recently in vascular biology within Europe. We feel momentum to team-up with the present multidisciplinary network consortium consisting of 8 'Flemish' teams from 3 Universities (A. Zwijsen (KUL1), E.A. Jones (KUL2), B. Loeys/A. Verstraeten (UA), A. Luttun (KUL3), R. Quarck/M. Delcroix (KUL4), P. Segers (UGent) and H. Van Oosterwyck (KUL5),) and 6 external teams (M.J. Goumans (NL1), F. Itoh (JP), P. Knaus (DE), F. Lebrin (NL2/FR2), G. Valdimarsdottir (IS) and M. Vikkula (BE)) to jointly address how i) dysfunctional BMP pathways contribute to vessel (instability) diseases, ii) how impaired BMP signaling affects mechanobiology (interpretation of flow, cellular tractions, matrix stiffness) in the vessel wall and iii) validate promising BMP-based vessel repair strategies across our different models. The various partners of this WOG network study different aspects of BMP/TGFβ signaling and/or vascular (mechano)biology and disease (see further). Within this multidisciplinary consortium, we aim to accelerate the unraveling of BMP-mediated mechanisms of EC heterogeneity and mechanotransduction to refine and improve etiology-based vascular repair strategies, a major challenge in curing vessel-related diseases. Our objectives are to: i) increase critical mass in Flanders on BMP signaling and its interplay with mechanotransduction in vascular diseases and boost trans- and interdisciplinary collaborations within this consortium, to underscore faster commonalities and specificities of (impaired) BMP functions in different vascular beds and vessel (instability) diseases; ii) model and validate vessel normalization strategies in our various physiopathological systems and translate results to a clinical setting; iii) create an "incubator" environment and solid basis for future successful funding applications (leverage); iv) expose and challenge each other's work at an early stage to strengthen and increase research output and competitiveness; v) increase visibility of all the teams in Flanders and internationally, propel the junior talents in the teams and deliver high-quality trained PhDs/masters/bachelors.

Keywords:BMP PATHWAY

Disciplines:Cardiology, Vascular diseases, Medical genomics, Medical transcriptomics, Cell signalling

Project type:Collaboration project