A high pressure in the pulmonary circulation (pulmonary hypertension, PH) complicates several highly prevalent chronic diseases, including left heart failure and chronic thrombo-embolic disease. Pulmonary arterial hypertension (PAH) is a fatally progressive form of PH with characteristic changes in small lung arteries, affecting 1/50.000 humans. Regardless of primary cause, PH almost invariably leads to right heart failure and death.

While vasoconstriction and vascular remodeling play some role in all forms of PH, the underlying mechanisms are incompletely understood. Mutations in the type II receptor for bone morphogenetic protein (BMP) are responsible for 80% of heritable PAH cases, yet deregulation of BMP signaling also occurs in non-hereditary forms of PAH. BMP is frequently antagonized by transforming growth factor-β (TGF-β). We hypothesize that an imbalance in TGF-β and BMP signaling and a vicious circle of alterations in pulmonary blood flow velocity and pressure are at the basis of vascular remodeling in all types of PH. Our aim is to break the vicious circle in a multidisciplinary approach in which patient and preclinical material is used to characterize altered TGF-β/BMP signaling and pulmonary vascular remodeling. Specific drugs will be identified to normalize the TGF-β/BMP imbalance and tested in preclinical models, thereby working towards clinical application. We will identify key factors which increase the vulnerability to develop PH and sustain the vicious circle of alterations in hemodynamics, vascular remodeling and right heart dysfunction. Our collaboration will define new strategies to assess, prevent and reverse pulmonary vascular remodeling and improve right heart function.