Despite the clinical importance of the right ventricle (RV) in pulmonary arterial hypertension (PAH), surprisingly little is known about the molecular and structural mechanisms of RV adaptive and maladaptive remodeling and the transition to RV failure. This is particularly important when the RV is not the primary cause of RV failure, but when a temporary support of the RV would be desirable until the primary cause can be fixed. Approaches that normalize pulmonary vascular resistance (PVR) and reduce RV afterload would improve RV function and reverse RV failure. Unfortunately, no currently available medical therapy is able to significantly reduce PVR long-term in chronic PAH or thromboembolic PH (CTEPH). As RV failure is the most common cause of death in PAH, approaches to support the RV to better adapt to an increased afterload are highly sought after. In this proposal, we will focus on two pathological features that put the RV uniquely at risk for failure: (1) cardiac fibrosis, that reduces RV systolic/diastolic function, disrupts the myocardial architecture, and impairs the exchange of oxygen/nutrients and (2) impaired microvascular adaptation (= capillary rarefaction) that results in RV ischemia. Both are controversially debated as to their role in RV adaptation, failure as well as in recovery. We use a novel mouse model of pulmonary artery banding (PAB) and de-banding (de-PAB) to quantitatively capture histological changes in the RV using 3-D deep tissue imaging and to link them to cardiac function with cardiac MRI (CMR). As a deficiency in Bone morphogenetic protein receptor 2 (BMPR2) signaling is thought to put the RV at risk for failure, we evaluate whether two repurposed drugs, Tacrolimus (FK506) and Enzastaurin, previously shown by our group to increase BMPR2 signaling, assist the RV by reducing cardiac fibrosis and improving vascular adaptation and accelerate recovery. Moreover, we have identified early, RV specific expression of SNAIL1 in cardiac fibroblasts as a promising and druggable target to improved cardiac fibrosis. We hypothesize that Inhibiting Snail and increasing BMPR2 with FK506 and Enzastaurin will reduce cardiac fibrosis, improve capillary density and improve RV function in the pressure overloaded murine RV. Our proposal has three significant parts, which are represented by our three specific aims: First, we will target molecular events that govern RV fibrosis in the pressure overloaded RV with genetic tools and repurposed drugs to improve RV function and strain as assessed by CMR in PAB mice. Second, we will characterize the adaptation of the RV microvasculature in PAB mice and human RV PH tissue, construct a 3- D model of the RV microcirculation to predict how structural changes in the RV influence fluid and diffusion dynamics and third, we will study histological and functional recovery of the RV in a novel de-banding mouse model. By studying and targeting RV adaptation and failure, we not only address the most importa...