Pulmonary Arterial Hypertension (PAH) is a deadly and disabling disease for which there is no marketed drug that addresses the underlying disease mechanism and targets to cure patients. The lack of understanding of the disease mechanism represents the main challenges in developing curative therapies. We here report, for the first time, that mice lacking natriuretic peptides clearance receptor develop PAH.Initial studies assessed cardiac structure and function in NPR-CThe above results suggest that NPR-C-mediated signalling pathways play a critical role in the development of PAH, indicating that NPR-C is an important protective receptor in the heart rather than just being a clearance receptor.