Pulmonary arterial hypertension (PAH) is a deadly disease with no effective therapy. Clinically, PAH is subdivided into categories based on etiology including hereditary, drug-induced, and idiopathic. Hereditary PAH is most often caused by a mutation in the Bmpr2 receptor, drug-induced PAH is due to activation of serotonergic pathways through the 5-HT2B receptor, and idiopathic shows associations with both. Regardless of subtype, PAH manifestations are strikingly similar both histologically and symptomatically, and evidence from previous studies implicates a convergence on a single molecular pathway. Our preliminary data illustrates that mice with a mutation in the cytoplasmic tail domain of Bmpr2 (one of the most common mutations found in hereditary PAH) have indicators of elevated Src signaling in the cells of their pulmonary microvasculature (PMVCs). Further data shows that these indicators are reduced to normal levels after treatment with a 5-HT2B antagonist, and treated mice ultimately fail to develop PAH. While antagonist treatment does not affect Src phosphorylation, it does significantly reduce Src motility in PMVCs. This preliminary data strongly suggests that irregular Src trafficking lies at the convergence between hereditary and serotonergic PAH and is ultimately responsible for the biomechanical and physiologic consequences of the Bmpr2 mutation. Biomechanical consequences of the Bmpr2 mutation include increased vessel wall stiffness as well as an increase in PMVC contractility reversed with 5-HT2B antagonism. We have identified three signaling pathways downstream of Src that we believe are responsible for regulating these vessel biomechanical properties, and aim to test the following independent hypotheses: (1) Src signaling is responsible for the pathologic biomechanical consequences of the Bmpr2 mutation in hereditary PAH, and these consequences can be reversed with 5- HT2B antagonism; (2) 5-HT2B antagonism normalizes Src activity in Bmpr2 mutant PMVCs by preventing intracellular trafficking of activated Src. The proposed studies will be the first to clarify the mechanism of Src signaling and trafficking in the molecular pathogenesis of PAH. They will also be the first to address the targeting of the 5-HT2B receptor for treating hereditary PAH, providing a molecular link between different PAH types and opening the door for a safe and specific therapy.
Pulmonary hypertension, or high blood pressure in the lung vasculature, is an insidious illness with no effective treatment that ultimately progresses to righ heart failure and death. This project aims to identify the sequence of molecular changes that lead to pulmonary hypertension, opening the door for safe and effective therapies.
| Bloodworth, Nathaniel C; Clark, Cynthia R; West, James D et al. (2018) Bone Marrow-Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Receptor Dependent Mechanism. Circ Res 123:e51-e64 |
| West, James D; Carrier, Erica J; Bloodworth, Nathaniel C et al. (2016) Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension. PLoS One 11:e0148657 |
