Secretin and the development of pulmonary arterial hypertension

Abstract

Secretin (SCT), a classical gut peptide, has recently been shown to be active at subfornical organ, paraventricular nucleus, posterior pituitary and distal tubules of the kidney to regulate water homeostasis. We have also shown that central actions of angiotensin II (ANGII) require an intact secretin-secretin receptor (SCTR) axis. The hyperosmolality-induced water drinking behavior depends in vivo SCTR/AT1aR GPCR heteromer formation. In this report, we have tested the effects of deleting the SCT gene in systemic and pulmonary circulation. Histopathological examinations SCT knockout (SCT-/-) revealed development of multiple pathological features of pulmonary arterial hypertension (PAH), including right ventricular (RV) hypertrophy and pulmonary vascular changes such as thickened arterial wall, enlarged medial area, narrowed lumen and perivascular edema. Significant fibrosis in RV wall was observed in SCT-/- 6 months of age. Hemodynamic measurement, echocardiographic study and transcript analysis confirmed RV pathology and changes of pulmonary blood flow. Increased endothelial cell (EC) apoptosis was observed in pulmonary arteries of SCT-/- mice, which is likely triggered by low levels of vascular endothelial growth factor (VEGF). Pulmonary vascular remodeling was significantly attenuated in 3-month old but not 6-month old SCT-/- after 3 months of continuously infusion of SCT. In conclusion, deletion of SCT gene leads to spontaneous development of moderate PAH in mice. A concurrent increased apoptosis and reduced VEGF in pulmonary arteries EC were observed, resulting in hypertension in the pulmonary arterial system, pulmonary vascular remodeling, and eventually increased RV pressure. Although its molecular basis is not identical to human idiopathic PAH, SCT-/- model can be useful for understanding mechanistic and providing therapeutic insights underlying PAH. Our study indicates that SCT replacement therapy is potentially a promising therapeutic approach for PAH, while human studies are required to confirm if mutations of the SCT gene is a factor in the pathogenesis of idiopathic PAH.