Abstract 377: Serotonin Decreases Angiopoietin-1 Expression Resulting in Exaggerated Lung Endothelial Apoptosis and Pulmonary Arterial Hypertension (PAH) in Tie2-Deficient Mice
Introduction: We have previously demonstrated significant downregulation in lung Tie2 receptor level and activity in experimental models of PAH, implicating reduced Tie2 signaling in the pathogenesis of this disease. Thus, we hypothesized that mice exhibiting Tie2 deficiency (Tie2+/−) would be predisposed to PAH.
Methods: Adult male Tie2+/− or littermate WT mice were subcutaneously implanted with osmotic mini-pumps to deliver saline (control) or serotonin (5-HT) at a rate of 5nmol/hour over 1 week.
Results: 13% of Tie2+/− mice exhibited spontaneous PAH (RVSP ≥38mmHg) under basal conditions (χ2 p<0.05). Infusion of 5-HT induced a greater increase in RVSP in Tie2+/− compared to WT mice, (40±4 vs. 30±2mmHg, respectively; p<0.05, n=15/group; Figure 1⇓). Protein analysis of lung samples revealed a significant decrease in Ang1 following 5-HT delivery in both WT and Tie2+/− mice (p<0.05, n=5/group; Figure 2⇓). Similarly, following in vitro exposure of pulmonary artery smooth muscle cells to 5-HT, Ang-1 secretion was decreased up to 60% in a concentration-dependent fashion. Interestingly, 5-HT infusion resulted in decreased Tie2 activity by phospho-Tie2 immunoblotting and increased microvascular apoptosis by TUNEL (6% in Tie2+/− vs. 0% in WT mice) and propidium iodide staining only in Tie2+/− mice.
Conclusions: Although a proportion of Tie2+/−mice exhibited spontaneous PAH, Tie2+/− mice had enhanced susceptibility to endothelial loss and hemodynamic changes following chronic exposure to 5-HT, associated with reduced Ang1 expression. These data suggest that endogenous endothelial survival signaling via the Ang1/Tie2 pathway is an important protective mechanism in PAH.