Abstract 606: Role of Circulating Caveolin-1+ Endothelial Cell-derived Extracellular Vesicles in Mediating Inflammation-induced Pulmonary Arterial Hypertension

Introduction: Cytokine-induced endothelial cell (EC) caveolin-1 (Cav-1) depletion is associated with a shift from BMPRII to pro-fibrotic TGFβR1 signaling suggesting loss of Cav-1 is a key switch associated with vascular injury that promotes onset of pulmonary vascular remodeling. Hypothesis: Persistent depletion of EC Cav-1 is associated with dysregulation in the TGFβ signaling axis, vascular remodeling, and pulmonary arterial hypertension (PAH). Methods and Results: Lung tissue and plasma were collected from Sprague-Dawley rats injected withSU5416 followed by exposure to hypoxia and normoxia(HxSu model). Blood leukocytes and accumulation of Cav-1 and extracellular vesicles (EV) in plasma were evaluated 1, 3 or 7 days after SU5416 injection. The specific role of EC Cav-1 depletion in the vascular injury/remodeling response was evaluated in C57BL6 WT ( Tie2.Cre - ;Cav1 lox/lox ) and EC- Cav1 -/- (Tie2.Cre + ; Cav1 fl/fl ) mice also exposed to normoxia or hypoxia for 1 month. Results indicate a significant reduction in Cav-1 expression in lung tissue of HxSu-treated rats compared to vehicle controls (1.39 ± 0.07 and 0.50 ± 0.14 arbitrary units; n=4, respectively), which was associated with an early increase in plasma Cav-1 level and EV shedding 7 days after SU5416. Exposure to hypoxia increased right ventricular systolic pressure and hypertrophy as well as microvascular remodeling in WT and EC- Cav1 -/- mice. However, the effect of hypoxia was significantly greater in EC- Cav1 -/- compared to WT controls, suggesting depletion of EC Cav-1 may play a significant role in onset of PAH. Cav-1 level and EV particle number were also significantly increased in plasma samples from idiopathic PAH human donor samples compared to healthy donors. Moreover, the increase in circulating Cav-1 level was associated with activation TGFβ-producing macrophages suggesting Cav-1+ EVs may contribute to PAH development. Conclusion: Taken together, these data indicate pulmonary vascular injury promotes EC Cav-1 depletion and accumulation of circulating Cav-1+ EVs in association with TGFβ secretion from macrophages and pro-fibrotic TGFβR1 signaling in ECs leading to defective vascular repair and PAH.