Abstract 17730: Aberrant Endothelial FGF Signaling Due to Disruption of MicroRNAs 424/503 in Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a disease characterized by the vascular remodeling of the pulmonary arterioles, including formation of plexiform and concentric lesions comprised of proliferative endothelial cells. We recently found that disruption of the G protein-coupled receptor signaling axis comprised of the ligand apelin and the receptor APJ leads to significant worsening of hypoxia induced pulmonary hypertension (PH) in mice, and found that the pathway is also perturbed in clinical PAH. To characterize novel downstream endothelial targets which may be utilized by apelin-APJ signaling to protect against the vascular remodeling processes in PAH, we carried out a microRNA (miRNA) array analysis of pulmonary artery endothelial cells (PAECs) subjected to knockdown of apelin, APJ, or both. We identified two miRNAs (miR-424 and miR-503) that are highly expressed in PAECs, but are significantly downregulated in the context of apelin/APJ knockdown. Remarkably, we found marked decrease in levels of miR-424 and miR-503 in the experimental monocrotaline (MCT) rat model of PH, as well as in PAECs isolated from a subset of patients with clinically diagnosed PAH. Our in vitro functional studies demonstrated that both miR-424 and miR-503 exert anti-proliferative, anti-angiogenic effects, via a mechanism that targets two key components of the fibroblast growth factor (FGF) signaling pathway, namely FGF2 and FGFR1. Consequently, we found marked increase in protein levels of FGF2 and FGFR1 in PAECs from PAH patients, as well as lungs of rats with MCT induced PH. Lastly, we found that restoration of miR-424/503 expression in the MCT induced model of PH by intranasal lentiviral delivery can significantly decrease FGF2 and FGFR1 expression and ameliorate the severity of the disease as demonstrated by decreased right ventricular systolic pressure (38 vs. 24.3 mmHg, p<0.001, n=5-8/group) and RV/LV+septum weight ratio (0.52 vs. 0.43, p<0.05). We conclude that miR-424/503 play a critical role in maintaining pulmonary vascular homeostasis, and that disruption of their expression serves a critical contribution to the aberrant endothelial proliferation that is a hallmark of PAH.
- © 2011 by American Heart Association, Inc.