Abstract 14306: Mural Cell SDF1 Signaling is Associated With the Pathogenesis of Pulmonary Arterial Hypertension

Abstract

Introduction: Pericytes and pulmonary artery smooth muscle cells (PASMCs) are NG2+ mural cells that provide structural support to pulmonary vessels. In pulmonary arterial hypertension (PAH), both mural cell types contribute to PA muscularization, but whether distinct mechanisms that are responsible for their behavior is unclear. Methods: RNA-Seq was used to compare the gene profile of pericytes and PASMCs isolated from PAH and healthy lungs. NG2-CreER mice were used to generate tamoxifen-inducible NG2-selective reporter mice (NG2tdT fl/+ ) for cell lineage identification and for NG2-selective SDF1 knockout (SDF1 NG2-KO ). Results: Hierarchical clustering of RNA-seq data demonstrated that the genetic profile of PAH pericytes and PASMCs is significantly similar. Cellular lineage staining studies on NG2tdT mice in chronic hypoxia showed that tdT+ cells accumulate in muscularized arteries. RNAseq analysis performed on these hypoxic tdT+ cells demonstrated significant upregulation of SDF1, a chemokine involved in chemotaxis and angiogenesis. Compared to controls, SDF1 NG2-KO mice in chronic hypoxia had reduced RVSP, fulton index, less muscularization and lower abundance of NG2+ cells around microvessels (Fig. 1). In addition, SDF1 stimulation in human healthy pericytes induced greater contractility, impaired their capacity to establish endothelial-pericyte tube formation and increased expression of SMC markers SMA, Calponin and SM22. In contrast, SDF1 knockdown reduced PAH pericyte proliferation, contractility and improved endothelial cell tube formation on matrigel. Conclusions: SDF1 is upregulated in NG2+ mural cells. High expression of SDF1 could drive pericyte detachment and gain an SMC-like phenotype that contributes to abnormal muscularization and vascular obstruction. Targeting SDF1 could help prevent and reverse muscularization in PAH.