In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug

• DOI: 10.1161/circulationaha.115.020617
• Publication Date: 2016-04-05T03:50:56Z
• Authors: Rachel K. Hopper; Jan-Renier A.J. M...; Isabel Diebold; Aiqin Cao; Christopher J. Rh...; Nancy F. Tojais; Jan K. Hennigs; Mingxia Gu; Lingli Wang; Marlene Rabinovitch
• Keywords: BMPR2; Slug

We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic hypertension (PAH) comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition cancer, we hypothesized increased could induce PAECs to a smooth muscle (SM)-like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation PAEC function and possible cellular contribution occlusive remodeling characterizes advanced PAH.We documented cultured PAH versus donor control lungs. Confocal microscopy lung explants localized increase consistently endothelium, many double-positive for SM22α plexogenic lesions. decreased bone morphogenetic protein receptor 2 (BMPR2) is observed PAH, reduced BMPR2 by small interfering an protein. Consistent HMGA1, detected platelet cell adhesion molecule (CD31) endothelial-to-mesenchymal markers, αSM actin, SM22α, calponin, phospho-vimentin, Slug. The was associated spindle SM-like morphology, actin largely reversed joint knockdown or Pulmonary mice cell-specific loss Bmpr2 showed similar gene changes.Increased resulting dysfunctional signaling can endothelium PAH.