• Christopher J Rhodes, Hogune Im, Aiqin Cao, Jan K Hennigs, Lingli Wang, Silin Sa, Pin-I Chen, Nils P Nickel, Kazuya Miyagawa, Rachel K Hopper, Nancy F Tojais, Caiyun G Li, Mingxia Gu, Edda Spiekerkoetter, Zhaoying Xian, Rui Chen, Mingming Zhao, Mark Kaschwich, Patricia A Del Rosario, Daniel Bernstein, Roham T Zamanian, Joseph C Wu, Michael P Snyder, and Marlene Rabinovitch.
• 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.
• Am. J. Respir. Crit. Care Med. 2015 Aug 1; 192 (3): 356-66.

RationalePulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.ObjectivesRNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts.MethodsThe endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse.Measurements And Main ResultsFold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries.ConclusionsThe novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

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