title: Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells.
abstract: A proliferative endothelial cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Bone morphogenetic protein type II receptor (BMPR2) loss-of-function is the most common cause of heritable PAH and has been closely linked to the formation of pathological plexiform lesions. Although some BMPR2 mutations leave ligand-dependent responses intact, the disruption of ligand-independent, noncanonical functions are universal among PAH-associated BMPR2 genotypes, but incompletely understood. This study examined the noncanonical signaling consequences of BMPR2 silencing in human pulmonary artery endothelial cells to identify potential therapeutic targets. BMPR2 siRNA silencing resulted in a proliferative, promigratory pulmonary artery endothelial cell phenotype and disruption of cytoskeletal architecture. Expression profiling closely reflected these phenotypic changes. Gene set enrichment and promoter analyses, as well as the differential expression of pathway components identified Ras/Raf/ERK signaling as an important consequence of BMPR2 silencing. Raf family members and ERK1/2 were constitutively activated after BMPR2 knockdown. Two Raf inhibitors, sorafenib and AZ628, and low-dose nintedanib, a triple receptor tyrosine kinase inhibitor upstream from Ras, reversed the abnormal proliferation and hypermotility of BMPR2 deficiency. Inhibition of dysregulated Ras/Raf/ERK signaling may be useful in reversing vascular remodeling in PAH.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Keytam S
authors.initials: KS
authors.lastname: Awad
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and elinoffj@cc.nih.gov.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Elinoff
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Shuibang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Salina
authors.initials: S
authors.lastname: Gairhe
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Ferreyra
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Rongman
authors.initials: R
authors.lastname: Cai
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Sun
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Solomon
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
mesh_terms: D000328:Adult; D000368:Aged; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011651:Pulmonary Artery / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D066253:Vascular Remodeling / Q000235:genetics; D055815:Young Adult; D048490:raf Kinases / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMPR2; endothelial cell dysfunction; nintedanib; pulmonary arterial hypertension