title: The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension.
abstract: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease that comprises sustained vasoconstriction, enhanced proliferation of pulmonary vascular cells, and in situ thrombosis. The discovery of several contributing signaling pathways in recent years has resulted in an expanding array of novel therapies; however, IPAH remains a progressive disease with poor outcome in most instances. To identify new regulatory pathways of vascular remodeling in IPAH, we performed transcriptome-wide expression profiling of laser-microdissected pulmonary arterial resistance vessels derived from explanted IPAH and nontransplanted donor lung tissues. Statistical analysis of the data derived from six individuals in each group showed significant regulation of several mediators of the canonical and noncanonical WNT pathway. As to the noncanonical WNT pathway, the planar cell polarity (PCP) pathway, the ras homolog gene family member A (RHOA), and ras-related C3 botulinum toxin substrate-1 (RAC1) were strongly up-regulated. Real-time PCR of laser-microdissected pulmonary arteries confirmed these array results and showed in addition significant up-regulation of further PCP mediators wingless member 11 (WNT11), disheveled associated activator of morphogenesis-1 (DAAM1), disheveled (DSV), and RHO-kinase (ROCK). Immunohistochemical staining and semiquantitative expression analysis confirmed the markedly enhanced expression of the PCP mediators in the pulmonary resistance vessels, in particular in the endothelial layer in IPAH. Therefore we propose the PCP pathway to be critically involved in the regulation of vascular remodeling in IPAH.
authors.affiliation: Department of Internal Medicine, University Hospital of Giessen, Giessen, Germany.
authors.forename: Isabel P
authors.initials: IP
authors.lastname: Laumanns
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Jens-C
authors.initials: JC
authors.lastname: Wolff
authors.forename: Rita
authors.initials: R
authors.lastname: Mitnacht-Kraus
authors.forename: Sabine
authors.initials: S
authors.lastname: Graef-Hoechst
authors.forename: Maria M
authors.initials: MM
authors.lastname: Stein
authors.forename: Rainer M
authors.initials: RM
authors.lastname: Bohle
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Mir A R
authors.initials: MA
authors.lastname: Hoda
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Robert
authors.initials: R
authors.lastname: Voswinckel
mesh_terms: D000328:Adult; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D016040:Lung Transplantation; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D008954:Models, Biological; D011651:Pulmonary Artery / Q000473:pathology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins