title: Plexiform lesions in pulmonary arterial hypertension composition, architecture, and microenvironment.
abstract: Pulmonary arterial hypertension (PAH) is a debilitating disease with a high mortality rate. A hallmark of PAH is plexiform lesions (PLs), complex vascular formations originating from remodeled pulmonary arteries. The development and significance of these lesions have been debated and are not yet fully understood. Some features of PLs resemble neoplastic disorders, and there is a striking resemblance to glomeruloid-like lesions (GLLs) in glioblastomas. To further elucidate PLs, we used in situ methods, such as (fluorescent) IHC staining, three-dimensional reconstruction, and laser microdissection, followed by mRNA expression analysis. We generated compartment-specific expression patterns in the lungs of 25 patients (11 with PAH associated with systemic shunts, 6 with idiopathic PAH, and 8 controls) and GLLs from 5 glioblastomas. PLs consisted of vascular channels lined by a continuously proliferating endothelium and backed by a uniform myogenic interstitium. They also showed up-regulation of remodeling-associated genes, such as HIF1a, TGF-β1, VEGF-α, VEGFR-1/-2, Ang-1, Tie-2, and THBS1, but also of cKIT and sprouting-associated markers, such as NOTCH and matrix metalloproteinases. The cellular composition and signaling seen in GLLs in neural neoplasms differed significantly from those in PLs. In conclusion, PLs show a distinct cellular composition and microenvironment, which contribute to the plexiform phenotype and set them apart from other processes of vascular remodeling in patients with PAH. Neoplastic models of angiogenesis seem to be of limited use in further study of plexiform vasculopathy.
authors.affiliation: Institute of Pathology, Hannover Medical School, Hanover, Germany. jonigk.danny@mh-hannover.de
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Heiko
authors.initials: H
authors.lastname: Golpon
authors.forename: Clemens L
authors.initials: CL
authors.lastname: Bockmeyer
authors.forename: Lavinia
authors.initials: L
authors.lastname: Maegel
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.forename: Jens
authors.initials: J
authors.lastname: Gottlieb
authors.forename: Nils
authors.initials: N
authors.lastname: Nickel
authors.forename: Kais
authors.initials: K
authors.lastname: Hussein
authors.forename: Ulrich
authors.initials: U
authors.lastname: Maus
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Johanna
authors.initials: J
authors.lastname: Rische
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Florian
authors.initials: F
authors.lastname: Laenger
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D012333:RNA, Messenger