title: Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth.
abstract: The plexiform lesions of severe pulmonary hypertension (PH) are complex vascular structures composed primarily of endothelial cells. In this study, we use immunohistochemical markers to identify the various cell layers of pulmonary vessels and to identify different endothelial cell phenotypes in pulmonary arteries affected by severe PH. Our computerized three-dimensional reconstructions of nine vessels in five patients with severe PH demonstrate that plexiform (n = 14) and concentric-obliterative (n = 6) lesions occur distal to branch points of small pulmonary arteries. And, whereas plexiform lesions occur as solitary lesions, concentric-obliterative lesions appear to be only associated with, and proximal to, plexiform structures. The endothelial cells of plexiform lesions express intensely and uniformly the vascular endothelial growth factor (VEGF) receptor KDR and segregate phenotypically into cyclin-kinase inhibitor p27/kip1-negative cells in the central core of the plexiform lesion and p27/kip1-positive cells in peripheral areas adjacent to incipient blood vessel formation. Using immunohistochemistry and three-dimensional reconstruction techniques, we show that plexiform lesions are dynamic vascular structures characterized by at least two endothelial cell phenotypes. Plexiform arteriopathy is not merely an end stage or postthrombotic change--it may represent one stage in an ongoing, angiogenic endothelial cell growth process.
authors.affiliation: Pulmonary Hypertension Center,Departments of Pathology, University of Colorado Health Sciences Center, Denver, Colorado, USA. carlyne.cool@uchsc.edu
authors.forename: C D
authors.initials: CD
authors.lastname: Cool
authors.forename: J S
authors.initials: JS
authors.lastname: Stewart
authors.forename: P
authors.initials: P
authors.lastname: Werahera
authors.forename: G J
authors.initials: GJ
authors.lastname: Miller
authors.forename: R L
authors.initials: RL
authors.lastname: Williams
authors.forename: N F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: R M
authors.initials: RM
authors.lastname: Tuder
mesh_terms: D000199:Actins / Q000032:analysis; D000328:Adult; D015415:Biomarkers; D018797:Cell Cycle Proteins; D002455:Cell Division; D003198:Computer Simulation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016228:Endothelial Growth Factors / Q000032:analysis; D004727:Endothelium / Q000033:anatomy & histology / Q000378:metabolism*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008168:Lung / Q000033:anatomy & histology / Q000473:pathology; D008222:Lymphokines / Q000032:analysis; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D008875:Middle Aged; D008954:Models, Biological; D009130:Muscle, Smooth / Q000033:anatomy & histology / Q000378:metabolism; D011651:Pulmonary Artery / Q000033:anatomy & histology* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D017978:Receptors, Growth Factor / Q000032:analysis; D040262:Receptors, Vascular Endothelial Growth Factor; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D000199:Actins; D015415:Biomarkers; D018797:Cell Cycle Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008869:Microtubule-Associated Proteins; D017978:Receptors, Growth Factor; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor