title: Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension.
abstract: In pulmonary arterial hypertension (PAH) structural and functional abnormalities of the small lung vessels interact and lead to a progressive increase in pulmonary vascular resistance and right heart failure. A current pathobiological concept characterizes PAH as a 'quasi-malignant' disease focusing on cancer-like alterations in endothelial cells (EC) and the importance of their acquired apoptosis-resistant, hyper-proliferative phenotype in the process of vascular remodeling. While changes in pulmonary blood flow (PBF) have been long-since recognized and linked to the development of PAH, little is known about a possible relationship between an altered PBF and the quasi-malignant cell phenotype in the pulmonary vascular wall. This review summarizes recognized and hypothetical effects of an abnormal PBF on the pulmonary vascular bed and links these to quasi-malignant changes found in the pulmonary endothelium. Here we describe that abnormal PBF does not only trigger a pulmonary vascular cell growth program, but may also maintain the cancer-like phenotype of the endothelium. Consequently, normalization of PBF and EC response to abnormal PBF may represent a treatment strategy in patients with established PAH.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research (ICaR-VU)/VU University Medical Center, Amsterdam, The Netherlands; Department of Pulmonary Medicine, Institute for Cardiovascular Research (ICaR-VU)/VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Happé
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research (ICaR-VU)/VU University Medical Center, Amsterdam, The Netherlands; Department of Pulmonary Medicine, Institute for Cardiovascular Research (ICaR-VU)/VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Szulcek
authors.affiliation: School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Voelkel
authors.affiliation: Department of Pulmonary Medicine, Institute for Cardiovascular Research (ICaR-VU)/VU University Medical Center, Amsterdam, The Netherlands. Electronic address: hj.bogaard@vumc.nl.
authors.forename: H J
authors.initials: HJ
authors.lastname: Bogaard
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004734:Energy Metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D040542:Mechanotransduction, Cellular; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010641:Phenotype; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D011652:Pulmonary Circulation; D012039:Regional Blood Flow; D013314:Stress, Mechanical
chemical_list: D042501:Angiogenic Proteins
keywords: Abnormal pulmonary blood flow; Cancer; Endothelial cell; Pulmonary arterial hypertension; Shear stress