title: Atrial natriuretic peptide-dependent modulation of hypoxia-induced pulmonary vascular remodeling.
abstract: Hypoxic stress upsets the balance in the normal relationships between mitogenic and growth inhibiting pathways in lung, resulting in pulmonary vascular remodeling characterized by hyperplasia of pulmonary arterial smooth muscle cells (PASMCs) and fibroblasts and enhanced deposition of extracellular matrix. Atrial natriuretic peptide (ANP) reduces pulmonary vascular resistance and attenuates hypoxia-induced pulmonary hypertension in vivo and PASMC proliferation and collagen synthesis in vitro. The current study utilized an ANP null mouse model (Nppa-/-) to test the hypothesis that ANP modulates the pulmonary vascular and alveolar remodeling response to normobaric hypoxic stress. Nine-10 wk old male ANP null (Nppa-/-) and wild type nontransgenic (NTG) mice were exposed to chronic hypoxia (10% O(2), 1 atm) or air for 6 wks.
  
  
  METHODS
  pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial and alveolar remodeling were assessed. Hypoxia-induced pulmonary arterial hypertrophy and muscularization were significantly increased in Nppa-/- mice compared to NTG controls. Furthermore, the stimulatory effects of hypoxia on alveolar myofibroblast transformation (8.2 and 5.4 fold increases in Nppa-/- and NTG mice, respectively) and expression of extracellular matrix molecule (including osteopontin [OPN] and periostin [PN]) mRNA in whole lung were exaggerated in Nppa-/- mice compared to NTG controls. Combined with our previous finding that ANP signaling attenuates transforming growth factor (TGF)-beta-induced expression of OPN and PN in isolated PASMCs, the current study supports the hypothesis that endogenous ANP plays an important anti-fibrogenic role in the pulmonary vascular adaptation to chronic hypoxia.
authors.affiliation: Vascular Biology and Hypertension Program, Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, 35296, USA. yfchen@uab.edu
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Feng
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Dongqi
authors.initials: D
authors.lastname: Xing
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000502:physiology*; D015152:Blotting, Northern; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000473:pathology*; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011650:Pulmonary Alveoli / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology*; D011652:Pulmonary Circulation / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000199:Actins; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D003094:Collagen