title: Selective inactivation of PTEN in smooth muscle cells synergizes with hypoxia to induce severe pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary vascular remodeling in pulmonary hypertension (PH) is characterized by increased vascular smooth muscle cell (SMC) and adventitial fibroblast proliferation, small vessel occlusion, and inflammatory cell accumulation. The underlying molecular mechanisms driving progression remain poorly defined. We have focused on loss of the phosphatase PTEN in SMCs as a major driver of pathological vascular remodeling. Our goal was to define the role of PTEN in human PH and in hypoxia-induced PH using a mouse model with inducible deletion of PTEN in SMCs.
  
  
  RESULTS
  Staining of human biopsies demonstrated enhanced inactive PTEN selectively in the media from hypertensive patients compared to controls. Mice with induced deletion of PTEN in SMCs were exposed to normoxia or hypoxia for up to 4 weeks. Under normoxia, SMC PTEN depletion was sufficient to induce features of PH similar to those observed in wild-type mice exposed to chronic hypoxia. Under hypoxia, PTEN depletion promoted an irreversible progression of PH characterized by increased pressure, extensive pulmonary vascular remodeling, formation of complex vascular lesions, and increased macrophage accumulation associated with synergistic increases in proinflammatory cytokines and proliferation of both SMCs and nonSMCs.
  
  
  CONCLUSIONS
  Chronic inactivation of PTEN selectively in SMC represents a critical mediator of PH progression, leading to cell autonomous events and increased production of factors correlated to proliferation and recruitment of adventitial and inflammatory cells, resulting in irreversible progression of the disease.
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Henrick
authors.initials: H
authors.lastname: Horita
authors.forename: Seth B
authors.initials: SB
authors.lastname: Furgeson
authors.forename: Allison
authors.initials: A
authors.lastname: Ostriker
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Olszewski
authors.forename: Timothy
authors.initials: T
authors.lastname: Sullivan
authors.forename: Leah R
authors.initials: LR
authors.lastname: Villegas
authors.forename: Michelle
authors.initials: M
authors.lastname: Levine
authors.forename: Jane E
authors.initials: JE
authors.lastname: Parr
authors.forename: Carlyne D
authors.initials: CD
authors.lastname: Cool
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
mesh_terms: D000818:Animals; D018450:Disease Progression; D006976:Hypertension, Pulmonary / Q000209:etiology*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D051381:Rats; D012720:Severity of Illness Index
chemical_list: D051059:PTEN Phosphohydrolase
keywords: hypoxia; inflammation; pulmonary hypertension; remodeling; smooth muscle