title: Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology.
abstract: BACKGROUND
  The von Hippel-Lindau tumour suppressor protein-hypoxia-inducible factor (VHL-HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL-HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL-HIF pathway in systemic human cardiopulmonary physiology.
  
  
  RESULTS
  Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased.
  
  
  CONCLUSIONS
  The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF.
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Smith
authors.forename: Jerome T
authors.initials: JT
authors.lastname: Brooks
authors.forename: George M
authors.initials: GM
authors.lastname: Balanos
authors.forename: Terence R
authors.initials: TR
authors.lastname: Lappin
authors.forename: D Mark
authors.initials: DM
authors.lastname: Layton
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Leedham
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Mary F
authors.initials: MF
authors.lastname: McMullin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McNamara
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Percy
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: Nick P
authors.initials: NP
authors.lastname: Talbot
authors.forename: Marilyn
authors.initials: M
authors.lastname: Treacy
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics* / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000337:Aerospace Medicine; D000531:Altitude; D002245:Carbon Dioxide / Q000097:blood; D002320:Cardiovascular Physiological Phenomena; D005260:Female; D005634:Fructose-Bisphosphate Aldolase / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007501:Iron / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000235:genetics; D010100:Oxygen / Q000008:administration & dosage / Q000097:blood / Q000502:physiology; D010313:Partial Pressure; D011086:Polycythemia / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D012123:Pulmonary Ventilation; D012143:Respiratory Physiological Phenomena; D013610:Tachycardia / Q000209:etiology / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D014661:Vasoconstriction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D002245:Carbon Dioxide; D007501:Iron; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D005634:Fructose-Bisphosphate Aldolase; C497446:VHL protein, human; D010100:Oxygen