title: Intermittent hypoxia induces early functional cardiovascular remodeling in mice.
abstract: BACKGROUND
  Intermittent hypoxia, a hallmark of sleep apnea, is a major factor for hypertension and impaired vasoreactivity.
  
  
  OBJECTIVE
  To examine the temporal occurrence of these two outcomes in order to provide insight into mechanisms and early cardiovascular disease identification.
  
  
  METHODS
  Functional and structural cardiovascular alterations were assessed in C57BL6 mice exposed to intermittent hypoxia (21-4% Fi(O(2)), 30-s cycle, 8 h/d) or air for up to 35 days. Blood pressure, heart rate, and urinary catecholamines were measured at Days 1 and 14. Hindquarter vasoreactivity was assessed at Days 14 and 35, including vasoconstriction to norepinephrine, endothelium-, and non-endothelium-dependent vasodilation. Aorta, heart, and hindquarter skeletal muscles were immunostained for vascular markers PECAM-1 and collagen IV.
  
  
  RESULTS
  Hemodynamic alterations occurred from Day 1, characterized by blood pressure surges with bradytachyarrhythmia driven by cyclic hypoxia. At Day 14, blood pressure at normoxia was elevated, with predominant diastolic increase. With hypoxia, vasopressive catecholamines were elevated, blood pressure surged with a lower hypoxic threshold, whereas heart rate fluctuations decreased. Histologic alterations started from Day 14, with decreased endothelial PECAM-1 expression in descending aorta and left heart. Impaired peripheral vasoreactivity occurred at Day 35, including hypervasoconstriction to norepinephrine secondary to sympathetic hyperactivity, without changes in pre- and postsynaptic alpha-adrenoceptors or in endothelium- and non-endothelium-dependent vasodilation.
  
  
  CONCLUSIONS
  Intermittent hypoxia induces sequential cardiovascular events suggesting increased chemoreflex and depressed baroreflex, resulting in sympathoadrenal hyperactivity, early hemodynamic alterations with proximal histologic remodeling, and delayed changes in peripheral vasoreactivity. Such early alterations before overt cardiovascular disease strengthen the need for identifying at-risk individuals for systematic treatment.
authors.affiliation: Laboratoire HP2, Institut Jean Roget, Faculté de Médecine de Grenoble, 38042 Grenoble Cedex 09, France. maurice.dematteis@ujf-grenoble.fr
authors.forename: Maurice
authors.initials: M
authors.lastname: Dematteis
authors.forename: Cécile
authors.initials: C
authors.lastname: Julien
authors.forename: Christiane
authors.initials: C
authors.lastname: Guillermet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sturm
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
authors.forename: Michel
authors.initials: M
authors.lastname: Mallaret
authors.forename: Patrick
authors.initials: P
authors.lastname: Lévy
authors.forename: Evelyne
authors.initials: E
authors.lastname: Gozal
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D002395:Catecholamines / Q000097:blood; D004195:Disease Models, Animal; D006339:Heart Rate; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D012891:Sleep Apnea Syndromes / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000097:blood; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation; D020257:Ventricular Remodeling
chemical_list: D002395:Catecholamines; D053773:Transforming Growth Factor beta1; D000109:Acetylcholine