title: Chronic hypoxia-induced angiogenesis normalizes blood pressure in spontaneously hypertensive rats.
abstract: We hypothesized that activation of angiogenesis by chronic hypoxia may affect vascular resistance and, subsequently, blood pressure levels in spontaneously hypertensive rats (SHRs). Five-week-old prehypertensive SHRs and age-matched normotensive Wistar-Kyoto (WKY) rats (n=8 per group) were maintained under normobaric normoxic or hypoxic (10% O(2)) conditions for 8 weeks. Three weeks later, the systolic blood pressure was lower by 26% in hypoxic SHRs compared to normoxic SHRs (P<0.05) and remained at the normoxic WKY level. Total peripheral vascular resistance, calculated as the mean arterial pressure/cardiac output (assessed by ultrasound imaging and Doppler), was 30% lower in hypoxic than in normoxic SHRs (P<0.001) and returned to WKY levels. Interestingly, chronic hypoxia also significantly reduced systolic blood pressure in adult 12-week-old SHRs with established hypertension; blood pressure was normalized (versus normoxic WKY rats) after 4 weeks of hypoxia. Changes in hemodynamic parameters were associated with activation of proangiogenic pathways. Protein levels of vascular endothelial growth factor (VEGF)-A in the skeletal muscles were increased by 2.2-fold in hypoxic compared to normoxic SHRs (P<0.001). At the end of the hypoxic period, capillary density in the quadriceps muscle was 1.2-fold higher in hypoxic than in normoxic SHRs (P<0.001). Myocardial capillary density and VEGF-A protein contents were also 1.2- and 2.1-fold higher in hypoxic compared to normoxic SHRs (P<0.001 and P<0.05, respectively). Moreover, treatment with neutralizing VEGF-A antibody abrogated the hypoxia-induced angiogenesis and subsequently worsened arterial hypertension. Therefore, our results suggest that chronic normobaric hypoxia (1) activates VEGF-A-induced angiogenesis and thereafter (2) prevents the occurrence of hypertension in young prehypertensive SHRs and (3) normalizes blood pressure in adult SHRs with established hypertension.
authors.affiliation: Cardiovascular Research Center, Institut National de la Santé et de la Recherche Médicale Lariboisière Unit 689, and Université Paris 7-Denis Diderot, Hôpital Lariboisière, Paris, France.
authors.forename: José
authors.initials: J
authors.lastname: Vilar
authors.forename: Ludovic
authors.initials: L
authors.lastname: Waeckel
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.forename: Clément
authors.initials: C
authors.lastname: Cochain
authors.forename: Céline
authors.initials: C
authors.lastname: Loinard
authors.forename: Micheline
authors.initials: M
authors.lastname: Duriez
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Lévy
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002302:Cardiac Output; D002908:Chronic Disease; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014655:Vascular Resistance
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat