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(Circulation Research. 2008;103:761.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Chronic Hypoxia–Induced Angiogenesis Normalizes Blood Pressure in Spontaneously Hypertensive Rats

José Vilar, Ludovic Waeckel, Philippe Bonnin, Clément Cochain, Céline Loinard, Micheline Duriez, Jean-Sébastien Silvestre, Bernard I. Lévy

From the 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.

Correspondence to Bernard Lévy, U689 INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris Cedex 10, France. E-mail bernard.levy{at}inserm.fr

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% O₂) 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.

Key Words: hypoxia • angiogenesis • hypertension