Chronic hypoxia-induced angiogenesis normalizes blood pressure in spontaneously hypertensive rats

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.