P262	Hypoxia-induced angiogenesis prevents the development of hypertension in Spontaneously Hypertensive Rats (SHR).
J.Vilar, L.Waeckel, Ph.Bonin, M.Duriez, J-S.Silvestre, B.I.Lévy
Cardiovascular Research Center Inserm U689, Paris, FR.

Introduction. In SHR, the development of hypertension is associated with increased peripheral vascular resistance and microvascular rarefaction. We hypothesized that activation of angiogenesis by chronic hypoxia in the setting of hypertension may affect vascular resistance and, subsequently blood pressure. Methods and Results. 5-week-old SHR and age-matched normotensive Wistar-Kyoto rats (WKY) (n=8 per groups) were maintained under normoxic or hypoxic (10% O2) conditions for 8 weeks. Tail cuff blood pressure (BP) was measured weekly in conscious rats. BP in 11 weeks-old hypoxic SHR returned to normoxic WKY levels, suggesting that chronic hypoxia significantly prevented the BP increase in SHR. However, returning rats to normoxia for 2 weeks caused BP to increase to BP levels of SHR maintained in normoxic conditions. At the end of the hypoxic period, skin foot perfusion was increased by 2.1-fold in hypoxic SHR compared to normoxic SHR, as assessed by laser Doppler imaging (p=0.0001). Furthermore, capillary density in the gastrocnemius muscle was upregulated by 1.2-fold in hypoxic compared to normoxic SHR (1014±20 versus 831±36 capillary/mm2, respectively , p=0.0006). Protein levels of VEGF, a key angiogenic factor, was also increased by 2.2–fold in hypoxic compared to normoxic SHR (p=0.012). Angiographic scores were not modified by hypoxia suggesting that hypoxia affects angiogenesis and not collateral growth. Myocardial capillary density and VEGF protein contents were also raised by 1.2- and 2.5-fold, respectively in hypoxic compared to normoxic SHR (p=0.0003 and p=0.05, respectively) demonstrating that hypoxia also improves angiogenesis in the heart. The overall increase in tissue capillary density may affect total peripheric resistance (TPR). Using echographic-Doppler, we evidenced that TPR was lower in hypoxic compared to normoxic SHR (601±49 versus 911±57 mmHg/ml/min.cm2 respectively; p=0.0004) and returned to normoxic WKY levels. Conclusion. Chronic hypoxia stimulates tissue angiogenesis and subsequently affects total peripheral vascular resistance preventing the development of hypertension in SHR.

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