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Archives of cardiovascular diseases
Volume 102, n° S1
page 44 (mars 2009)
Doi : 10.1016/S1875-2136(09)72231-4
Themes et posters

D021 Sildenafil induced-revascularization of rat hindlimb involved arteriogenesis through PI3K/-Akt and eNOS activation
 

C. Menguy 1, A. Bocquet 1, A.-L. Guihot 1, B. Toutain 1, M. Rolli-derkinderen 2, D. Chappard 3, P. Pacaud 2, G. Loirand 2, D. Henrion 1, L. Loufrani 1
1 UMR CNRS 6214 Inserm 771, Angers, France 
2 Inserm U915, Nantes, France 
3 Inserm EMI 0335, Angers, France 

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Hypoxia and inflammation play a major role in the revascularization following ischemia. Sildenafil inhibits phosphodiesterase-5, increases intracellular cGMP content and thus induces vasodilation. Sildenafil also induces neovascularization following ischemia but through a pathway remaining incompletely understood. Thus, we investigated the consequences of a long-term sildenafil treatment on post-ischemic revascularization.

The left femoral artery was ligated in sildenafil (25mg/kg per day)-treated rats. Vascular density and blood flow were evaluated in both legs and expressed as left/right leg (L/R) ratio. After 7 or 21 days, the L/R ratio was 33¡Ó2 % and 54¡Ó9 %, respectively in control rats. Sildenafil increased significantly the ratio to 47¡Ó4 % and 128¡Ó11 %, respectively. A neutralizing VEGF antibody significantly decreased vascular density (×0.48-fold) in control rats without affecting density in sildenafil-treated animals. Blood flow and arteriolar density followed the same pattern. In the ischemic leg, HIF1ƒÑ and VEGF expression level increased in control, not in sidenafil ¡Vtreated rats, suggesting that sildenafil might not preferentially induce angiogenesis. PI3-kinase, Akt and eNOS were activated after 7 days with a down-regulation after 21 days. Sildenafil-induced migration of endothelial cells was prevented by PI3-kinase inhibition with LY294002. Finally, sildenafil-induced rise in blood flow in mesenteric resistance arteries was associated with an increased luminal diameter (outward remodeling or arteriogenesis). This arteriogenesis was also associated with eNOS proteins activation.

Conclusion

– Long term sildenafil treatment increased local blood flow and collateral arteries growth independent of VEGF but in association with activation of PI3-kinase, Akt and eNOS which might preferentially activate arteriogenesis.

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