Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension.
Arterial hypertension is a major risk factor that can lead to complication of peripheral vascular disease due, in part, to endothelial dysfunction. Because sodium nitrite (SN) can be converted to nitric oxide (NO), which counteracts endothelial dysfunction, we explored the effect of nitrite on neovascularization following hind limb ischemia in different models of hypertension (HT). Chronic delivery of angiotensin II (Ang II, 400 ng/kg/min) or N(omega)-nitro-L-arginine-methyl-ester (L-NAME, 0.1 g/L) was used for a 2-week period to induce hypertension. Mice were subjected to femoral artery ligation-induced ischemia in the hind limb followed by treatment with SN (50 mg/L) for 2 weeks. SN significantly reduced systolic arterial blood pressure in mice receiving Ang II and L-NAME but had no effect in sham animals. After 2 weeks, blood flow and microangiography showed 60 % ± 1.0 recovery in sham compared with 40 % ± 1.3 in HT mice. Importantly, sham and HT mice treated with SN showed a 100 % blood flow recovery associated with normalization in capillary density. The inhibition of xanthine-oxido-reductase (allopurinol) or VEGFR (SU-5416) prevented the neovascularization in HT mice treated with SN. Cyclic GMP (cGMP) content in the hind limb was significantly increased in mice treated with SN compared with non-treated mice. Nitrite/nitrate content was only increased in the sham group treated with SN. Immunoprecipitation and Western blot analysis revealed an increase in eNOS/Akt/VEGFR phosphorylation in skeletal muscle from mice treated with SN compared with non-treated mice. Our findings indicate that SN therapy rescues the neovascularization and blood flow recovery in the ischemic hind limb of sham and HT mice likely through the Akt/NO/cGMP and VEGFR pathways.
Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, 1430 Tulane Ave, New Orleans, LA 70112, USA.
Ali
A
Amin
Soo-Kyoung
SK
Choi
Yehia
Y
Osman-Elazeik
Nariman K
NK
Badr El-Din
Christopher G
CG
Kevil
Louis G
LG
Navar
Philip
P
Kadowitz
Mohamed
M
Trebak
Khalid
K
Matrougui
D000493:Allopurinol / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects*; D012977:Sodium Nitrite / Q000494:pharmacology*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D007211:Indoles; D011758:Pyrroles; D000804:Angiotensin II; D009569:Nitric Oxide; D000493:Allopurinol; C116890:Semaxinib; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; D014968:Xanthine Dehydrogenase; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP; D012977:Sodium Nitrite; D019331:NG-Nitroarginine Methyl Ester