OBJECTIVES: Mechanisms involved in hypertension in homozygous mice for the defective endothelial nitric oxide synthase gene (eNOS-/-) have not been fully elucidated. As NO is a potent vasodilator agent and possibly promotes angiogenesis, we investigated whether vasoconstriction and/or microvascular rarefaction could explain hypertension in these mice. METHODS: Immunohistochemistry with mouse monoclonal smooth muscle alpha-actin antibody was used to detect arterioles, and quantification of arteriolar density was performed in the left ventricle and in the gracilis muscle of 12-week-old male eNOS+/+ and eNOS-/- mice. Haemodynamic parameters - mean arterial pressure (MAP), cardiac index (CI), total peripheral résistance (TPR), myocardial blood flow, muscular blood flow and corresponding resistances - were measured or calculated using the fluorescent microsphere method in basal conditions and after infusion of sodium nitroprusside (SNP) (5 to 150 microg/kg per min) in eNOS-/- mice, compared with eNOS+/+ mice. RESULTS: We evidenced a significant decrease in arteriolar density in the heart (-16%, P < 0.02) and in the gracilis muscle (-22%, P < 0.05) in eNOS-/- mice. In basal conditions, eNOS-/- mice developed significant hypertension (MAP = 127 +/- 14 versus 77 +/- 14 mmHg, P < 0.001) associated with decreased CI (-29%, P < 0.001) and increased TPR (+ 125%, P < 0.001). Coronary and gracilis muscular resistances were increased (by 75 and 89% respectively, P < 0.001) compared with eNOS+/+ mice, whereas myocardial and skeletal muscle tissue blood flows were not affected. After SNP administration (10 microg/kg per min), a dose that did not significantly modify haemodynamic parameters in eNOS+/+ mice, MAP, TPR and regional resistances were normalized in eNOS-/- mice, showing that vasodilation may correct hypertension in eNOS-/- mice. However, under maximal vasodilating conditions, TPR and regional resistances remained significantly higher in eNOS-/- mice than those of eNOS+/+ mice. CONCLUSION: Anatomical and functional results show that both vasoconstriction and arteriolar rarefaction are involved in hypertension of eNOS-/- mice. Indeed, under maximal vasodilation, arterial pressure and TPR remained significantly higher in eNOS-/- mice than in eNOS+/+ mice, evidencing a major role of microvascular rarefaction in this model of hypertension.
OBJECTIVES: Mechanisms involved in hypertension in homozygous mice for the defective endothelial nitric oxide synthase gene (eNOS-/-) have not been fully elucidated. As NO is a potent vasodilator agent and possibly promotes angiogenesis, we investigated whether vasoconstriction and/or microvascular rarefaction could explain hypertension in these mice. METHODS: Immunohistochemistry with mouse monoclonal smooth muscle alpha-actin antibody was used to detect arterioles, and quantification of arteriolar density was performed in the left ventricle and in the gracilis muscle of 12-week-old male eNOS+/+ and eNOS-/- mice. Haemodynamic parameters - mean arterial pressure (MAP), cardiac index (CI), total peripheral résistance (TPR), myocardial blood flow, muscular blood flow and corresponding resistances - were measured or calculated using the fluorescent microsphere method in basal conditions and after infusion of sodium nitroprusside (SNP) (5 to 150 microg/kg per min) in eNOS-/- mice, compared with eNOS+/+ mice. RESULTS: We evidenced a significant decrease in arteriolar density in the heart (-16%, P < 0.02) and in the gracilis muscle (-22%, P < 0.05) in eNOS-/- mice. In basal conditions, eNOS-/- mice developed significant hypertension (MAP = 127 +/- 14 versus 77 +/- 14 mmHg, P < 0.001) associated with decreased CI (-29%, P < 0.001) and increased TPR (+ 125%, P < 0.001). Coronary and gracilis muscular resistances were increased (by 75 and 89% respectively, P < 0.001) compared with eNOS+/+ mice, whereas myocardial and skeletal muscle tissue blood flows were not affected. After SNP administration (10 microg/kg per min), a dose that did not significantly modify haemodynamic parameters in eNOS+/+ mice, MAP, TPR and regional resistances were normalized in eNOS-/- mice, showing that vasodilation may correct hypertension in eNOS-/- mice. However, under maximal vasodilating conditions, TPR and regional resistances remained significantly higher in eNOS-/- mice than those of eNOS+/+ mice. CONCLUSION: Anatomical and functional results show that both vasoconstriction and arteriolar rarefaction are involved in hypertension of eNOS-/- mice. Indeed, under maximal vasodilation, arterial pressure and TPR remained significantly higher in eNOS-/- mice than in eNOS+/+ mice, evidencing a major role of microvascular rarefaction in this model of hypertension.
Authors: Zoltan Ungvari; Stefano Tarantini; Tamas Kiss; Jonathan D Wren; Cory B Giles; Courtney T Griffin; Walter Lee Murfee; Pal Pacher; Anna Csiszar Journal: Nat Rev Cardiol Date: 2018-09 Impact factor: 32.419
Authors: Ian M Williams; P Mason McClatchey; Deanna P Bracy; Francisco A Valenzuela; David H Wasserman Journal: Diabetes Date: 2018-07-12 Impact factor: 9.461
Authors: Liliana Viera; Milka Radmilovich; Marcelo R Vargas; Cassandra N Dennys; Landon Wilson; Stephen Barnes; Maria Clara Franco; Joseph S Beckman; Alvaro G Estévez Journal: Free Radic Biol Med Date: 2012-11-27 Impact factor: 7.376