An increase in pulse pressure (PP) is highly associated with hypertension. The goal of this study was to determine the effect of increased aortic stiffness on PP and endothelial dysfunction as precursors to hypertension. A rat model of suddenly increased aortic stiffness by use of a nonconstrictive restraint (glue coating) on aortic surface was created to investigate the change of PP and mean arterial pressure (MAP). Group I (n ϭ 16) underwent aorta restraint for 4 wk. Group II (n ϭ 12) underwent aortic restraint for 4 wk, followed by restraint removal to evaluate extent of reversibility for additional 4 wk. The aortic and peripheral endothelial function was assessed by ACh-stimulated endothelium-dependent vasodilation. The level of nitrate/nitrite (NOx), endothelin-1 (ET-1), and prostacyclin (PGI 2) were measured in the serum and artery tissue. We found that aortic stiffening causes a significant increase in PP and MAP (P Ͻ 0.05). The endothelial function was markedly blunted (P Ͻ 0.05) in both aorta and small peripheral artery. After removal of the restraint, the impaired endothelium function persisted in the aorta likely due to sustained deterioration of aortic wall, but was partially restored in peripheral artery. The endothelial dysfunction was correlated with a decrease in NOx and PGI 2 (P Ͻ 0.05) and an increase in ET-1 (P Ͻ 0.05). Our results show that aortic stiffening results in widening of PP, which affected endothelium function through changes in synthesis of NOx, ET-1, and PGI 2. These findings suggest that increased aortic stiffness may be a cause of increased PP and a precursor to hypertension. hypertension; endothelial function; nitric oxide; endothelin; prostacyclin AORTIC STIFFENING HAS DEMONSTRATED an independent predictive value for cardiovascular events such as aging (29), hypertension (4, 13), diabetes (9), myocardial infarction (20), heart failure (6), and stroke (17). The blood pressure (BP) waveform is a composite of steady component [mean arterial pressure (MAP)] and pulsatile component [pulse pressure (PP)] (23). Previous studies have shown that, independent of MAP, PP was a strong determinant of cardiovascular diseases in hypertensive patients and in general population, especially in the elderly (2, 3). Increased aortic stiffness may contribute to the widening of PP and development of systolic hypertension (21). Although the conventional theory is that arterial stiffness is the result of hypertension rather than its cause, some recent studies suggest that the relationship between hypertension and arterial stiffness may be bidirectional (10, 18). There is lack of direct evidence, however, for the cause-and-effect relation between increased arterial stiffness and increased PP (a precursor to hypertension).Dysfunction of the vascular endothelium occurs in hypertension and related cardiovascular diseases (24,25). It is known that the vascular endothelium regulates vascular tone and maintains cardiovascular homeostasis by the release of some vasoactive factors (24). Of these, nitric oxide ...

Slow moving blood flow and changes in flow direction, e.g., negative wall shear stress, can cause increased superoxide (O2 ·Ϫ ) production in vascular endothelial cells. The mechanism by which shear stress increases O2·Ϫ production, however, is not well established. We tested the hypothesis that actin depolymerization, which occurs during flow reversal, mediates O2 ·Ϫ production in vascular endothelial cells via NADPH oxidase, and more specifically, the subunit p47 phox . Using a swine model, we created complete blood flow reversal in one carotid artery, while the contralateral vessel maintained forward blood flow as control. We measured actin depolymerization, NADPH oxidase activity, and reactive oxygen species (ROS) production in the presence of various inhibitors. Flow reversal was found to induce actin depolymerization and a 3.9 Ϯ 1.0-fold increase in ROS production as compared with forward flow. NADPH oxidase activity was 1.4 Ϯ 0.2 times higher in vessel segments subjected to reversed blood flow when measured by a direct enzyme assay. The NADPH oxidase subunits gp91 phox (Nox2) and p47 phox content in the vessels remained unchanged after 4 h of flow reversal. In contrast, p47 phox phosphorylation was increased in vessels with reversed flow. The response caused by reversed flow was reduced by in vivo treatment with jasplakinolide, an actin stabilizer (only a 1.7 Ϯ 0.3-fold increase). Apocynin (an antioxidant) prevented reversed flow-induced ROS production when the animals were treated in vivo. Cytochalasin D mimicked actin depolymerization in vitro and caused a 5.2 Ϯ 3.0-fold increase in ROS production. These findings suggest that actin filaments play an important role in negative shear stress-induced ROS production by potentiating NADPH oxidase activity, and more specifically, the p47 phox subunit in vascular endothelium.endothelial cells

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Although hemodynamics changes occur in heart failure (HF) and generally influence vascular function, it is not clear whether various HF models will affect the conduit vessels differentially or whether local hemodynamic forces or systemic factors are more important determinants of vascular response in HF. Here, we studied the hemodynamic changes in tachycardia or volume-overload HF swine model (created by either high rate pacing or distal abdominal aortic-vena cava fistula, respectively) on carotid, femoral, and renal arteries function and molecular expression. The ejection fraction was reduced by 50% or 30% in tachycardia or volume-overload model in four weeks, respectively. The LV end diastolic volume was increased from 65±22 to 115±78 ml in tachycardia and 67±19 to 148±68 ml in volume-overload model. Flow reversal was observed in diastolic phase in carotid artery of both models and femoral artery in volume-overload model. The endothelial function was also significantly impaired in carotid and renal arteries of tachycardia and volume-overload animals. The endothelial dysfunction was observed in femoral artery of volume-overload animals but not tachycardia animals. The adrenergic receptor-dependent contractility decreased in carotid and femoral arteries of tachycardia animals. The protein expressions of NADPH oxidase subunits increased in the three arteries and both animal models while expression of MnSOD decreased in carotid artery of tachycardia and volume-overload model. In conclusion, different HF models lead to variable arterial hemodynamic changes but similar vascular and molecular expression changes that reflect the role of both local hemodynamics as well as systemic changes in HF.