Objective-Angiotensin (Ang) II-induced vascular damage may be partially mediated by reactive oxygen species generation and inflammation. Homozygous osteopetrotic mice (Op/Op), deficient in macrophage colony-stimulating factor (m-CSF), exhibit reduced inflammation. We therefore investigated Ang II effects on vascular structure, function, and oxidant stress generation in this model. Methods and Results-Adult Op/Op, heterozygous (Op/ϩ), and wild type (ϩ/ϩ) mice underwent 14-day Ang II (1000 ng/kg per minute) or saline infusion. Blood pressure (BP) was assessed by radiotelemetry, mesenteric resistance artery vascular reactivity was studied on a pressurized myograph, and vascular superoxide and NAD(P)H oxidase activity by lucigenin chemiluminescence. Ang II increased BP in Op/ϩ and ϩ/ϩ mice but not in Op/Op. Ang II-treated Op/ϩ and ϩ/ϩ mice showed reduced acetylcholine-mediated relaxation (maximal relaxation, respectively, 64% and 67% versus 84% and 93% in respective controls; PϽ0.05), which was unaffected by L-NAME. Ang II-infused Op/Op mice arteries showed significantly less endothelial dysfunction than vehicle-infused counterparts (maximal relaxation 87% versus 96% in shams). Resistance arteries from Ang II-infused ϩ/ϩ and Op/ϩ mice had significantly increased media-tolumen ratio and media thickness, neither of which was altered in Op/Op mice compared with untreated littermates. Vascular media cross-sectional area, NAD(P)H oxidase activity and expression, and vascular cell adhesion molecule (VCAM)-1 expression were significantly increased by Ang II only in ϩ/ϩ mice (PϽ0.05). Key Words: hypertension Ⅲ macrophages Ⅲ reactive oxygen species I nflammation plays an important pathophysiological role in the development and progression of atherosclerosis, hypertension, and other conditions associated with vascular damage. 1 Macrophage colony-stimulating factor (m-CSF) functions as a chemotactic factor for monocytes, regulates effector functions of mature monocytes and macrophages, and modulates inflammatory responses by stimulating the production of other cytokines, adhesion molecules, and growth factors. 2,3 Macrophages have the ability to secrete various cytokines, including tumor necrosis factor (TNF)-␣ that can ultimately influence vascular inflammation. 4 Mice deficient in m-CSF, the result of a spontaneously occurring osteopetrotic mutation within the m-CSF gene, possess macrophage deficiency, monocytopenia, and defective bone formation. [5][6][7] Recently, it was demonstrated that m-CSF-deficient mice fed an atherogenic diet or crossed into a hypercholesterolemic apolipoprotein E-null background have significant reduction in atherosclerotic lesions. 8,9 However, whether reduced macrophage number as a result of the osteopetrotic mutation confers microvascular protection in hypertension remains to be determined. These mice may represent a good model to better understand mechanisms leading to vascular injury mediated by oxidative stress and inflammation in hypertension associated with the activation of the renin-angio...

The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFHFS) and control rats were studied using micro-PET (microPET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [(18)F]fluorodeoxyglucose ([(18)F]FDG) was reduced by approximately 81% (P < 0.05), whereas myocardial plasma nonesterified fatty acid (NEFA) uptake as determined by [(18)F]fluorothia-6-heptadecanoic acid ([(18)F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [(11)C]acetate and myocardial perfusion index as assessed by [(13)N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by microPET was reduced by 26% in HFHFS rats (P < 0.05). Without glucose clamp, NEFA uptake was approximately 40% lower in HFHFS rats (P < 0.05). However, myocardial uptake of [(18)F]FTHA administered by gastric gavage was significantly higher in HFHFS rats (P < 0.05). These abnormalities were associated with reduced Glut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase 1 activity (P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA.

Abstract-We investigated the role of angiotensin II type 1 (AT 1 ) and AT 2 receptors, matrix metalloproteinases (MMPs), and extracellular matrix (ECM) components involved in vascular remodeling of resistance arteries induced by angiotensin II (Ang II). Sprague-Dawley rats received Ang II (120 ng/kg per minute SC) Ϯ the AT 1 antagonist losartan (10 mg/kg per day PO), the AT 1 /AT 2 antagonist Sar 1 -Ile 8 -Ang II (Sar-Ile; 10 g/kg per minute SC), or hydralazine (25 mg/kg per day PO) for 7 days. Structure and mechanical properties of small mesenteric arteries were evaluated on a pressurized myograph. Ang II increased growth index (ϩ21%), which was partially decreased by losartan (Ϫ11%) and abrogated by Sar-Ile. Hydralazine markedly increased growth index (ϩ32%) despite systolic blood pressure (BP) lowering, suggesting a BP-independent effect of Ang II on vascular growth. Elastic modulus was increased by Sar-Ile compared with Ang II and control. Vascular type I collagen was reduced (PϽ0.05), whereas fibronectin increased significantly with Sar-Ile. Vascular tissue inhibitor of metalloproteinase-2 binding to MMP-2 was abrogated by Sar-Ile, but MMP-2 activity was significantly increased compared with losartan, Ang II, and controls. Thus, AT 1 blockade exerted antigrowth effects and reduced stiffness of small resistance arteries by decreasing nonelastic fibrillar components (collagen and fibronectin). Concomitant AT 1 /AT 2 blockade prevented growth, reduced collagen type I and elastin deposition but increased vascular stiffness, fibronectin, and MMP-2 activity. These results demonstrate opposing roles of AT 1 receptors that increase fibronectin and vascular stiffness and AT 2 receptors that decrease MMP-2 and increase elastin. Changes in vascular wall mechanics, ECM deposition, and MMP activity are thus modulated differentially by Ang II receptors. Key Words: collagen Ⅲ extracellular matrix Ⅲ renin-angiotensin system A ngiotensin II (Ang II), a potent vasoconstrictor of small resistance arteries, induces hypertrophy and hyperplasia of vascular smooth muscle cells (SMCs) mainly via Ang II type 1 (AT 1 ) receptors and has been implicated in the development and maintenance of hypertension. 1 Most of the biological effects of Ang II are mediated through AT 1 receptors. AT 2 receptor function is less well defined. Despite low AT 2 receptor expression in adult tissues, their abundance is increased after blood vessel injury 2 and can equal or exceed that of AT 1 in pathophysiological conditions. 3 The functional significance of AT 2 receptors remains uncertain. However, a recent study demonstrated that intrabrachial infusion of the AT 2 receptor antagonist PD123319 had significant systemic effects on mean arterial pressure during placebo and therapy with the AT 1 receptor antagonist telmisartan without affecting forearm blood flow, suggesting the presence of functionally effective AT 2 receptors. 4 Additionally, the AT 1 receptor antagonist candesartan unmasked the vasodilatory response to Ang II, suggesting that AT 2 rece...

Increased RaNEFA and OxNEFA during intravascular lipolysis at high insulin levels occur early in the natural history of type 2 diabetes.