Hypercholesterolemia Inhibits Angiogenesis in Response to Hindlimb Ischemia : Nitric Oxide-Dependent Mechanism

Duan, Jun‐Li; Murohara, Toyoaki; Ikeda, Hisao; Katoh, Atsushi; Shintani, Satoshi; Sasaki, Ken-ichiro; Kawata, Hidemichi; Yamamoto, Naoki; Imaizumi, Tsutomu

doi:10.1161/01.cir.102.suppl_3.iii-370

Cited by 111 publications

(129 citation statements)

References 25 publications

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“…This conclusion is consistent with the observation that the impaired angiogenic response to hindlimb ischemia in fat-fed rats is associated with an increase in tissue ADMA levels and a reduction of skeletal muscle cGMP. 35 A role for DDAH in angiogenesis has recently been outlined by other investigators. Transfection of DDAH into a glioma tumor cell line promotes tumor angiogenesis and growth in vivo.…”

Section: Discussionmentioning

confidence: 94%

Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis

et al. 2005

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Background-This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Methods and Results-In DDAH1 transgenic (TG) and wild-type mice (each nϭ42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each nϭ21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or N -nitro-L-arginine methyl ester (L-NAME; each 250 mol · kg Ϫ1 · d Ϫ1 ) by use of osmotic minipumps (each nϭ7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity. Conclusions-We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion. (Circulation.

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Section: Discussionmentioning

confidence: 94%

Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis

et al. 2005

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“…Although a great deal of research has been conducted on the effects of exogenous L-arginine on the circulatory system, most of the studies have focused on the effect of L-arginine administration on blood pressure in experimental models of hypertension (20)(21)(22) and in patients (16,23,24); the improvement of blood flow or exercise capacity in patients with chronic heart failure (17), hypertension (18), and hypercholesterolemia (25); and the prevention of atherosclerosis (11). Few reports exist on the effect of L-arginine on capillary blood flow in normotensive subjects (16,(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Low-dose l -arginine administration increases microperfusion of hindlimb muscle without affecting blood pressure in rats

Ohta

Takagi

Sato

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The objective of this work was to evaluate the influence of exogenous L-arginine on the capillary blood flow of peripheral tissues of normotensive subjects. Rats were anesthetized with sodium pentobarbital, and the blood flow of femoral, dorsal, and ventral skin and gastrocnemius and soleus muscle was measured by laser Doppler flow and microsphere methods to compare the blood flow before and after the L-arginine infusion. L-Arginine lowered the mean blood pressure in a dose-dependent manner, but a statistically significant reduction in mean blood pressure was detected only at a high dose of 500 mg/kg of body weight. The significant blood flow increment was detected after the L-arginine infusion at doses of 50 and 150 mg/kg without causing hypotension. Nicardipine, a calcium channel blocker, also increased the skin blood flow, but the blood flow increment and blood pressure fall were comparable. A significant increment in microperfusion was detected in gastrocnemius, soleus muscle, and ventral skin compared with control group by the microsphere method. No adverse effects were observed during L-arginine and microsphere infusion. The present work indicates that L-arginine infusion increases muscle capillary blood flow in rats that are not performing exercise. Supplementation with L-arginine might provide additional blood flow at rest and during exercise and result in the improvement of muscle performance and exercise capacity.exercise ͉ nitric oxide N itric oxide (NO) is a widespread signaling molecule that is involved in mammalian physiological processes including the relaxation of blood vessels (1-3), immune function (4), inhibition of platelet aggregation (5, 6), and neurotransmission (7). The amino acid L-arginine is the natural precursor for the formation of NO (8), and exogenous L-arginine administration causes the relaxation of blood vessels through the action of NO (9, 10). Although NO synthase, the enzyme that produces NO from L-arginine, is theoretically saturated with its natural substrate, exogenous L-arginine administration leads to increased NO production, and this phenomenon is known as the arginine paradox (9, 10). Therefore, many investigators have been interested in the effects of supplementation with L-arginine to produce increased beneficial effects of NO, including prevention of the progression of atherosclerosis (11, 12), prevention of pulmonary artery endothelial dysfunction (13, 14), enhancement of cellular immune response of T lymphocytes (4), and amelioration of hypertension (15,16). Other studies indicate that oral supplementation of L-arginine also corrects endothelial dysfunction of chronic heart failure (17), and it increases exercise capacity in patients with precapillary pulmonary hypertension by increasing peak oxygen consumption and decreasing pulmonary arterial pressure and pulmonary vascular resistance thorough the action of NO (18).Because oxygen and carbon dioxide exchange takes place only in the capillary bed, the peripheral blood flow correlates with the rate of oxygen uptake...

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“…Twenty different random microscopic fields on five different sections from each animal were photographed and analyzed by MetaMorph software. Capillary density was expressed as number of capillaries per high power field (ϫ400) as described previously (27,28).…”

Section: Generation Of Ec-selective Mir-15a Transgenic (Ec-mir-15a Tg)mentioning

confidence: 99%

Vascular Endothelial Cell-specific MicroRNA-15a Inhibits Angiogenesis in Hindlimb Ischemia

Yin

Olsen

Hamblin

et al. 2012

Journal of Biological Chemistry

124

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Background: MicroRNAs mediate angiogenesis in both physiological and pathological conditions, but underlying molecular mechanisms are largely unexplored. Results: Endothelial miR-15a negatively regulates angiogenesis in vivo and in vitro by suppression of FGF2 and VEGF. Conclusion: MiR-15a inhibits endothelial autonomous angiogenesis. Significance: MiR-15a is a negative regulator of angiogenesis and a potential target for the restorative therapy of ischemic diseases.

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Hypercholesterolemia Inhibits Angiogenesis in Response to Hindlimb Ischemia : Nitric Oxide-Dependent Mechanism

Cited by 111 publications

References 25 publications

Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis

Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis

Low-dose l -arginine administration increases microperfusion of hindlimb muscle without affecting blood pressure in rats

Vascular Endothelial Cell-specific MicroRNA-15a Inhibits Angiogenesis in Hindlimb Ischemia

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