Vascular endothelial growth factor is expressed in endothelial cells isolated from skeletal muscles of nitric oxide synthase knockout mice during prazosin-induced angiogenesis

Silva-Azevedo, Luis Da; Baum, Oliver; Zakrzewicz, Andreas; Pries, Axel R.

doi:10.1016/s0006-291x(02)02370-7

Cited by 40 publications

(38 citation statements)

References 34 publications

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“…eNOS has been shown to be important for shear stress-induced angiogenesis (Baum et al, 2004), an effect likely mediated in part by NO stimulation of vascular endothelial growth factor (VEGF) production (Tsurumi et al, 1997;Da Silva-Azevedo et al, 2002). VEGF is thought to be one of the most important growth factors regulating capillary supply in muscle (Wagner, 2011).…”

Section: Introductionmentioning

confidence: 99%

Alpha adrenergic receptor blockade increases capillarization and fractional O₂ extraction and lowers blood flow in contracting human skeletal muscle

et al. 2017

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Aim To assess the effect of elevated basal shear stress on angiogenesis in humans and the role of enhanced skeletal muscle capillarization on blood flow and O2 extraction. Methods Limb haemodynamics and O2 extraction were measured at rest and during one‐leg knee‐extensor exercise (12 and 24 W) in 10 healthy untrained young men before and after 4‐week treatment with an α1 receptor‐antagonist (Terazosin, 1–2 mg day−1). Corresponding biopsies were taken from the m. vastus lateralis. Results Resting leg blood flow was increased by 57% 6 h following Terazosin treatment (P < 0.05), while basal capillary‐to‐fibre ratio was 1.69 ± 0.08 and increased to 1.90 ± 0.08 after treatment (P < 0.05). Leg O2 extraction during knee‐extensor exercise was higher (4–5%; P < 0.05), leg blood flow and venous lactate levels lower (6–7%; P < 0.05), while leg VO2 was not different after Terazosin treatment. Conclusions These results demonstrate that daily treatment with an α‐adrenergic receptor blocker induces capillary growth in human skeletal muscle, likely due to increased shear stress. The increase in capillarization resulted in an increased fractional O2 extraction, a lower blood flow and venous lactate levels in the exercising leg. The increase in capillarization, and concomitant functional readouts in the exercising leg, may provide a basis for novel angiotherapy.

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Section: Introductionmentioning

confidence: 99%

Alpha adrenergic receptor blockade increases capillarization and fractional O₂ extraction and lowers blood flow in contracting human skeletal muscle

et al. 2017

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“…Given the increased expression of VEGF in diabetes, the reduced NO bioavailability theoretically could result in an uncoupling of VEGF with NO. It is interesting that there is evidence that blockade of eNO results in a compensatory increase in VEGF (12), which engages an NOindependent pathway to stimulate endothelial cell proliferation (13). This may result in deleterious as opposed to beneficial effects of VEGF (14 -17).…”

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confidence: 99%

Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy

Nakagawa¹,

Sato²,

Glushakova³

et al. 2007

Journal of the American Society of Nephrology

343

347

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The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.

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“…In rat and mice models it has been shown that an enhanced level of shear stress, induced by the ␣-adrenergic receptor blocker prazosin, leads to an upregulation of VEGF mRNA and an enhanced capillarization but has no effect on MMP-2 expression in skeletal muscle tissue (25). This effect of shear stress on VEGF furthermore appears to be dependent on nitric oxide, because prazosin treatment does not upregulate VEGF mRNA in eNOS knockout mice (4,7). Moreover, a period of mechanical stretch/overload of the rat extensor digitorum longus muscle, achieved by unilateral extirpation of the tibialis anterior, has been shown to induce an up regulation of basal levels of VEGF and MMP-2 and an increase in capillarization (32).…”

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confidence: 99%

Passive leg movement enhances interstitial VEGF protein, endothelial cell proliferation, and eNOS mRNA content in human skeletal muscle

Hellsten¹,

Rufener²,

Nielsen³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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The present study used passive limb movement as an experimental model to study the effect of increased blood flow and passive stretch, without enhanced metabolic demand, in young healthy male subjects. The model used was 90 min of passive movement of the leg leading to a 2.8-fold increase ( P < 0.05) in blood flow without a significant enhancement in oxygen uptake. Muscle interstitial fluid was sampled with microdialysis technique and analyzed for vascular endothelial growth factor (VEGF) protein and for the effect on endothelial cell proliferation. Biopsies obtained from the musculus vastus lateralis were analyzed for mRNA content of VEGF, endothelial nitric oxide synthase (eNOS), and matrix metalloproteinase-2 (MMP-2). The passive leg movement caused an increase ( P < 0.05) in interstitial VEGF protein concentration above rest (73 ± 21 vs. 344 ± 83 pg/ml). Addition of muscle dialysate to cultured endothelial cells revealed that dialysate obtained during leg movement induced a 3.2-fold higher proliferation rate ( P < 0.05) than dialysate obtained at rest. Passive movement also enhanced ( P < 0.05) the eNOS mRNA level fourfold above resting levels. VEGF mRNA and MMP-2 mRNA levels were unaffected. The results show that a session of passive leg movement, elevating blood flow and causing passive stretch, augments the interstitial concentrations of VEGF, the proliferative effect of interstitial fluid, and eNOS mRNA content in muscle tissue. We propose that enhanced blood flow and passive stretch are positive physiological stimulators of factors associated with capillary growth in human muscle.

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Vascular endothelial growth factor is expressed in endothelial cells isolated from skeletal muscles of nitric oxide synthase knockout mice during prazosin-induced angiogenesis

Cited by 40 publications

References 34 publications

Alpha adrenergic receptor blockade increases capillarization and fractional O₂ extraction and lowers blood flow in contracting human skeletal muscle

Alpha adrenergic receptor blockade increases capillarization and fractional O₂ extraction and lowers blood flow in contracting human skeletal muscle

Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy

Passive leg movement enhances interstitial VEGF protein, endothelial cell proliferation, and eNOS mRNA content in human skeletal muscle

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Vascular endothelial growth factor is expressed in endothelial cells isolated from skeletal muscles of nitric oxide synthase knockout mice during prazosin-induced angiogenesis

Cited by 40 publications

References 34 publications

Alpha adrenergic receptor blockade increases capillarization and fractional O2 extraction and lowers blood flow in contracting human skeletal muscle

Alpha adrenergic receptor blockade increases capillarization and fractional O2 extraction and lowers blood flow in contracting human skeletal muscle

Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy

Passive leg movement enhances interstitial VEGF protein, endothelial cell proliferation, and eNOS mRNA content in human skeletal muscle

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Alpha adrenergic receptor blockade increases capillarization and fractional O₂ extraction and lowers blood flow in contracting human skeletal muscle

Alpha adrenergic receptor blockade increases capillarization and fractional O₂ extraction and lowers blood flow in contracting human skeletal muscle