Increased Vascular Endothelial Growth Factor Expression But Impaired Vascular Endothelial Growth Factor Receptor Signaling in the Myocardium of Type 2 Diabetic Patients With Chronic Coronary Heart Disease

Sasso, Ferdinando Carlo; Torella, Daniele; Carbonara, Ornella; Ellison, Georgina M.; Torella, Michele; Scardone, Michelangelo; Marra, Claudio; Nasti, Rodolfo; Marfella, Raffaele; Cozzolino, Domenico; Indolfi, Ciro; Cotrufo, Maurizio; Torella, Roberto; Salvatore, Teresa

doi:10.1016/j.jacc.2005.06.007

Cited by 164 publications

(144 citation statements)

References 40 publications

(46 reference statements)

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“…Sasso et al (19) showed that patients with diabetes had reduced VEGF signaling in the myocardium despite an increase in VEGF ligand (19). We found greater levels of the VEGF ligand with reduced VEGF signaling in hindlimb muscle before ligation, and after ligation this was associated with an impaired perfusion recovery by laser Doppler and a greater extent of tissue necrosis.…”

Section: Discussionsupporting

confidence: 47%

In Mice With Type 2 Diabetes, a Vascular Endothelial Growth Factor (VEGF)-Activating Transcription Factor Modulates VEGF Signaling and Induces Therapeutic Angiogenesis After Hindlimb Ischemia

et al. 2007

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Peripheral arterial disease is a major complication of diabetes. The ability to promote therapeutic angiogenesis may be limited in diabetes. Type 2 diabetes was induced by high-fat feeding C57BL/6 mice (n ‫؍‬ 60). Normal chow-fed mice (n ‫؍‬ 20) had no diabetes. Mice underwent unilateral femoral artery ligation and excision. A plasmid DNA encoded an engineered transcription factor designed to increase vascular endothelial growth factor expression (ZFP-VEGF). On day 10 after the operation, the ischemic limbs received 125 g ZFP-VEGF plasmid or control. Mice were killed 3, 10, or 20 days after injection (n ‫؍‬ 10/group, at each time point). Limb blood flow was measured by laser Doppler perfusion imaging. VEGF mRNA expression was examined by real-time PCR. VEGF, Akt, and phospho-Akt protein were measured by enzyme-linked immunosorbent assay. Capillary density, proliferation, and apoptosis were assessed histologically. Compared with normal mice, mice with diabetes had greater VEGF protein, reduced phosphoAkt-to-Akt ratio before ligation, and an impaired perfusion recovery after ligation. At 3 and 10 days after injection, in mice with diabetes, gene transfer increased VEGF expression and signaling. At later time points, gene transfer resulted in better perfusion recovery. Gene transfer with ZFP-VEGF was able to promote therapeutic angiogenesis mice with type 2 diabetes. Diabetes 56:656 -665, 2007

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Section: Discussionsupporting

confidence: 47%

In Mice With Type 2 Diabetes, a Vascular Endothelial Growth Factor (VEGF)-Activating Transcription Factor Modulates VEGF Signaling and Induces Therapeutic Angiogenesis After Hindlimb Ischemia

et al. 2007

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“…The samples (20 g of protein) were then subjected to heat denaturation at 96°C for 7 min with Laemmli buffer. Western blot analysis for detection of phosphorylated and nonphosphorylated forms of different target molecules was performed according to the method described in previous studies with minor modification (15,18,25,28,45,52). Briefly, each sample was separated on 10% SDS-polyacrylamide gel and transferred to a polyvinylidene difluoride (Millipore, Billerica, MA) membrane.…”

Section: Methodsmentioning

confidence: 99%

“…Aliquots of protein lysates were obtained as described in previous studies (28,45,52). Protein extracts were incubated overnight at 4°C with 3 g of rabbit polyclonal anti-Flk-1 (Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts

Jesmin¹,

Zaedi²,

Shimojo³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the presence of pharmacological intervention on these defects in diabetes remains unsettled. Here, we studied the effect of endothelin (ET) receptor blockade on cardiac VEGF signaling pathways and cardiac function in Sprague-Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age-matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with the ET receptor antagonist SB-209670 (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric-oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real-time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with SB-209670 reversed these alterations to the control levels and ameliorated impairment of cardiac function. From a molecular point of view, the present study is the first to indicate the potential usefulness of an ET receptor antagonist in the treatment of cardiac dysfunction in type I diabetes.

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“…It is suggested that without considering the serum VEGF level, the VEGF signaling pathway is impaired during diabetes which is considered as VEGF resistance 28,29 . Therefore, it is possible that reduced serum NO concentration may be responsible for lower neovascularization in hindlimb ischemic tissue of diabetic animals.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone enhances neovascularization in diabetic rat ischemic hindlimb model

Khazaei¹,

Salehi²

2012

BIOMED PAP

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Background. There is increasing evidence that peroxisome proliferator-activated receptors (PPARs) may be involved in the regulation of angiogenesis. In this study, we examined whether rosiglitazone, a PPARγ agonist, can restore angiogenesis in a rat hindlimb ischemia model of diabetes. Methods. Male wistar rats were divided into four groups (n=6 each): control, diabetic and control and diabetic rats who received rosiglitazone (8 mg/kg/day). Diabetes was induced by streptozotocin (55 mg/kg; ip). After 21 days, serum concentrations of nitric oxide (NO), vascular endothelial growth factor (VEGF) and soluble VEGF receptor-2 (VEGFR-2) were measured and neovascularization in ischemic legs was evaluated by immunohistochemistry. Results. Capillary density and capillary/fiber ratio in hindlimb ischemia of diabetic animals were significantly lower than the control group (P<0.05). Rosiglitazone significantly restored neovascularization in diabetic animals (P<0.05). Conclusions. rosiglitazone enhances neovascularization in diabetic ischemic skeletal muscle and could be considered for treatment of peripheral artery disease in diabetic subjects.

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Increased Vascular Endothelial Growth Factor Expression But Impaired Vascular Endothelial Growth Factor Receptor Signaling in the Myocardium of Type 2 Diabetic Patients With Chronic Coronary Heart Disease

Cited by 164 publications

References 40 publications

In Mice With Type 2 Diabetes, a Vascular Endothelial Growth Factor (VEGF)-Activating Transcription Factor Modulates VEGF Signaling and Induces Therapeutic Angiogenesis After Hindlimb Ischemia

In Mice With Type 2 Diabetes, a Vascular Endothelial Growth Factor (VEGF)-Activating Transcription Factor Modulates VEGF Signaling and Induces Therapeutic Angiogenesis After Hindlimb Ischemia

Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts

Rosiglitazone enhances neovascularization in diabetic rat ischemic hindlimb model

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