Approaches to regulating angiogenesis in the brain, which may diminish parenchymal damage after stroke, are lacking. Survivin, the inhibitor of apoptosis protein, is up-regulated in vitro in vascular endothelial cells...
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Approaches to regulating angiogenesis in the brain, which may diminish parenchymal damage after stroke, are lacking. Survivin, the inhibitor of apoptosis protein, is up-regulated in vitro in vascular endothelial cells by angiogenic factors, including vascular endothelial cell growth factor (VEGF). To evaluate the in vivo role of survivin in the brain in response to hypoxia/ischemia, we used a mouse model of stroke and show that 2 days after permanent middle cerebral artery occlusion, survivin is uniquely expressed by microvessels that form in the peri-infarct and infarct regions. The extent of vascularization of the infarct is dependent on expression of survivin, since vessel density is significantly reduced in mice with heterozygous deficiency of the survivin gene (survivin +/- mice), even though infarct sizes were not different. Hypoxia alone induces survivin expression in the brain, by cultured endothelial cells and by embryonic stem cells, but this response is at least partially independent of VEGF, hypoxia inducible factor la, or placental growth factor. Delineating the spatiotemporal pattern of expression of survivin after stroke, and the molecular mechanisms by which this is regulated, may provide novel approaches to therapeutically optimize angiogenesis in a variety of ischemic disorders.
OBJECTIVES The aims of the present study were to assess 1) the effect of 8-Cl-cAMP (cyclic-3'-5'-adenosine monophosphate) on vascular smooth muscle cell (VSMC) proliferation in vitro and 2) the efficacy of sys...
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OBJECTIVES The aims of the present study were to assess 1) the effect of 8-Cl-cAMP (cyclic-3'-5'-adenosine monophosphate) on vascular smooth muscle cell (VSMC) proliferation in vitro and 2) the efficacy of systemic administration of 8-Cl-cAMP on neointimal formation after balloon injury in vivo. BACKGROUND Neointimal formation after vascular injury is responsible for restenosis after arterial stenting. Recently, 8-Cl-cAMP, a cAMP analogue that induces growth arrest, has been safely administered in phase I studies in humans. METHODS The effect of 8-Cl-cAMP on cell proliferation was first assessed on SMCs in vitro. To study the effects of cAMP in vivo, balloon injury was performed in 67 rats using a 2F Fogarty balloon catheter. RESULTS The 8-Cl-cAMP markedly inhibited VSMC proliferation in vitro, reduced protein kinase A (PKA) RIalpha subunit expression, and induced PKA RIIbeta subunit expression. In addition, 8-Cl-cAMP reduced, in a dose-dependent manner, neointimal area and neointima/media ratio after balloon injury. The proliferative activity, assessed by proliferating nuclear cell antigen immunostaining, revealed a reduction of proliferative activity of VSMCs in vivo in the 8-Cl-cAMP group. Moreover, the systemic administration of 8-Cl-cAMP did not affect renal function, blood pressure and heart rate. CONCLUSIONS We conclude that 8-Cl-cAMP potently inhibits VSMC proliferation in vitro and reduces neointima formation by balloon injury in vivo after systemic administration. These data may have a clinical relevance in designing future strategies to prevent restenosis after arterial stenting and perhaps after percutaneous transluminal coronary angioplasty. (C) 2000 by the American College of Cardiology.
Peripheral arterial occlusive disease (PAOD) patients with intermittent claudication are functionally limited and deconditioned. This study examined whether peak aerobic capacity ((V)over doto(2) peak) was associated ...
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Peripheral arterial occlusive disease (PAOD) patients with intermittent claudication are functionally limited and deconditioned. This study examined whether peak aerobic capacity ((V)over doto(2) peak) was associated with PAOD severity, muscle mass, and comorbidities in 109 PAOD patients (93 men and 16 women) aged 48-86 years. The (V)over dot o(2) peak (1.12 +/- 0.34 L/min), percentage body fat (30.6 +/- 8.3%), lean tissue mass of the total body (51.4 +/- 8.4 kg), lean tissue mass of the legs (16.6 +/- 3.0 kg), and appendicular skeletal mass (22.8 +/- 4.2 kg) were determined. The lean tissue mass of the total body (r = .44), lean tissue of the legs (r = .43) and resting ankle/brachial systolic pressure index (ABI;r = .41) correlated with peak (V)over doto(2) (all p < .001). None of the comorbidity variables (obesity, arthritis, coronary artery disease, hypertension, diabetes, and smoking history) were significantly associated with peak (V)over doto(2) except smoking status. The final model for the prediction of peak (V)over doto(2) included lean tissue mass of the legs, resting ABI, smoking status, and ABI x smoking status (r(2) = .37,p < .001). In older patients with intermittent claudication, lean tissue mass is an important determinant of physical performance independent of PAOD severity and smoking status. Prevention of muscle atrophy may preserve ambulatory function and peak exercise capacity in older PAOD patients.
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