Letter by Bellien and Kamel Regarding Article, ``Dipeptidyl Peptidase-4 Induces Aortic Valve Calcification by Inhibiting Insulin-Like Growth Factor-1 Signaling in Valvular Interstitial Cells''

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Dipeptidyl Peptidase-4 Inhibition Prevents Vascular Calcification by Potentiating the Insulin-Like Growth Factor-1 Signaling Pathway

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AT 1} receptor blockade prevents the decrease in conduit artery flow-mediated dilatation during NOS inhibition in humans

International audienceWhether AT1 receptor blockade can prevent the decrease in conduit artery flow-mediated dilatation during NO-synthase inhibition by endothelial alternative pathways has not previously been explored in humans. In 12 healthy subjects, we measured radial artery diameter (echotracking) and flow (Doppler) during flow-mediated dilatation induced by sustained reactive hyperemia in control period and following NO-synthase inhibition (L-NMMA: 1.5 mg.min -1}.L -1}), after single oral administration of telmisartan (80 mg) or placebo, during a double-blind, randomized, cross-over study. In 6 volunteers, we also assessed the roles of prostacyclin and endothelium-derived hyperpolarizing factor during radial flow-mediated dilatation after AT 1} receptor blockade by oral administration of aspirin (500 mg) alone and associated with L-NMMA and by the addition of the cytochrome epoxygenases inhibitor fluconazole (0.37 mg.min -1}.L -1}). Telmisartan did not affect radial artery flow-mediated dilatation in control period (placebo: 10.9±0.6% vs. telmisartan: 9.9±0.7%) but prevented its decrease after L-NMMA (placebo: 9.3±0.8% vs. telmisartan: 12.6±1.2%, P<0.05) with no modification in baseline parameters, hyperemia and radial artery endothelium-independent dilatation to sodium nitroprusside. Moreover, in telmisartan-treated subjects, the radial flow-mediated dilatation, compared with control (9.0±1.0%), was not modified by aspirin alone (9.4±0.7%) or associated with L-NMMA (9.5±0.5%) but in fact was reduced by the combination of aspirin, L-NMMA and fluconazole (7.5±0.6%, P<0.05). These results demonstrate that AT 1} receptor blockade prevents the decrease in conduit artery flow-mediated dilatation during NO-synthase inhibition in humans suggesting the development of an endothelial compensatory mechanism. This mechanism seems to be independent of prostacyclin and could possibly be related to an endothelium-derived hyperpolarizing factor release

5/6 nephrectomy induces different renal, cardiac and vascular consequences in 129/Sv and C57BL/6JRj mice

International audienceExperimental models of cardiovascular diseases largely depend on the genetic background. Subtotal 5/6 nephrectomy (5/6 Nx) is the most frequently used model of chronic kidney disease (CKD) in rodents. However, in mice, cardiovascular consequences of 5/6 Nx are rarely reported in details and comparative results between strains are scarce. The present study detailed and compared the outcomes of 5/6 Nx in the 2 main strains of mice used in cardiovascular and kidney research, 129/Sv and C57BL/6JRj. Twelve weeks after 5/6 Nx, CKD was demonstrated by a significant increase in plasma creatinine in both 129/Sv and C57BL/6JRj male mice. Polyuria and kidney histological lesions were more pronounced in 129/Sv than in C57BL/6JRj mice. Increase in albuminuria was significant in 129/Sv but not in C57BL/6JRj mice. Both strains exhibited an increase in systolic blood pressure after 8 weeks associated with decreases in cardiac systolic and diastolic function. Heart weight increased significantly only in 129/Sv mice. Endothelium-dependent mesenteric artery relaxation to acetylcholine was altered after 5/6 Nx in C57BL/6JRj mice. Marked reduction of endothelium-dependent vasodilation to increased intraluminal flow was demonstrated in both strains after 5/6 Nx. Cardiovascular and kidney consequences of 5/6 Nx were more pronounced in 129/Sv than in C57BL/6JRj mice

Combined Electron Microscopy Approaches for Arterial Glycocalyx Visualization

International audienceMainly constituted of glycosaminoglycans and proteoglycans, the glycocalyx is anchored in the plasma membrane, covering, in particular, the extracellular face of the arterial endothelium. Due to its complex three-dimensional (3D) architecture, the glycocalyx interacts with a wide variety of proteins, contributing to vascular permeability, the flow of mechanotransduction, and the modulation of local inflammatory processes. Alterations of glycocalyx structure mediate the endothelial dysfunction and contribute to the aggravation of peripheral vascular diseases. Therefore, the exploration of its ultrastructure becomes a priority to evaluate the degree of injury under physiopathological conditions and to assess the impact of therapeutic approaches. The objective of this study was to develop innovative approaches in electron microscopy to visualize the glycocalyx at the subcellular scale. Intravenous perfusion on rats with a fixing solution containing aldehyde fixatives enriched with lanthanum ions was performed to prepare arterial samples. The addition of lanthanum nitrate in the fixing solution allowed the enhancement of the staining of the glycocalyx for transmission electron microscopy (TEM) and to detect elastic and inelastic scattered electrons, providing complementary qualitative information. The strength of scanning electron microscopy (SEM) was used on resin-embedded serial sections, allowing rapid and efficient large field imaging and previous correlative TEM observations for ultrastructural fine details. To demonstrate the dynamic feature of the glycocalyx, 3D tomography was provided by dual-beam focus-ion-beam-SEM (FIB-SEM). These approaches allowed us to visualize and characterize the ultrastructure of the pulmonary artery glycocalyx under physiological conditions and in a rat pulmonary ischemia-reperfusion model, known to induce endothelial dysfunction. This study demonstrates the feasibility of combined SEM, TEM, and FIB-SEM tomography approaches on the same sample as the multiscale visualization and the identification of structural indicators of arterial endothelial glycocalyx integrity

Alteration in the availability of epoxyeicosatrienoic acids contributes with NO to the development of endothelial dysfunction in conduit arteries during aging

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Combined Electron Microscopy Approaches for Arterial Glycocalyx Visualization

International audienceMainly constituted of glycosaminoglycans and proteoglycans, the glycocalyx is anchored in the plasma membrane, covering, in particular, the extracellular face of the arterial endothelium. Due to its complex three-dimensional (3D) architecture, the glycocalyx interacts with a wide variety of proteins, contributing to vascular permeability, the flow of mechanotransduction, and the modulation of local inflammatory processes. Alterations of glycocalyx structure mediate the endothelial dysfunction and contribute to the aggravation of peripheral vascular diseases. Therefore, the exploration of its ultrastructure becomes a priority to evaluate the degree of injury under physiopathological conditions and to assess the impact of therapeutic approaches. The objective of this study was to develop innovative approaches in electron microscopy to visualize the glycocalyx at the subcellular scale. Intravenous perfusion on rats with a fixing solution containing aldehyde fixatives enriched with lanthanum ions was performed to prepare arterial samples. The addition of lanthanum nitrate in the fixing solution allowed the enhancement of the staining of the glycocalyx for transmission electron microscopy (TEM) and to detect elastic and inelastic scattered electrons, providing complementary qualitative information. The strength of scanning electron microscopy (SEM) was used on resin-embedded serial sections, allowing rapid and efficient large field imaging and previous correlative TEM observations for ultrastructural fine details. To demonstrate the dynamic feature of the glycocalyx, 3D tomography was provided by dual-beam focus-ion-beam-SEM (FIB-SEM). These approaches allowed us to visualize and characterize the ultrastructure of the pulmonary artery glycocalyx under physiological conditions and in a rat pulmonary ischemia-reperfusion model, known to induce endothelial dysfunction. This study demonstrates the feasibility of combined SEM, TEM, and FIB-SEM tomography approaches on the same sample as the multiscale visualization and the identification of structural indicators of arterial endothelial glycocalyx integrity