MyD88-dependent, superoxide-initiated inflammation is necessary for flow-mediated inward remodeling of conduit arteries

Vascular remodeling normalizes abnormal hemodynamic stresses through structural changes affecting vessel size and wall thickness. We investigated the role of inflammation in flow-mediated vascular remodeling using a murine model of partial outflow reduction without flow cessation or neointima formation. Common carotid arteries decreased in size after ipsilateral external carotid artery ligation in wild-type mice, but not in myeloid differentiation protein-88 (MyD88)–deficient mice. Inward remodeling was associated with MyD88-dependent and superoxide-initiated cytokine and chemokine production, as well as transient adventitial macrophage accumulation and activation. Macrophage depletion prevented flow-mediated inward vascular remodeling. Expression of MyD88 by intrinsic vascular cells was necessary for cytokine and chemokine production and changes in vessel size, whereas MyD88 expression by bone marrow–derived cells was obligatory for changes in vessel size. We conclude that there are at least two distinct roles for MyD88 in flow-mediated inward remodeling of conduit arteries. Our findings suggest that inflammation is necessary for vascular adaptation to changes in hemodynamic forces

Rôle de la kallicréine tissulaire dans l'adaptation de la paroi vasculaire à des modifications de flux

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

WNK1 regulates vasoconstriction and blood pressure response to α 1-adrenergic stimulation in mice.

International audienceGain-of-function mutations in the human WNK1 (with-no-lysine[K]1) gene are responsible for a monogenic form of arterial hypertension, and WNK1 polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now. WNK1 complete inactivation in the mouse is embryonically lethal. We, thus, examined in Wnk1(+/-) haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation. Wnk1(+/-) mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following α(1)-adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in Wnk1(+/-) arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na(+)-K(+)-2Cl(-) cotransporter 1) in Wnk1(+/-) arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to α(1)-adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α(1)-adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension

Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels

Caveolae in endothelial cells have been implicated as plasma membrane microdomains that sense or transduce hemodynamic changes into biochemical signals that regulate vascular function. Therefore we compared long- and short-term flow-mediated mechanotransduction in vessels from WT mice, caveolin-1 knockout (Cav-1 KO) mice, and Cav-1 KO mice reconstituted with a transgene expressing Cav-1 specifically in endothelial cells (Cav-1 RC mice). Arterial remodeling during chronic changes in flow and shear stress were initially examined in these mice. Ligation of the left external carotid for 14 days to lower blood flow in the common carotid artery reduced the lumen diameter of carotid arteries from WT and Cav-1 RC mice. In Cav-1 KO mice, the decrease in blood flow did not reduce the lumen diameter but paradoxically increased wall thickness and cellular proliferation. In addition, in isolated pressurized carotid arteries, flow-mediated dilation was markedly reduced in Cav-1 KO arteries compared with those of WT mice. This impairment in response to flow was rescued by reconstituting Cav-1 into the endothelium. In conclusion, these results showed that endothelial Cav-1 and caveolae are necessary for both rapid and long-term mechanotransduction in intact blood vessels

Analysis of Hepatitis C Virus Particle Heterogeneity in Immunodeficient Human Liver Chimeric fah-/- MiceSummary

Background & Aims: Hepatitis C virus (HCV) is a leading cause of chronic liver diseases and the most common indication for liver transplantation in the United States. HCV particles in the blood of infected patients are characterized by heterogeneous buoyant densities, likely owing to HCV association with lipoproteins. However, clinical isolates are not infectious in vitro and the relative infectivity of the particles with respect to their buoyant density therefore cannot be determined, pointing to the need for better in vivo model systems. Methods: To analyze the evolution of the buoyant density of in vivoâderived infectious HCV particles over time, we infected immunodeficient human liver chimeric fumaryl acetoacetate hydrolase-/- mice with J6/JFH1 and performed ultracentrifugation of infectious mouse sera on isopicnic iodixanol gradients. We also evaluated the impact of a high sucrose diet, which has been shown to increase very-low-density lipoprotein secretion by the liver in rodents, on lipoprotein and HCV particle characteristics. Results: Similar to the severe combined immunodeficiency disease/Albumin-urokinase plasminogen activator human liver chimeric mouse model, density fractionation of infectious mouse serum showed higher infectivity in the low-density fractions early after infection. However, over the course of the infection, viral particle heterogeneity increased and the overall in vitro infectivity diminished without loss of the human liver graft over time. In mice provided with a sucrose-rich diet we observed a minor shift in HCV infectivity toward lower density that correlated with a redistribution of triglycerides and cholesterol among lipoproteins. Conclusions: Our work indicates that the heterogeneity in buoyant density of infectious HCV particles evolves over the course of infection and can be influenced by diet. Keywords: HCV, Lipoprotein, Mouse Model, Human Liver Chimeric Mic

DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice

Funding for this project included: U.S. Public Health Service (P01HL146367) to AMS, AS, and RR and 1P01HL131481 (EF, AMS, and RR). Support was also provided from the Diabetes Research Program, NYU Grossman School of Medicine. Primary data are available in Supplementary Data 1–6. RNAseq data are deposited to NCBI GEO GSE156403. Any materials reported in this research are available through Material Transfer Agreement (MTA) with NYU Grossman School of Medicine.Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr−/− mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr−/− mice, male Ldlr−/− Diaph1−/− mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr−/− Diaph1−/− mice displayed significantly less atherosclerosis compared to Ldlr−/− mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu