Selective Deletion of Leptin Signaling in Endothelial Cells Enhances Neointima Formation and Phenocopies the Vascular Effects of Diet-Induced Obesity in Mice

Hubert, Astrid; Bochenek, Magdalena L.; Schütz, Eva; Gogiraju, Rajinikanth; Münzel, Thomas; Schäfer, Katrin

doi:10.1161/atvbaha.117.309798

Cited by 40 publications

(36 citation statements)

References 51 publications

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“…Loss of endothelial normal function or structural integrity results in acute thrombosis, or chronic vascular changes that predispose to thrombosis among a variety of diseases, such as atherosclerosis, restenosis, diabetes mellitus, obesity, etc. [70][71][72][73] Understanding the mechanism by which endothelium regulates thrombosis not only provides insights into thrombosis mechanism and pathology of relevant diseases but also fuel the therapeutic endeavor for discovering effective antithrombotic drugs with minimal or no bleeding risk, which constitute a substantial unmet medical need.…”

Section: Discussionmentioning

confidence: 99%

Thrombotic Regulation From the Endothelial Cell Perspectives

Wang

Hao

Leeper

et al. 2018

ATVB

136

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Section: Discussionmentioning

confidence: 99%

Thrombotic Regulation From the Endothelial Cell Perspectives

Wang

Hao

Leeper

et al. 2018

ATVB

136

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“…Metamizole (ratiopharm, Ulm, Germany) was added to the drinking water (at a concentration of 2 mg/mL) for three days as analgetic. Carotid artery injury and neointima formation were induced using 10% ferric chloride (FeCl 3 ) [14,53].…”

Section: Carotid Artery Injurymentioning

confidence: 99%

“…Experiments were performed in cells between passage 3 and 7. To examine SMC migration, the scratch-wound assay was employed [53].…”

Section: Isolation and Analysis Of Primary Smooth Muscle Cellsmentioning

confidence: 99%

Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation

Schütz

Gogiraju

Pavlaki

et al. 2019

IJMS

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Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks (“middle-aged”) were compared to tissue or cells from mice aged 16 weeks (“adult”). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.

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“…14,15 Cre recombinase activity was induced with tamoxifen-containing rodent chow (TD55125; Harlan Teklad). [16][17][18] Cre-wild-type (WT) 3 p53 fl/fl mice fed tamoxifen were used as controls (End.p53-WT). Age-and sex-matched littermates were used throughout the study.…”

Section: Experimental Animalsmentioning

confidence: 99%

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Bochenek

Bauer

Gogiraju³

et al. 2018

Blood Advances

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Key Points• Deletion of p53 in endothelial cells prevents venous thrombosis in aged, but not in adult, mice.• Neutralization of heparanase in aged mice using TFPI2 peptides restores the thrombotic phenotype of adult mice. End.p53-KO mice were protected from vein thrombosis. Analysis of primary endothelial cells from aged mice or human vein endothelial cells after induction of replicative senescence revealed significantly increased early growth response gene-1 (Egr1) and heparanase expression, and plasma factor Xa levels were elevated in aged End.p53-WT, but not in End.p53-KO mice. Increased endothelial Egr1 and heparanase expression also was observed after doxorubicin-induced p53 overexpression, whereas p53 inhibition using pifithrin-a reduced tissue factor (TF) expression. Importantly, inhibition of heparanase activity using TF pathway inhibitor-2 (TFPI2) peptides prevented the enhanced venous thrombus formation in aged mice and restored it to the thrombotic phenotype of adult mice.Our findings suggest that p53 accumulation and heparanase overexpression in senescent endothelial cells are critically involved in mediating the increased risk of venous thrombosis with age and that heparanase antagonization may be explored as strategy to ameliorate the prothrombotic endothelial phenotype with age.

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Selective Deletion of Leptin Signaling in Endothelial Cells Enhances Neointima Formation and Phenocopies the Vascular Effects of Diet-Induced Obesity in Mice

Cited by 40 publications

References 51 publications

Thrombotic Regulation From the Endothelial Cell Perspectives

Thrombotic Regulation From the Endothelial Cell Perspectives

Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

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