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Bernah M. Fahning B Fahning, Department of Physics and Chemistry, USP, Ribeirão Preto, Brazil

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Simone Regina Potje S Potje, Medical Sciences, University of Minas Gerais State, Passos, 37902-407, Brazil

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Tiago D. Paula T Paula, Department of Physics and Chemistry, USP, Ribeirão Preto, Brazil

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Marcella D. Grando M Grando, Department of Physics and Chemistry, USP, Ribeirão Preto, Brazil

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Lusiane M. Bendhack L Bendhack, Department of Physics and Chemistry, USP, Ribeirão Preto, Brazil

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Renin-angiotensin system plays a critical role in blood pressure control and the abnormal activation of AT1 receptor contributes to the development of renovascular hypertension. This study aimed to evaluate the underlying cellular signaling for AT1 receptor activation by Ang II and to compare this mechanism between aortas from 2K-1C and 2K rats. Effects of antagonists and enzyme inhibitors were investigated on Ang II-induced contractions in denuded or intact-endothelium aortas. AT1 receptor antagonist abolished Ang II-induced contraction in 2K-1C and 2K rat aortas, while AT2 and Mas receptors antagonists had no effect. Endothelial nitric oxide synthase inhibition increased the maximal effect (Emax) of Ang II in 2K, which was not changed in 2K-1C aortas. It was associated with lower eNOS mRNA levels in 2K-1C. Endothelium removal increased the Emax of Ang II in 2K-1C and mainly in of 2K rat aortas. The Nox and COX inhibition did not alter Ang II-induced contraction in 2K and 2K-1C rat aortas. Otherwise, AT1 expression was higher in 2K-1C as compared to 2K rat aortic rings, whereas expression of phosphorylated (active) IP3 receptors was lower in 2K-1C than in 2K rats. These results demonstrate that the endothelium removal impairs Ang II-stimulated contraction in the aorta of 2K-1C rats, which is associated with the reduction of IP3 receptor phosphorylation and activation. In addition, eNOS plays a critical role in Ang II-induced contraction in 2K rat aortas. It is possible that the high Ang II plasma levels could desensitize AT1 receptor in 2K-1C rats leading to impaired IP3 receptors activation.

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Jamie I van der Vaart Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Robin van Eenige Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Patrick C N Rensen Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Sander Kooijman Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Cardiovascular disease, the primary cause of human mortality globally, is predominantly caused by a progressive disorder known as atherosclerosis. Atherosclerosis refers to the process of accumulation of cholesterol-enriched lipoproteins and the concomitant initiation of inflammatory processes in the arterial wall, including the recruitment of immune cells. This leads to the formation of atherosclerotic plaques, initially causing a thickening of the arterial wall and narrowing of arteries. However, as plaque formation progresses, atherosclerotic plaques may become unstable and rupture, leading to a blood clot that blocks the affected artery or travels through the blood to block blood flow elsewhere. In the early 1990s, emerging gene editing methods enabled the development of apolipoprotein E knockout (Apoe−/− ) and low-density lipoprotein receptor knockout (Ldlr−/− ) mice. These mice have been instrumental in unraveling the complex pathogenesis of atherosclerosis. Around the same time, human APOE*3-Leiden transgenic mice were generated, which were more recently cross-bred with human cholesteryl ester transfer protein (CETP) transgenic mice to generate APOE*3-Leiden.CETP mice. This model appears to closely mimic human lipoprotein metabolism and responds to classic lipid-lowering interventions due to an intact ApoE–LDLR pathway of lipoprotein remnant clearance. In this review, we describe the role of lipid metabolism and inflammation in atherosclerosis development and highlight the characteristics of the frequently used animal models to study atherosclerosis, with a focus on mouse models, discussing their advantages and limitations. Moreover, we present a detailed methodology to quantify atherosclerotic lesion area within the aortic root region of the murine heart, as well as details required for scoring atherosclerotic lesion severity based on guidelines of the American Heart Association adapted for mice.

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Isabelle Coornaert Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium

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Annelies Breynaert NatuRAPT Research Group, University of Antwerp, Antwerp, Belgium

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Nina Hermans NatuRAPT Research Group, University of Antwerp, Antwerp, Belgium

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Guido R Y De Meyer Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium

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Wim Martinet Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium

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Ferroptosis is a type of regulated necrosis that is associated with iron-dependent accumulation of lipid hydroperoxides. Given that iron deposition and lipid peroxidation initiate ferroptosis in atherosclerosis and contribute to further plaque development, we hypothesized that inhibition of ferroptosis could be of value in the treatment of atherosclerosis. Glutathione peroxidase 4 (GPX4) is the only enzyme known capable of reducing lipid hydroperoxides. Previous studies have demonstrated that inactivation of GPX4 results in ferroptosis, while overexpression of GPX4 confers resistance to ferroptosis. In the present study, we examined the impact of GPX4 overexpression on the development of atherosclerotic plaques. GPX4-overexpressing mice (GPX4Tg/+) were crossbred with ApoE−/− mice and fed a western-type diet for 16 weeks. Atherosclerotic plaques of GPX4Tg/+ ApoE−/− mice showed increased GPX4 expression and a reduced amount of lipid hydroperoxides. However, plaque size and composition were not different as compared to control animals. Similarly, GPX4-overexpressing vascular smooth muscle cells and bone marrow-derived macrophages were not protected against lipid peroxidation and cell death triggered by the ferroptosis inducers erastin and 1S,3R-RSL3. We concluded that GPX4 overexpression reduces lipid peroxidation in plaques of ApoE−/− mice, yet GPX4 overexpression is not sufficiently powerful to change plaque size or composition.

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Sarah Schnabellehner Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

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Marle Kraft Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

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Hans Schoofs Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

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Henrik Ortsäter Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

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Taija Mäkinen Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

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Endothelial cells (ECs) of blood and lymphatic vessels have distinct identity markers that define their specialized functions. Recently, hybrid vasculatures with both blood and lymphatic vessel-specific features have been discovered in multiple tissues. Here, we identify the penile cavernous sinusoidal vessels (pc-Ss) as a new hybrid vascular bed expressing key lymphatic EC identity genes Prox1, Vegfr3,and Lyve1. Using single-cell transcriptome data of human corpus cavernosum tissue, we found heterogeneity within pc-S endothelia and observed distinct transcriptional alterations related to inflammatory processes in hybrid ECs in erectile dysfunction associated with diabetes. Molecular, ultrastructural, and functional studies further established hybrid identity of pc-Ss in mouse, and revealed their morphological adaptations and ability to perform lymphatic-like function in draining high-molecular-weight tracers. Interestingly, we found that inhibition of the key lymphangiogenic growth factor VEGF-C did not block the development of pc-Ss in mice, distinguishing them from other lymphatic and hybrid vessels analyzed so far. Our findings provide a detailed molecular characterization of hybrid pc-Ss and pave the way for the identification of molecular targets for therapies in conditions of dysregulated penile vasculature, including erectile dysfunction.

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Isabelle Coornaert Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium

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Annelies Breynaert NatuRAPT Research Group, University of Antwerp, Antwerp, Belgium

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Nina Hermans NatuRAPT Research Group, University of Antwerp, Antwerp, Belgium

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Guido R Y De Meyer Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium

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Wim Martinet Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium

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The impact of α-tocopherol on atherosclerosis is unclear and controversial. While some studies suggest potential benefits, such as antioxidant properties that may reduce oxidative stress, other studies indicate no significant preventive effects. The intricate interplay of various factors, including dosage, individual differences, and study methodologies, contributes to the ongoing uncertainty surrounding α-tocopherol’s role in atherosclerosis. Further research is needed to clarify its impact and establish clearer guidelines. Therefore, we aimed to evaluate the impact of α-tocopherol on atherogenesis in ApoE−/− fibrillin (Fbn)1C1039G/+ mice, which is a unique mouse model of advanced atherosclerosis with typical features, such as large necrotic cores, high levels of inflammation, and intraplaque neovascularization, that resemble the unstable phenotype of human plaques. ApoE−/− Fbn1C1039G+/− mice were fed a western-type diet (WD) supplemented with a high dose of α-tocopherol (500 mg/kg diet), while control mice were fed a WD containing a low dose of α-tocopherol (50 mg/kg diet). The high dose of α-tocopherol reduced plaque thickness and necrotic core area in the right common carotid artery (RCCA) after 24 weeks WD. Moreover, α-tocopherol decreased plaque formation and intraplaque neovascularization in the RCCA. In addition to its antiatherogenic effect, chronic supplementation of α-tocopherol improved cardiac function in ApoE−/− Fbn1C1039G/+ mice. However, chronic supplementation of α-tocopherol did not decrease lipid peroxidation. On the contrary, α-tocopherol acted as a prooxidant by increasing plasma levels of oxidized LDL and plaque malondialdehyde, an end product of lipid peroxidation. Our data indicate that α-tocopherol inhibits atherogenesis and improves cardiac function independent of its antioxidant properties.

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Emily Warren Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA

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Sharon Gerecht Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA

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The vasculature is crucial for tissue development and survival, and the stability of blood vessels to perform these functions relies on the interplay between endothelial cells (ECs) and mural cells. Pericytes are a subtype of mural cells found in the microvasculature that extend their processes to wrap around the endothelial monolayer. Pericytes are recruited during vessel growth through the excretion of soluble factors from ECs where they stabilize angiogenic sprouts and induce maturation of the resident cells. Alterations in these interactions between ECs and pericytes are associated with aberrant vessel growth and disrupted vasculature function characteristic of numerous diseases. Therefore, deeper understanding of the cross-talk between these cell types has numerous implications for understanding morphogenesis and elucidating disease mechanisms. In this review, we highlight recent advances and current trends studying the interactions between ECs and pericytes in vitro. We begin by analyzing three-dimensional hydrogel platforms that mimic the tissue extracellular matrix to investigate signaling pathways and altered vascular function in disease-specific cells. We next examine how microfluidic vasculature-on-a-chip platforms have elucidated the interplay of these vascular cells during angiogenesis and vascular network formation under controlled physiochemical cues and interstitial flow. Additionally, studies have utilized microvessels to measure the effect of shear stress on barrier function through the control of luminal flow and the impact of inflammation on these vascular cell interactions. Finally, we briefly highlight self-assembling human blood vessel organoids, an emerging high-throughput platform to study ECs and pericyte interactions.

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Sheridan M Sargent Neuroscience Graduate Program, University of Washington, Seattle, Washington, USA

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Stephanie K Bonney Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA

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Yuandong Li Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA

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Stefan Stamenkovic Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA

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Marc M Takeno Allen Institute for Brain Science, Seattle, Washington, USA

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Vanessa Coelho-Santos Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Portugal
Institute of Nuclear Sciences Applied to Health, University of Coimbra, Portugal

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Andy Y Shih Neuroscience Graduate Program, University of Washington, Seattle, Washington, USA
Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA
Department of Pediatrics, University of Washington, Seattle, Washington, USA
Department of Bioengineering, University of Washington, Seattle, Washington, USA

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The high metabolic demand of brain tissue is supported by a constant supply of blood flow through dense microvascular networks. Capillaries are the smallest class of vessels in the brain and their lumens vary in diameter between ~2 and 5 μm. This diameter range plays a significant role in optimizing blood flow resistance, blood cell distribution, and oxygen extraction. The control of capillary diameter has largely been ascribed to pericyte contractility, but it remains unclear if the architecture of the endothelial wall also contributes to capillary diameter. Here, we use public, large-scale volume electron microscopy data from mouse cortex (MICrONS Explorer, Cortical mm3) to examine how endothelial cell number, endothelial cell thickness, and pericyte coverage relates to microvascular lumen size. We find that transitional vessels near the penetrating arteriole and ascending venule are composed of two to six interlocked endothelial cells, while the capillaries intervening these zones are composed of either one or two endothelial cells, with roughly equal proportions. The luminal area and diameter are on average slightly larger with capillary segments composed of two interlocked endothelial cells vs one endothelial cell. However, this difference is insufficient to explain the full range of capillary diameters seen in vivo. This suggests that both endothelial structure and other influences, including pericyte tone, contribute to the basal diameter and optimized perfusion of brain capillaries.

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Dai Yamanouchi Department of Surgery, Division of Vascular Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
Department of Vascular Surgery, Fujita Health University, Toyoake City, Japan

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Kimihiro Igari Department of Surgery, Division of Vascular Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

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Abdominal aortic aneurysms (AAAs) have been linked to the activation of osteoclastogenic macrophages. Reports have suggested that Wnt signaling has a dual effect of proliferation and differentiation during osteoclastogenesis. The Wnt/β-Catenin pathway is a critical regulator of cell pluripotency, cell survival, and cell fate decisions. It regulates cell proliferation and differentiation through transcriptional co-activators, CBP, and p300, respectively. The inhibition of β-catenin suppresses proliferation but induces differentiation of osteoclast precursor cells. This study aimed to examine the effect of ICG-001, a β-catenin/CBP-specific Wnt signaling inhibitor, on osteoclastogenesis by inhibiting proliferation without inducing differentiation. To induce osteoclastogenesis, RAW 264.7 macrophages were stimulated with a soluble receptor activator of NF-κB ligand (RANKL). The effect of Wnt signaling inhibition was examined by treating macrophages with or without ICG-001 during RANKL stimulation. The activation and differentiation of macrophages were examined through western blotting, quantitative PCR, and tartrate-resistant acid phosphate (TRAP) staining in vitro. The relative expression level of the nuclear factor of activated T-cells cytoplasmic 1 protein was significantly suppressed by ICG-001 treatment. The relative expression levels of mRNA of TRAP, cathepsin K, and matrix metalloproteinase-9 were significantly lower in the ICG-001-treated group. The number of TRAP-positive cells decreased in the ICG-001-treated group relative to the non-treated group. The inhibition of Wnt signaling pathway via ICG-001 suppressed osteoclastogenic macrophage activation. Our previous studies have shown the importance of osteoclastogenic macrophage activation in AAA. Further research to examine the therapeutic potential of ICG-001 on AAA is warranted.

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