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Jamie I. van der Vaart J van der Vaart, Leiden University Medical Center, Division of Endocrinology, Department of Medicine, Leiden, Netherlands

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Robin van Eenige R van Eenige, Leiden University Medical Center, Division of Endocrinology, Department of Medicine, Leiden, Netherlands

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Patrick C.n. Rensen P Rensen, Leiden University Medical Center, Division of Endocrinology, Department of Medicine, Leiden, Netherlands

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Sander Kooijman S Kooijman, Leiden University Medical Center, Division of Endocrinology, Department of Medicine, Leiden, 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 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 appeared 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 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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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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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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Max L B Grönloh Department of Medical Biochemistry, Vascular Biology Lab, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Leeuwenhoek Centre for Advanced Microscopy, Section Molecular Cytology at Swammerdam Institute for Life Sciences, the University of Amsterdam, Amsterdam, the Netherlands

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Merel E Tebbens Department of Medical Biochemistry, Vascular Biology Lab, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Marianthi Kotsi Department of Medical Biochemistry, Vascular Biology Lab, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Janine J G Arts Leeuwenhoek Centre for Advanced Microscopy, Section Molecular Cytology at Swammerdam Institute for Life Sciences, the University of Amsterdam, Amsterdam, the Netherlands
Department of Molecular Hematology, Sanquin Research, and Landsteiner Laboratory, Molecular Cell Biology Lab, Amsterdam, the Netherlands

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Jaap D van Buul Department of Medical Biochemistry, Vascular Biology Lab, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Leeuwenhoek Centre for Advanced Microscopy, Section Molecular Cytology at Swammerdam Institute for Life Sciences, the University of Amsterdam, Amsterdam, the Netherlands
Department of Molecular Hematology, Sanquin Research, and Landsteiner Laboratory, Molecular Cell Biology Lab, Amsterdam, the Netherlands

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Intercellular adhesion molecules (ICAMs) are cell surface proteins that play a crucial role in the body’s immune response and inflammatory processes. ICAM1 and ICAM2 are two ICAM family members expressed on the surface of various cell types, including endothelial cells. They mediate the interaction between immune cells and endothelial cells, which are critical for the trafficking of leukocytes across the blood vessel wall during inflammation. Although ICAM1 plays a prominent role in the leukocyte extravasation cascade, it is less clear if ICAM2 strengthens ICAM1 function or has a separate function in the cascade. With CRISPR–)Cas9 technology, endothelial cells were depleted for ICAM1,ICAM2, or both, and we found that neutrophils favored ICAM1 over ICAM2 to adhere to. However, the absence of only ICAM2 resulted in neutrophils that were unable to find the transmigration hotspot, i.e. the preferred exit site. Moreover, we found that ICAM2 deficiency prevented neutrophils to migrate against the flow. Due to this deficiency, we concluded that ICAM2 helps neutrophils find the preferred exit sites and thereby contributes to efficient leukocyte extravasation.

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Hafsa Khan International Centre for Chemical and Biological Sciences (ICCBS), Pakistan

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Tahira Ghulam Aga Khan University Medical College, Pakistan

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Naseer Ahmed Institute of Basic Medical Sciences, Khyber Medical University, Pakistan

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Muhammad Rafai Babar Aga Khan University Medical College, Pakistan

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Simon DJ Calaminus Hull York Medical School, University of Hull, UK

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Muhammad Zuhair Yusuf Aga Khan University Medical College, Pakistan

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Platelets have a pivotal role in maintaining cardiovascular homeostasis. They are kept docile by endothelial-derived mediators. Aberration in haemostatic balance predisposes an individual to an elevated risk of a prothrombotic environment. Anti-platelet therapy has been a key component to reduce this risk. However, understanding how these medications affect the balance between the activation and inhibition of platelets is critical. There is no evidence that a key anti-platelet therapy – aspirin, may not be the most efficacious medicine of choice, as it can compromise both platelet inhibition and activation pathways. In this review, the rationale of aspirin as an anti-thrombotic drug has been critically discussed. This review looks at how recently published trials are raising key questions about the efficacy and safety of aspirin in countering cardiovascular diseases. There is an increasing portfolio of evidence that identifies that although aspirin is a very cheap and accessible drug, it may be used in a manner that is not always beneficial to a patient, and a more nuanced and targeted use of aspirin may increase its clinical benefit and maximize patient response. The questions about the use of aspirin raise the potential for changes in its clinical use for dual anti-platelet therapy. This highlights the need to ensure that treatment is targeted in the most effective manner and that other anti-platelet therapies may well be more efficacious and beneficial for CVD patients in their standard and personalized approaches.

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Ana Correia-Branco Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

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Ariel Mei Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

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Sreehari Pillai Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

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Nirmala Jayaraman Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

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Radhika Sharma Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

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Alison G Paquette University of Washington, Department of Pediatrics, Seattle, Washington, USA

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Naveen K Neradugomma Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA

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Ciara Benson Department of Bioengineering, University of Washington, Seattle, Washington, USA

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Nicholas W Chavkin Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA

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Qingcheng Mao Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA

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Mary C Wallingford Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

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The placenta mediates the transport of nutrients, such as inorganic phosphate (Pi), between the maternal and fetal circulatory systems. The placenta itself also requires high levels of nutrient uptake as it develops to provide critical support for fetal development. This study aimed to determine placental Pi transport mechanisms using in vitro and in vivo models. We observed that Pi (P33) uptake in BeWo cells is sodium dependent and that SLC20A1/Slc20a1 is the most highly expressed placental sodium-dependent transporter in mouse (microarray), human cell line (RT-PCR) and term placenta (RNA-seq), supporting that normal growth and maintenance of the mouse and human placenta requires SLC20A1/Slc20a1. Slc20a1 wild-type (Slc20a1+/+ ) and knockout (Slc20a1–/– ) mice were produced through timed intercrosses and displayed yolk sac angiogenesis failure as expected at E10.5. E9.5 tissues were analyzed to test whether placental morphogenesis requires Slc20a1. At E9.5, the developing placenta was reduced in size in Slc20a1–/– . Multiple structural abnormalities were also observed in the Slc20a1–/– chorioallantois. We determined that monocarboxylate transporter 1 protein (MCT1+) cells were reduced in developing Slc20a1–/– placenta, confirming that Slc20a1 loss reduced trophoblast syncytiotrophoblast 1 (SynT-I) coverage. Next, we examined the cell type-specific Slc20a1 expression and SynT molecular pathways in silico and identified Notch/Wnt as a pathway of interest that regulates trophoblast differentiation. We further observed that specific trophoblast lineages express Notch/Wnt genes that associate with endothelial cell tip-and-stalk cell markers. In conclusion, our findings support that Slc20a1 mediates the symport of Pi into SynT cells, providing critical support for their differentiation and angiogenic mimicry function at the developing maternalfetal interface.

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