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1. Diet alters age-related remodeling of aortic collagen in mice susceptible to atherosclerosis

   https://doi.org/10.1152/ajpheart.00420.2020  

   Watson, Shana R. ; Cooper, Kara M. ; Liu, Piaomu ; Gharraee, Nazli ; Du, Liya ; Han, Savannah M. ; Peña, Edsel A. ; Sutton, Michael A. ; Eberth, John F. ; Lessner, Susan M. ( January 2021 , American Journal of Physiology-Heart and Circulatory Physiology)

   null (Ed.)

   Vascular cells restructure extracellular matrix in response to aging or changes in mechanical loading. Here, we characterized collagen architecture during age-related aortic remodeling in atherosclerosis-prone mice. We hypothesized that changes in collagen fiber orientation reflect an altered balance between passive and active forces acting on the arterial wall. We examined two factors that can alter this balance, endothelial dysfunction and reduced smooth muscle cell (SMC) contractility. Collagen fiber organization was visualized by second-harmonic generation microscopy in aortic adventitia of apolipoprotein E (apoE) knockout (KO) mice at 6 wk and 6 mo of age on a chow diet and at 7.5 mo of age on a Western diet (WD), using image analysis to yield mean fiber orientation. Adventitial collagen fibers became significantly more longitudinally oriented with aging in apoE knockout mice on chow diet. Conversely, fibers became more circumferentially oriented with aging in mice on WD. Total collagen content increased significantly with age in mice fed WD. We compared expression of endothelial nitric oxide synthase and acetylcholine-mediated nitric oxide release but found no evidence of endothelial dysfunction in older mice. Time-averaged volumetric blood flow in all groups showed no significant changes. Wire myography of aortic rings revealed decreases in active stress generation with age that were significantly exacerbated in WD mice. We conclude that the aorta displays a distinct remodeling response to atherogenic stimuli, indicated by altered collagen organization. Collagen reorganization can occur in the absence of altered hemodynamics and may represent an adaptive response to reduced active stress generation by vascular SMCs. NEW & NOTEWORTHY The following major observations were made in this study: 1) aortic adventitial collagen fibers become more longitudinally oriented with aging in apolipoprotein E knockout mice fed a chow diet; 2) conversely, adventitial collagen fibers become more circumferentially oriented with aging in apoE knockout mice fed a high-fat diet; 3) adventitial collagen content increases significantly with age in mice on a high-fat diet; 4) these alterations in collagen organization occur largely in the absence of hemodynamic changes; and 5) circumferential reorientation of collagen is associated with decreased active force generation (contractility) in aged mice on a high-fat diet. 

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2. Transforming Endothelium with Platelet‐Rich Plasma in Engineered Microvessels

   https://doi.org/10.1002/advs.201901725  

   Nagao, Ryan J. ; Marcu, Raluca ; Wang, Yuliang ; Wang, Lu ; Arakawa, Chris ; DeForest, Cole ; Chen, Junmei ; López, José A. ; Zheng, Ying ( October 2019 , Advanced Science)

   Vascularization remains an obstacle when engineering complex tissues for regeneration and disease modeling. Although progress has been made in recreating 3D vascular structures, challenges exist in generating a mature, functional endothelium. It is demonstrated that perfusing engineered microvessels with platelet‐rich plasma, a critical homeostatic component in vivo that is often overlooked in vitro, substantially transforms the endothelium, both maturing endothelial cells and improving functionality in 24 h. Platelets readily adhered to the exposed collagen‐I substrate through small gaps within engineered vessels without forming thrombi. The adherent platelets improve barrier function, enhance endothelial glycolysis, reduce thrombogenicity, and enrich smooth muscle cell growth surrounding the endothelium. These findings demonstrate that platelets are essential to the function of endothelium during vascular maturation and remodeling. This study sheds light on a potential strategy to engineer stable, implantable vascular networks.

    

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3. Shear stress magnitude and transforming growth factor-βeta 1 regulate endothelial to mesenchymal transformation in a three-dimensional culture microfluidic device

   https://doi.org/10.1039/C6RA16607E  

   Mina, Sara G. ; Wang, Wei ; Cao, Qingfeng ; Huang, Peter ; Murray, Bruce T. ; Mahler, Gretchen J. ( January 2016 , RSC Advances)

   Normal fibroblasts are present within the extracellular matrix (ECM). They can become activated, leading to increased proliferation and ECM protein secretion such as collagen type I to promote tissue remodeling. These cells are also involved in adult pathologies including cancer metastasis and cardiac and renal fibrosis. One source of activated fibroblasts is endothelial to mesenchymal transformation (EndMT), in which endothelial cells lose their cell–cell and cell–ECM adhesions, gain invasive properties, and become mesenchymal cells. While EndMT is well characterized in developmental biology, the mechanisms and functional role of EndMT in adult physiology and pathology have not been fully investigated. A microfluidic device with an incorporated three-dimensional ECM chamber was developed to study the role of combined steady fluid shear stress magnitudes and transforming growth factor-βeta 1 (TGF-β1) on EndMT. Low (1 dyne per cm 2 ) steady shear stress and TGF-β1 exposure induced EndMT in endothelial cells, including upregulation of mesenchymal protein and gene expression markers. Cells exposed to TGF-β1 and high (20 dynes per cm 2 ) steady shear stress did not undergo EndMT, and protein and gene expression of mesenchymal markers was significantly downregulated. Mesenchymally transformed cells under static conditions with and without TGF-β1 showed significantly more collagen production when compared to fluidic conditions. These results confirm that both low shear stress and TGF-β1 induce EndMT in endothelial cells, but this process can be prevented by exposure to physiologically relevant high shear stress. These results also show conditions most likely to cause tissue pathology. 

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4. Pericytes Contribute to Dysfunction in a Human 3D Model of Placental Microvasculature through VEGF‐Ang‐Tie2 Signaling

   https://doi.org/10.1002/advs.201900878  

   Haase, Kristina ; Gillrie, Mark R. ; Hajal, Cynthia ; Kamm, Roger D. ( October 2019 , Advanced Science)

   Placental vasculopathies are associated with a number of pregnancy‐related diseases, including pre‐eclampsia (PE)—a leading cause of maternal–fetal morbidity and mortality worldwide. Placental presentations of PE are associated with endothelial dysfunction, reduced vessel perfusion, white blood cell infiltration, and altered production of angiogenic factors within the placenta (a candidate mechanism). Despite maintaining vascular quiescence in other tissues, how pericytes contribute to vascular growth and signaling in the placenta remains unknown. Here, pericytes are hypothesized to play a detrimental role in the pathogenesis of placental vascular growth. A perfusable triculture model is developed, consisting of human endothelial cells, fibroblasts, and pericytes, capable of recapitulating growth and remodeling in a system that mimics inflamed placental microvessels. Placental pericytes are shown to contribute to growth restriction of microvessels over time, an effect that is strongly regulated by vascular endothelial growth factor and Angiopoietin/Tie2 signaling. Furthermore, this model is capable of recapitulating essential processes including tumor necrosis factor alpha (TNFα)‐mediated vascular leakage and leukocyte infiltration, both important aspects associated with placental PE. This placental vascular model highlights that an imbalance in endothelial–pericyte crosstalk can play a critical role in the development of vascular pathology and associated diseases.

    

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5. Collagen Fibril Abnormalities in Human and Mice Abdominal Aortic Aneurysm

   Jones, B. ; Tonniges, J. R. ; Debsk, A.i ; Albert, B. ; Yeung, D. A. ; Gadde, N. ; Mahajan, A. ; Sharma, N. ; Calomeni, E. P. ; Go, M. ; et al ( August 2020 , Biomedical Engineering Society 2020 Annual Meeting)

   null (Ed.)

   Introduction: Vascular diseases like abdominal aortic aneurysms (AAA) are characterized by a drastic remodeling of the vessel wall, accompanied with changes in the elastin and collagen content. At the macromolecular level, the elastin fibers in AAA have been reported to undergo significant structural alterations. While the undulations (waviness) of the collagen fibers is also reduced in AAA, very little is understood about changes in the collagen fibril at the sub-fiber level in AAA as well as in other vascular pathologies. Materials and Methods: In this study we investigated structural changes in collagen fibrils in human AAA tissue extracted at the time of vascular surgery and in aorta extracted from angiotensin II (AngII) infused ApoE−/− mouse model of AAA. Collagen fibril structure was examined using transmission electron microscopy and atomic force microscopy. Images were analyzed to ascertain length and depth of D-periodicity, fibril diameter and fibril curvature. Tissues were also stained using collagen hybridizing peptide (CHP) and analyzed using fluorescent microscopy and second harmonic generation (SHG) microscopy to locate regions of healthy and degraded collagen. Results: Abnormal collagen fibrils with compromised D-periodic banding were observed in the excised human tissue and in remodeled regions of AAA in AngII infused mice (Figure 1). These abnormal fibrils were characterized by statistically significant reduction in depths of D-periods and an increased curvature of collagen fibrils. These features were more pronounced in human AAA as compared to murine samples. Additionally, regions of abnormal collagen were located within the remodeled areas of AAA tissue and were distinct from healthy collagen regions as ascertained using CHP staining and SHG (Figure 1). Thoracic aorta from Ang II-infused mice, abdominal aorta from saline-infused mice, and abdominal aorta from non-AAA human controls did not contain abnormal collagen fibrils. Conclusions: The structural alterations in abnormal collagen fibrils appear similar to those reported for collagen fibrils subjected to mechanical overload or chronic inflammation in other tissues. Detection of abnormal collagen could be utilized to better understand the functional properties of the underlying extracellular matrix in vascular as well as other pathologies. 

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