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Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 14160

Special Issue Editor

Special Issue Information

Dear Colleagues,

Endothelial cells (ECs) are not just passive conduits for delivering blood. Rather, ECs also play tissue-specific functions by providing highly specialized sets of angiocrine factors whose expression can be controlled by cell-intrinsic regulatory networks as well as by a variety of cell-extrinsic biophysical cues found at different body locations. Angiocrine factors modulate organ development, homeostasis, metabolism and regeneration, and their alteration could be directly involved in the pathogenesis of multiple conditions. This Special Issue of International Journal of Molecular Sciences will focus on the regulation and functional roles of tissue-specific ECs and angiocrine factors in physiological and pathological contexts, and the therapeutic potential of tailoring ECs to improve human health.

Dr. Ignacio Benedicto
Guest Editor

Manuscript Submission Information

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Keywords

  • endothelial cells
  • angiocrine factors
  • development
  • homeostasis
  • regeneration
  • vascular dysfunction
  • angiogenesis

Published Papers (5 papers)

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Research

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16 pages, 2796 KiB  
Article
The Distinct Role of the HDL Receptor SR-BI in Cholesterol Homeostasis of Human Placental Arterial and Venous Endothelial Cells
by Manuela Strahlhofer-Augsten, Carolin Schliefsteiner, Silvija Cvitic, Meekha George, Ingrid Lang-Olip, Birgit Hirschmugl, Gunther Marsche, Uwe Lang, Boris Novakovic, Richard Saffery, Gernot Desoye and Christian Wadsack
Int. J. Mol. Sci. 2022, 23(10), 5364; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105364 - 11 May 2022
Cited by 3 | Viewed by 1845
Abstract
As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from human placenta are enriched with cholesterol [...] Read more.
As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from human placenta are enriched with cholesterol compared to venous endothelial cells (ECV). Moreover, umbilical venous and arterial plasma cholesterol levels differ markedly. We tested the hypothesis that the uptake of HDL-cholesteryl esters differs between ECA and ECV because of the differential expression of SR-BI. We aimed to identify the key regulators underlying these differences and the functional consequences. Immunohistochemistry was used for visualization of SR-BI in situ. ECA and ECV were isolated from the chorionic plate of human placenta and used for RT-qPCR, Western Blot, and HDL uptake assays with 3H- and 125I-labeled HDL. DNA was extracted for the methylation profiling of the SR-BI promoter. SR-BI regulation was studied by exposing ECA and ECV to differential oxygen concentrations or shear stress. Our results show elevated SR-BI expression and protein abundance in ECA compared to ECV in situ and in vitro. Immunohistochemistry demonstrated that SR-BI is mainly expressed on the apical side of placental endothelial cells in situ, allowing interaction with mature HDL circulating in the fetal blood. This was functionally linked to a higher increase of selective cholesterol ester uptake from fetal HDL in ECA than in ECV, and resulted in increased cholesterol availability in ECA. SR-BI expression on ECV tended to decrease with shear stress, which, together with heterogeneous immunostaining, suggests that SR-BI expression is locally regulated in the placental vasculature. In addition, hypomethylation of several CpG sites within the SR-BI promoter region might contribute to differential expression of SR-BI between chorionic arteries and veins. Therefore, SR-BI contributes to a local cholesterol homeostasis in ECA and ECV of the human feto-placental vasculature. Full article
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18 pages, 7070 KiB  
Article
Tracking of Endothelial Cell Migration and Stiffness Measurements Reveal the Role of Cytoskeletal Dynamics
by Dominick J. Romano, Jesus M. Gomez-Salinero, Zoran Šunić, Antonio Checco and Sina Y. Rabbany
Int. J. Mol. Sci. 2022, 23(1), 568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010568 - 05 Jan 2022
Cited by 3 | Viewed by 2768
Abstract
Cell migration is a complex, tightly regulated multistep process in which cytoskeletal reorganization and focal adhesion redistribution play a central role. Core to both individual and collective migration is the persistent random walk, which is characterized by random force generation and resistance to [...] Read more.
Cell migration is a complex, tightly regulated multistep process in which cytoskeletal reorganization and focal adhesion redistribution play a central role. Core to both individual and collective migration is the persistent random walk, which is characterized by random force generation and resistance to directional change. We first discuss a model that describes the stochastic movement of ECs and characterizes EC persistence in wound healing. To that end, we pharmacologically disrupted cytoskeletal dynamics, cytochalasin D for actin and nocodazole for tubulin, to understand its contributions to cell morphology, stiffness, and motility. As such, the use of Atomic Force Microscopy (AFM) enabled us to probe the topography and stiffness of ECs, while time lapse microscopy provided observations in wound healing models. Our results suggest that actin and tubulin dynamics contribute to EC shape, compressive moduli, and directional organization in collective migration. Insights from the model and time lapse experiment suggest that EC speed and persistence are directionally organized in wound healing. Pharmacological disruptions suggest that actin and tubulin dynamics play a role in collective migration. Current insights from both the model and experiment represent an important step in understanding the biomechanics of EC migration as a therapeutic target. Full article
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19 pages, 4269 KiB  
Article
Transcriptomic Analysis Reveals Differential Expression of Genes between Lung Capillary and Post Capillary Venules in Abdominal Sepsis
by Milladur Rahman, Zhiyi Ding, Carl-Fredrik Rönnow and Henrik Thorlacius
Int. J. Mol. Sci. 2021, 22(19), 10181; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910181 - 22 Sep 2021
Cited by 4 | Viewed by 2390
Abstract
Lung endothelial cell dysfunction plays a central role in septic-induced lung injury. We hypothesized that endothelial cell subsets, capillary endothelial cells (capEC) and post capillary venules (PCV), might play different roles in regulating important pathophysiology in sepsis. In order to reveal global transcriptomic [...] Read more.
Lung endothelial cell dysfunction plays a central role in septic-induced lung injury. We hypothesized that endothelial cell subsets, capillary endothelial cells (capEC) and post capillary venules (PCV), might play different roles in regulating important pathophysiology in sepsis. In order to reveal global transcriptomic changes in endothelial cell subsets during sepsis, we induced sepsis in C57BL/6 mice by cecal ligation and puncture (CLP). We confirmed that CLP induced systemic and lung inflammation in our model. Endothelial cells (ECs) from lung capillary and PCV were isolated by cell sorting and transcriptomic changes were analyzed by bioinformatic tools. Our analysis revealed that lung capEC are transcriptionally different than PCV. Comparison of top differentially expressed genes (DEGs) of capEC and PCV revealed that capEC responses are different than PCV during sepsis. It was found that capEC are more enriched with genes related to regulation of coagulation, vascular permeability, wound healing and lipid metabolic processes after sepsis. In contrast, PCV are more enriched with genes related to chemotaxis, cell–cell adhesion by integrins, chemokine biosynthesis, regulation of actin filament process and neutrophil homeostasis after sepsis. In addition, we predicted some transcription factor targets that regulate a significant number of DEGs in sepsis. We proposed that targeting certain DEGs or transcriptional factors would be useful in protecting against sepsis-induced lung damage. Full article
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15 pages, 17126 KiB  
Article
Distinctive Properties of Endothelial Cells from Tumor and Normal Tissue in Human Breast Cancer
by Kinga Wilkus, Klaudia Brodaczewska, Arkadiusz Kajdasz and Claudine Kieda
Int. J. Mol. Sci. 2021, 22(16), 8862; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168862 - 17 Aug 2021
Cited by 4 | Viewed by 2656
Abstract
Tumor microenvironments shape aggressiveness and are largely maintained by the conditions of angiogenesis formation. Thus, endothelial cells’ (ECs) biological reactions are crucial to understand and control the design of efficient therapies. In this work, we used models of ECs to represent a breast [...] Read more.
Tumor microenvironments shape aggressiveness and are largely maintained by the conditions of angiogenesis formation. Thus, endothelial cells’ (ECs) biological reactions are crucial to understand and control the design of efficient therapies. In this work, we used models of ECs to represent a breast cancer tumor site as well as the same, healthy tissue. Cells characterization was performed at the transcriptome and protein expression levels, and the cells functional biological responses (angiogenesis and permeability) were assessed. We showed that the expression of proteins specific to ECs (ACE+, VWF+), their differentiation (CD31+, CD 133+, CD105+, CD34-), their adhesion properties (ICAM-1+, VCAM-1+, CD62-L+), and their barrier formation (ZO-1+) were all downregulated in tumor-derived ECs. NGS-based differential transcriptome analysis confirmed CD31-lowered expression and pointed to the increase of Ephrin-B2 and SNCAIP, indicative of dedifferentiation. Functional assays confirmed these differences; angiogenesis was impaired while permeability increased in tumor-derived ECs, as further validated by the distinctly enhanced VEGF production in response to hypoxia, reflecting the tumor conditions. This work showed that endothelial cells differed highly significantly, both phenotypically and functionally, in the tumor site as compared to the normal corresponding tissue, thus influencing the tumor microenvironment. Full article
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Review

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20 pages, 1480 KiB  
Review
Cytoskeleton Reorganization in EndMT—The Role in Cancer and Fibrotic Diseases
by Wojciech Michał Ciszewski, Marta Ewelina Wawro, Izabela Sacewicz-Hofman and Katarzyna Sobierajska
Int. J. Mol. Sci. 2021, 22(21), 11607; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111607 - 27 Oct 2021
Cited by 12 | Viewed by 3641
Abstract
Chronic inflammation promotes endothelial plasticity, leading to the development of several diseases, including fibrosis and cancer in numerous organs. The basis of those processes is a phenomenon called the endothelial–mesenchymal transition (EndMT), which results in the delamination of tightly connected endothelial cells that [...] Read more.
Chronic inflammation promotes endothelial plasticity, leading to the development of several diseases, including fibrosis and cancer in numerous organs. The basis of those processes is a phenomenon called the endothelial–mesenchymal transition (EndMT), which results in the delamination of tightly connected endothelial cells that acquire a mesenchymal phenotype. EndMT-derived cells, known as the myofibroblasts or cancer-associated fibroblasts (CAFs), are characterized by the loss of cell–cell junctions, loss of endothelial markers, and gain in mesenchymal ones. As a result, the endothelium ceases its primary ability to maintain patent and functional capillaries and induce new blood vessels. At the same time, it acquires the migration and invasion potential typical of mesenchymal cells. The observed modulation of cell shape, increasedcell movement, and invasion abilities are connected with cytoskeleton reorganization. This paper focuses on the review of current knowledge about the molecular pathways involved in the modulation of each cytoskeleton element (microfilaments, microtubule, and intermediate filaments) during EndMT and their role as the potential targets for cancer and fibrosis treatment. Full article
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