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Biomedicines
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Vascular Endothelial Functions: Insights from Molecular Perspectives
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Vascular Endothelial Functions: Insights from Molecular Perspectives

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 28049

Special Issue Editor

Dr. Vladimir P. Shirinsky

E-Mail Website
Guest Editor
National Medical Research Center for Cardiology, 121552 Moscow, Russia
Interests: molecular bases of cardiovascular pathophysiology; cardiovascular drug discovery; biosimilars; functional genomics of myosin light chain kinase (MYLK1)

Special Issue Information

Dear Colleagues,

In addition to being a single cellular layer separating blood from underlying tissues, vascular endothelium executes multiple functions including angiogenesis, control of vascular tone and hemodynamics, participation in blood clotting, modulation of immune reactions, and exchange of substances between blood and tissues. Endothelial dysfunction or damage is a hallmark of major human pathologies such as cardiovascular diseases, diabetes, cancer, severe lung and brain injury and infectious diseases, including the global threat of COVID-19. Advancement in endothelial protection and correction of endothelial dysfunction requires identification of the key molecules that participate in signaling cascades, metabolic health, and macromolecule interaction networks in endothelial cells. Some of these molecules are predicted to gain pharmacologic value in emerging vasculoprotective therapies.

In this Special Issue, we hope to attract contributions elucidating molecular events underlying endothelial physiology and multiple faces of endothelial dysfunction, as well as contributions on endothelial pharmacology dealing with molecular mechanisms of the action of known and novel endothelial protective substances.

Dr. Vladimir P. Shirinsky
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • endothelium
  • dysfunction
  • barrier
  • angiogenesis
  • cytoskeletal and adhesive proteins
  • transendothelial transport
  • gene expression
  • glycocalyx
  • intracellular signaling
  • metabolism

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review, Other

7 pages, 179 KiB  
Editorial
Vascular Endothelium at the Molecular Level: From Fundamental Knowledge Toward Medical Implementation
by Vladimir P. Shirinsky
Biomedicines 2025, 13(1), 2; https://doi.org/10.3390/biomedicines13010002 - 24 Dec 2024
Cited by 1 | Viewed by 757
Abstract
The concept of multiple physiologic roles played by a single layer of endothelium on the intimal face of blood vessels started gaining recognition in the 1960s [...] Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)

Research

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14 pages, 2650 KiB  
Article
Shear Stress and the AMP-Activated Protein Kinase Independently Protect the Vascular Endothelium from Palmitate Lipotoxicity
by Asker Y. Khapchaev, Alexander V. Vorotnikov, Olga A. Antonova, Mikhail V. Samsonov, Ekaterina A. Shestakova, Igor A. Sklyanik, Alina O. Tomilova, Marina V. Shestakova and Vladimir P. Shirinsky
Biomedicines 2024, 12(2), 339; https://doi.org/10.3390/biomedicines12020339 - 1 Feb 2024
Cited by 3 | Viewed by 1803
Abstract
Saturated free fatty acids are thought to play a critical role in metabolic disorders associated with obesity, insulin resistance, type 2 diabetes (T2D), and their vascular complications via effects on the vascular endothelium. The most abundant saturated free fatty acid, palmitate, exerts lipotoxic [...] Read more.
Saturated free fatty acids are thought to play a critical role in metabolic disorders associated with obesity, insulin resistance, type 2 diabetes (T2D), and their vascular complications via effects on the vascular endothelium. The most abundant saturated free fatty acid, palmitate, exerts lipotoxic effects on the vascular endothelium, eventually leading to cell death. Shear stress activates the endothelial AMP-activated protein kinase (AMPK), a cellular energy sensor, and protects endothelial cells from lipotoxicity, however their relationship is uncertain. Here, we used isoform-specific shRNA-mediated silencing of AMPK to explore its involvement in the long-term protection of macrovascular human umbilical vein endothelial cells (HUVECs) against palmitate lipotoxicity and to relate it to the effects of shear stress. We demonstrated that it is the α1 catalytic subunit of AMPK that is critical for HUVEC protection under static conditions, whereas AMPK-α2 autocompensated a substantial loss of AMPK-α1, but failed to protect the cells from palmitate. Shear stress equally protected the wild type HUVECs and those lacking either α1, or α2, or both AMPK-α isoforms; however, the protective effect of AMPK reappeared after returning to static conditions. Moreover, in human adipose microvascular endothelial cells isolated from obese diabetic individuals, shear stress was a strong protector from palmitate lipotoxicity, thus highlighting the importance of circulation that is often obstructed in obesity/T2D. Altogether, these results indicate that AMPK is important for vascular endothelial cell protection against lipotoxicity in the static environment, however it may be dispensable for persistent and more effective protection exerted by shear stress. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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12 pages, 5760 KiB  
Article
Colocalization Analysis of Cytoplasmic Actin Isoforms Distribution in Endothelial Cells
by Anton S. Shakhov, Polina A. Kovaleva, Alexandra S. Churkina, Igor I. Kireev and Irina B. Alieva
Biomedicines 2022, 10(12), 3194; https://doi.org/10.3390/biomedicines10123194 - 9 Dec 2022
Cited by 1 | Viewed by 2530
Abstract
Actin cytoskeleton is an essential component of living cells and plays a decisive role in many cellular processes. In mammals, β- and γ-actin are cytoplasmic actin isoforms in non-muscle cells. Despite minor differences in the amino acid sequence, β- and γ-actin localize in [...] Read more.
Actin cytoskeleton is an essential component of living cells and plays a decisive role in many cellular processes. In mammals, β- and γ-actin are cytoplasmic actin isoforms in non-muscle cells. Despite minor differences in the amino acid sequence, β- and γ-actin localize in different cell structures and perform different functions. While cytoplasmic β-actin is involved in many intracellular processes including cell contraction, γ-actin is responsible for cell mobility and promotes tumor transformation. Numerous studies demonstrate that β- and γ-actin are spatially separated in the cytoplasm of fibroblasts and epithelial cells; this separation is functionally determined. The spatial location of β/γ-actin in endothelial cells is still a subject for discussion. Using super-resolution microscopy, we investigated the β/γ-actin colocalization in endotheliocytes and showed that the β/γ-actin colocalization degree varies widely between different parts of the marginal regions and near the cell nucleus. In the basal cytoplasm, β-actin predominates, while the ratio of isoforms evens out as it moves to the apical cytoplasm. Thus, our colocalization analysis suggests that β- and γ-actin are segregated in the endotheliocyte cytoplasm. The segregation is greatly enhanced during cell lamella activation in the nocodazole-induced endothelial barrier dysfunction, reflecting a different functional role of cytoplasmic actin isoforms in endothelial cells. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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17 pages, 1234 KiB  
Article
Characterization of Vascular Patterns Associated with Endothelial Glycocalyx Damage in Early- and Late-Onset Preeclampsia
by Marina M. Ziganshina, Kamilla T. Muminova, Nailia R. Khasbiullina, Zulfiya S. Khodzhaeva, Ekaterina L. Yarotskaya and Gennady T. Sukhikh
Biomedicines 2022, 10(11), 2790; https://doi.org/10.3390/biomedicines10112790 - 2 Nov 2022
Cited by 7 | Viewed by 2198
Abstract
This paper provides an assessment of molecular and functional changes in blood vessels, and a description of vascular patterns during preeclampsia (PE). Patients with normal pregnancy, and pregnancy complicated by PE at earlier (20–34 weeks) and later terms (≥34 weeks) underwent a 24 [...] Read more.
This paper provides an assessment of molecular and functional changes in blood vessels, and a description of vascular patterns during preeclampsia (PE). Patients with normal pregnancy, and pregnancy complicated by PE at earlier (20–34 weeks) and later terms (≥34 weeks) underwent a 24 h monitoring of blood pressure, central hemodynamics, arterial stiffness, and myocardial function. The blood levels of the structural components of endothelial glycocalyx (eGC): syndecan-1 (SDC 1), heparan sulfate proteoglycan 2 (HSPG2), and hyaluronic acid (HA) were determined. In early-onset PE, the vascular pattern comprised changes in all structural components of eGCs, including transmembrane proteoglycans levels, and severe disorders of central hemodynamics, arterial stiffness, and myocardial changes, probably leading to more severe course of PE and the formation of morphological grounds for cardiovascular disorders. The vascular pattern in late-onset PE, including changes in HA levels, central hemodynamics, and myocardial function, may be a signal of potential cardiovascular disorder. PE may change adaptive hemodynamic responses to a pathological reaction affecting both arterial elasticity and the left ventricular myocardium, with its subsequent hypertrophy and decompensation, leading to a delayed development of cardiovascular disorders after PE. Further clinical studies of these indicators will possibly identify predictors of PE and long-term consequences of the disease. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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10 pages, 982 KiB  
Article
Effect of Anti-Hypertensive Medication on Plasma Concentrations of Lysyl Oxidase: Evidence for Aldosterone-IL-6-Dependent Regulation of Lysyl Oxidase Blood Concentration
by Rolf Schreckenberg, Oliver Dörr, Sabine Pankuweit, Bernhard Schieffer, Christian Troidl, Holger Nef, Christian W. Hamm, Susanne Rohrbach, Ling Li and Klaus-Dieter Schlüter
Biomedicines 2022, 10(7), 1748; https://doi.org/10.3390/biomedicines10071748 - 20 Jul 2022
Viewed by 2100
Abstract
Lysyl oxidase (LOX) is a secretory protein that catalyzes elastin and collagen cross-linking. Lowering LOX expression and activity in endothelial cells is associated with a high risk of aneurysms and vascular malformation. Interleukin-6 (IL-6), elevated in hypertension, is known to suppress LOX expression. [...] Read more.
Lysyl oxidase (LOX) is a secretory protein that catalyzes elastin and collagen cross-linking. Lowering LOX expression and activity in endothelial cells is associated with a high risk of aneurysms and vascular malformation. Interleukin-6 (IL-6), elevated in hypertension, is known to suppress LOX expression. The influence of anti-hypertensive medication on the plasma LOX concentration is currently unknown. In a cohort of 34 patients diagnosed with resistant hypertension and treated with up to nine different drugs, blood concentration of LOX was analyzed to identify drugs that have an impact on plasma LOX concentration. Key findings were confirmed in a second independent patient cohort of 37 patients diagnosed with dilated cardiomyopathy. Blood concentrations of aldosterone and IL-6 were analyzed. In vitro, the effect of IL-6 on LOX expression was analyzed in endothelial cells. Patients receiving aldosterone antagonists had the highest plasma LOX concentration in both cohorts. This effect was independent of sex, age, blood pressure, body mass index, and co-medication. Blood aldosterone concentration correlates with plasma IL-6 concentration. In vitro, IL-6 decreased the expression of LOX in endothelial cells but not fibroblasts. Aldosterone was identified as a factor that affects blood concentration of LOX in an IL-6-dependent manner. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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Review

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18 pages, 1614 KiB  
Review
Endothelin-1 and Its Role in Cancer and Potential Therapeutic Opportunities
by Madeline Harrison, Dmitry Zinovkin and Md Zahidul Islam Pranjol
Biomedicines 2024, 12(3), 511; https://doi.org/10.3390/biomedicines12030511 - 23 Feb 2024
Cited by 10 | Viewed by 2856
Abstract
Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be overactivated within cancers. ET-1 has been found to potentiate hallmarks of cancer progression such as cell proliferation, [...] Read more.
Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be overactivated within cancers. ET-1 has been found to potentiate hallmarks of cancer progression such as cell proliferation, invasion and metastasis, as well as angiogenesis. ET-1 has also been implicated in inducing the epithelial–mesenchymal transition (EMT) and promoting resistance to anticancer drugs. Many preclinical efforts have been made to target ET-1 expression within cancer, such as by using ET-1 receptor antagonists, many of which have been approved for treating pulmonary hypertension. Targeting ET-1 has been shown to improve the response to various other cancer therapeutics, highlighting the potential benefits targeting this peptide may exert. Drug repurposing is an attractive strategy, and exploration of this avenue may be promising for targeting ET-1 in cancer. There are many clinical trials which have been completed and are currently undergoing involving the repurposing of ET-1 receptor antagonists for cancer treatment. In this review, the pathways through which ET-1 potentiates cancer will be discussed, as well as where the opportunity for therapeutic intervention lies in relation to cancer. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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23 pages, 2641 KiB  
Review
Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation
by Rahul S. Patil, Anita Kovacs-Kasa, Boris A. Gorshkov, David J. R. Fulton, Yunchao Su, Robert K. Batori and Alexander D. Verin
Biomedicines 2023, 11(6), 1638; https://doi.org/10.3390/biomedicines11061638 - 5 Jun 2023
Cited by 4 | Viewed by 3211
Abstract
Vascular barrier dysfunction is characterized by increased permeability and inflammation of endothelial cells (ECs), which are prominent features of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis, and a major complication of the SARS-CoV-2 infection and COVID-19. Functional impairment of [...] Read more.
Vascular barrier dysfunction is characterized by increased permeability and inflammation of endothelial cells (ECs), which are prominent features of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis, and a major complication of the SARS-CoV-2 infection and COVID-19. Functional impairment of the EC barrier and accompanying inflammation arises due to microbial toxins and from white blood cells of the lung as part of a defensive action against pathogens, ischemia-reperfusion or blood product transfusions, and aspiration syndromes-based injury. A loss of barrier function results in the excessive movement of fluid and macromolecules from the vasculature into the interstitium and alveolae resulting in pulmonary edema and collapse of the architecture and function of the lungs, and eventually culminates in respiratory failure. Therefore, EC barrier integrity, which is heavily dependent on cytoskeletal elements (mainly actin filaments, microtubules (MTs), cell-matrix focal adhesions, and intercellular junctions) to maintain cellular contacts, is a critical requirement for the preservation of lung function. EC cytoskeletal remodeling is regulated, at least in part, by Ser/Thr phosphorylation/dephosphorylation of key cytoskeletal proteins. While a large body of literature describes the role of phosphorylation of cytoskeletal proteins on Ser/Thr residues in the context of EC barrier regulation, the role of Ser/Thr dephosphorylation catalyzed by Ser/Thr protein phosphatases (PPases) in EC barrier regulation is less documented. Ser/Thr PPases have been proposed to act as a counter-regulatory mechanism that preserves the EC barrier and opposes EC contraction. Despite the importance of PPases, our knowledge of the catalytic and regulatory subunits involved, as well as their cellular targets, is limited and under-appreciated. Therefore, the goal of this review is to discuss the role of Ser/Thr PPases in the regulation of lung EC cytoskeleton and permeability with special emphasis on the role of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) as major mammalian Ser/Thr PPases. Importantly, we integrate the role of PPases with the structural dynamics of the cytoskeleton and signaling cascades that regulate endothelial cell permeability and inflammation. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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22 pages, 1375 KiB  
Review
In Vitro Modeling of Diabetes Impact on Vascular Endothelium: Are Essentials Engaged to Tune Metabolism?
by Alexander V. Vorotnikov, Asker Y. Khapchaev, Alexey V. Nickashin and Vladimir P. Shirinsky
Biomedicines 2022, 10(12), 3181; https://doi.org/10.3390/biomedicines10123181 - 8 Dec 2022
Cited by 8 | Viewed by 2738
Abstract
Angiopathy is a common complication of diabetes mellitus. Vascular endothelium is among the first targets to experience blood-borne metabolic alterations, such as hyperglycemia and hyperlipidemia, the hallmarks of type 2 diabetes. To explore mechanisms of vascular dysfunction and eventual damage brought by these [...] Read more.
Angiopathy is a common complication of diabetes mellitus. Vascular endothelium is among the first targets to experience blood-borne metabolic alterations, such as hyperglycemia and hyperlipidemia, the hallmarks of type 2 diabetes. To explore mechanisms of vascular dysfunction and eventual damage brought by these pathologic conditions and to find ways to protect vasculature in diabetic patients, various research approaches are used including in vitro endothelial cell-based models. We present an analysis of the data available from these models that identifies early endothelial cell apoptosis associated with oxidative stress as the major outcome of mimicking hyperglycemia and hyperlipidemia in vitro. However, the fate of endothelial cells observed in these studies does not closely follow it in vivo where massive endothelial damage occurs mainly in the terminal stages of diabetes and in conjunction with comorbidities. We propose that the discrepancy is likely in missing essentials that should be available to cultured endothelial cells to adjust the metabolic state and withstand the immediate apoptosis. We discuss the role of carnitine, creatine, and AMP-activated protein kinase (AMPK) in suiting the endothelial metabolism for long-term function in diabetic type milieu in vitro. Engagement of these essentials is anticipated to expand diabetes research options when using endothelial cell-based models. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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20 pages, 2644 KiB  
Review
Succinate at the Crossroad of Metabolism and Angiogenesis: Roles of SDH, HIF1α and SUCNR1
by Reham Atallah, Andrea Olschewski and Akos Heinemann
Biomedicines 2022, 10(12), 3089; https://doi.org/10.3390/biomedicines10123089 - 1 Dec 2022
Cited by 13 | Viewed by 4622
Abstract
Angiogenesis is an essential process by which new blood vessels develop from existing ones. While adequate angiogenesis is a physiological process during, for example, tissue repair, insufficient and excessive angiogenesis stands on the pathological side. Fine balance between pro- and anti-angiogenic factors in [...] Read more.
Angiogenesis is an essential process by which new blood vessels develop from existing ones. While adequate angiogenesis is a physiological process during, for example, tissue repair, insufficient and excessive angiogenesis stands on the pathological side. Fine balance between pro- and anti-angiogenic factors in the tissue environment regulates angiogenesis. Identification of these factors and how they function is a pressing topic to develop angiogenesis-targeted therapeutics. During the last decade, exciting data highlighted non-metabolic functions of intermediates of the mitochondrial Krebs cycle including succinate. Among these functions is the contribution of succinate to angiogenesis in various contexts and through different mechanisms. As the concept of targeting metabolism to treat a wide range of diseases is rising, in this review we summarize the mechanisms by which succinate regulates angiogenesis in normal and pathological settings. Gaining a comprehensive insight into how this metabolite functions as an angiogenic signal will provide a useful approach to understand diseases with aberrant or excessive angiogenic background, and may provide strategies to tackle them. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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Other

28 pages, 1897 KiB  
Systematic Review
Endothelium-Derived Relaxing Factors and Endothelial Function: A Systematic Review
by Francesco Nappi, Antonio Fiore, Joyce Masiglat, Teresa Cavuoti, Michela Romandini, Pierluigi Nappi, Sanjeet Singh Avtaar Singh and Jean-Paul Couetil
Biomedicines 2022, 10(11), 2884; https://doi.org/10.3390/biomedicines10112884 - 10 Nov 2022
Cited by 21 | Viewed by 4003
Abstract
Background: The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular smooth muscle. Large amounts of work have been dedicated towards identifying mediators of vasodilation and vasoconstriction alongside the deleterious [...] Read more.
Background: The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular smooth muscle. Large amounts of work have been dedicated towards identifying mediators of vasodilation and vasoconstriction alongside the deleterious effects of reactive oxygen species on the endothelium. We conducted a systematic review to study the role of the factors released by the endothelium and the effects on the vessels alongside its role in atherosclerosis. Methods: A search was conducted with appropriate search terms. Specific attention was offered to the effects of emerging modulators of endothelial functions focusing the analysis on studies that investigated the role of reactive oxygen species (ROS), perivascular adipose tissue, shear stress, AMP-activated protein kinase, potassium channels, bone morphogenic protein 4, and P2Y2 receptor. Results: 530 citations were reviewed, with 35 studies included in the final systematic review. The endpoints were evaluated in these studies which offered an extensive discussion on emerging modulators of endothelial functions. Specific factors such as reactive oxygen species had deleterious effects, especially in the obese and elderly. Another important finding included the shear stress-induced endothelial nitric oxide (NO), which may delay development of atherosclerosis. Perivascular Adipose Tissue (PVAT) also contributes to reparative measures against atherosclerosis, although this may turn pathological in obese subjects. Some of these factors may be targets for pharmaceutical agents in the near future. Conclusion: The complex role and function of the endothelium is vital for regular homeostasis. Dysregulation may drive atherogenesis; thus, efforts should be placed at considering therapeutic options by targeting some of the factors noted. Full article
(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)
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