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13 pages, 3596 KiB

Open AccessArticle

Time Dependent Changes in the Ovine Neurovascular Unit; A Potential Neuroprotective Role of Annexin A1 in Neonatal Hypoxic-Ischemic Encephalopathy

by Hyun Young Park, Valéry L. E. van Bruggen, Carine J. Peutz-Kootstra, Daan R. M. G. Ophelders, Reint K. Jellema, Chris P. M. Reutelingsperger, Bart P. F. Rutten and Tim G. A. M. Wolfs

Int. J. Mol. Sci. 2023, 24(6), 5929; https://doi.org/10.3390/ijms24065929 - 21 Mar 2023

Viewed by 1517

Abstract

Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since [...] Read more.

Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFRβ for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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16 pages, 2260 KiB

Open AccessArticle

Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion

by Yuexi Guo and Venkateswarlu Kanamarlapudi

Int. J. Mol. Sci. 2023, 24(6), 5664; https://doi.org/10.3390/ijms24065664 - 16 Mar 2023

Cited by 4 | Viewed by 6266

Abstract

Coronavirus disease COVID-19, which is caused by severe acute respiratory syndrome coronavirus SARS-CoV-2, has become a worldwide pandemic in recent years. In addition to being a respiratory disease, COVID-19 is a ‘vascular disease’ since it causes a leaky vascular barrier and increases blood [...] Read more.

Coronavirus disease COVID-19, which is caused by severe acute respiratory syndrome coronavirus SARS-CoV-2, has become a worldwide pandemic in recent years. In addition to being a respiratory disease, COVID-19 is a ‘vascular disease’ since it causes a leaky vascular barrier and increases blood clotting by elevating von Willebrand factor (vWF) levels in the blood. In this study, we analyzed in vitro how the SARS-CoV-2 spike protein S1 induces endothelial cell (EC) permeability and its vWF secretion, and the underlying molecular mechanism for it. We showed that the SARS-CoV-2 spike protein S1 receptor-binding domain (RBD) is sufficient to induce endothelial permeability and vWF-secretion through the angiotensin-converting enzyme (ACE)2 in an ADP-ribosylation factor (ARF)6 activation-dependent manner. However, the mutants, including those in South African and South Californian variants of SARS-CoV-2, in the spike protein did not affect its induced EC permeability and vWF secretion. In addition, we have identified a signaling cascade downstream of ACE2 for the SARS-CoV-2 spike protein-induced EC permeability and its vWF secretion by using pharmacological inhibitors. The knowledge gained from this study could be useful in developing novel drugs or repurposing existing drugs for treating infections of SARS-CoV-2, particularly those strains that respond poorly to the existing vaccines. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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17 pages, 38912 KiB

Open AccessArticle

Visualization of Organ-Specific Lymphatic Growth: An Efficient Approach to Labeling Molecular Markers in Cleared Tissues

by Carolin Christ and Zoltán Jakus

Int. J. Mol. Sci. 2023, 24(6), 5075; https://doi.org/10.3390/ijms24065075 - 07 Mar 2023

Cited by 3 | Viewed by 1660

Abstract

Organ-specific lymphatics are essential for the maintenance of healthy organ function and lymphatic dysfunction can lead to the development of various diseases. However, the precise role of those lymphatic structures remains unknown, mainly due to inefficient visualization techniques. Here, we present an efficient [...] Read more.

Organ-specific lymphatics are essential for the maintenance of healthy organ function and lymphatic dysfunction can lead to the development of various diseases. However, the precise role of those lymphatic structures remains unknown, mainly due to inefficient visualization techniques. Here, we present an efficient approach to visualizing organ-specific lymphatic growth. We used a modified CUBIC protocol to clear mouse organs and combined it with whole-mount immunostaining to visualize lymphatic structures. We acquired images using upright, stereo and confocal microscopy and quantified them with AngioTool, a tool for the quantification of vascular networks. Using our approach, we then characterized the organ-specific lymphatic vasculature of the Flt4^kd/+ mouse model, showing symptoms of lymphatic dysfunction. Our approach enabled us to visualize the lymphatic vasculature of organs and to analyze and quantify structural changes. We detected morphologically altered lymphatic vessels in all investigated organs of Flt4^kd/+ mice, including the lungs, small intestine, heart and uterus, but no lymphatic structures in the skin. Quantifications showed that these mice have fewer and dilated lymphatic vessels in the small intestine and the lungs. Our results demonstrate that our approach can be used to investigate the importance of organ-specific lymphatics under both physiological and pathophysiological conditions. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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17 pages, 4368 KiB

Open AccessArticle

The PPAR-γ Agonist Pioglitazone Modulates Proliferation and Migration in HUVEC, HAOSMC and Human Arteriovenous Fistula-Derived Cells

by Carmen Ciavarella, Ilenia Motta, Francesco Vasuri, Teresa Palumbo, Anthony Paul Lisi, Alice Costa, Annalisa Astolfi, Sabrina Valente, Piera Versura, Eugenio F. Fornasiero, Raffaella Mauro, Mauro Gargiulo and Gianandrea Pasquinelli

Int. J. Mol. Sci. 2023, 24(5), 4424; https://doi.org/10.3390/ijms24054424 - 23 Feb 2023

Viewed by 1549

Abstract

The failure of arteriovenous fistulas (AVFs) following intimal hyperplasia (IH) increases morbidity and mortality rates in patients undergoing hemodialysis for chronic kidney disease. The peroxisome-proliferator associated receptor (PPAR-γ) may be a therapeutic target in IH regulation. In the present study, we investigated PPAR-γ [...] Read more.

The failure of arteriovenous fistulas (AVFs) following intimal hyperplasia (IH) increases morbidity and mortality rates in patients undergoing hemodialysis for chronic kidney disease. The peroxisome-proliferator associated receptor (PPAR-γ) may be a therapeutic target in IH regulation. In the present study, we investigated PPAR-γ expression and tested the effect of pioglitazone, a PPAR-γ agonist, in different cell types involved in IH. As cell models, we used Human Endothelial Umbilical Vein Cells (HUVEC), Human Aortic Smooth Muscle Cells (HAOSMC), and AVF cells (AVFCs) isolated from (i) normal veins collected at the first AVF establishment (T0), and (ii) failed AVF with IH (T1). PPAR-γ was downregulated in AVF T1 tissues and cells, in comparison to T0 group. HUVEC, HAOSMC, and AVFC (T0 and T1) proliferation and migration were analyzed after pioglitazone administration, alone or in combination with the PPAR-γ inhibitor, GW9662. Pioglitazone negatively regulated HUVEC and HAOSMC proliferation and migration. The effect was antagonized by GW9662. These data were confirmed in AVFCs T1, where pioglitazone induced PPAR-γ expression and downregulated the invasive genes SLUG, MMP-9, and VIMENTIN. In summary, PPAR-γ modulation may represent a promising strategy to reduce the AVF failure risk by modulating cell proliferation and migration. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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12 pages, 4649 KiB

Open AccessArticle

The Effects of Sirolimus and Magnesium on Primary Human Coronary Endothelial Cells: An In Vitro Study

by Giorgia Fedele, Sara Castiglioni, Jeanette A. M. Maier and Laura Locatelli

Int. J. Mol. Sci. 2023, 24(3), 2930; https://doi.org/10.3390/ijms24032930 - 02 Feb 2023

Viewed by 1334

Abstract

Drug eluting magnesium (Mg) bioresorbable scaffolds represent a novel paradigm in percutaneous coronary intervention because Mg-based alloys are biocompatible, have adequate mechanical properties and can be resorbed without adverse events. Importantly, Mg is fundamental in many biological processes, mitigates the inflammatory response and [...] Read more.

Drug eluting magnesium (Mg) bioresorbable scaffolds represent a novel paradigm in percutaneous coronary intervention because Mg-based alloys are biocompatible, have adequate mechanical properties and can be resorbed without adverse events. Importantly, Mg is fundamental in many biological processes, mitigates the inflammatory response and is beneficial for the endothelium. Sirolimus is widely used as an antiproliferative agent in drug eluting stents to inhibit the proliferation of smooth muscle cells, thus reducing the occurrence of stent restenosis. Little is known about the potential interplay between sirolimus and Mg in cultured human coronary artery endothelial cells (hCAEC). Therefore, the cells were treated with sirolimus in the presence of different concentrations of extracellular Mg. Cell viability, migration, barrier function, adhesivity and nitric oxide synthesis were assessed. Sirolimus impairs the viability of subconfluent, but not of confluent cells independently from the concentration of Mg in the culture medium. In confluent cells, sirolimus inhibits migration, while it cooperates with Mg in exerting an anti-inflammatory action that might have a role in preventing restenosis and thrombosis. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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15 pages, 1431 KiB

Open AccessArticle

Deciphering the Role of miR-200c-3p in Type 1 Diabetes (Subclinical Cardiovascular Disease) and Its Correlation with Inflammation and Vascular Health

by Sherin Bakhashab, Megan Li Yuen Yeoh, David J. Coulson, Samuel Christian Steel, Sabina L. Ray and Jolanta U. Weaver

Int. J. Mol. Sci. 2022, 23(24), 15659; https://doi.org/10.3390/ijms232415659 - 10 Dec 2022

Cited by 1 | Viewed by 1236

Abstract

Uncomplicated type 1 diabetes (T1DM) displays all features of subclinical cardiovascular disease (CVD) as is associated with inflammation, endothelial dysfunction and low endothelial progenitor cells. MiR-200c-3p has been shown in animal tissues to be pro-atherogenic. We aimed to explore the role of miR-200c-3p [...] Read more.

Uncomplicated type 1 diabetes (T1DM) displays all features of subclinical cardiovascular disease (CVD) as is associated with inflammation, endothelial dysfunction and low endothelial progenitor cells. MiR-200c-3p has been shown in animal tissues to be pro-atherogenic. We aimed to explore the role of miR-200c-3p in T1DM, a model of subclinical CVD. 19 samples from T1DM patients and 20 from matched controls (HC) were analyzed. MiR-200c in plasma and peripheral blood mononuclear cells (PBMCs) was measured by real-time quantitative polymerase chain reaction. The results were compared with the following indices of vascular health: circulating endothelial progenitor cells, (CD45^dimCD34⁺VEGFR-2⁺ or CD45^dimCD34⁺CD133⁺) and proangiogenic cells (PACs). MiR-200c-3p was significantly downregulated in PBMCs but not in plasma in T1DM. There was a significant negative correlation between the expression of miR-200c-3p and HbA1c, interleukin-7 (IL-7), vascular endothelial growth factor-C (VEGF-C), and soluble vascular cell adhesion molecule-1, and a positive correlation with CD45^dimCD34⁺VEGFR-2⁺, CD45^dimCD34⁺CD133⁺ and PACs. Receiver operating curve analyses showed miR-200c-3p as a biomarker for T1DM with significant downregulation of miR-200c-3p, possibly defining subclinical CVD at HbA1c > 44.8 mmol/mol (6.2%). In conclusion, downregulated miR-200c-3p in T1DM correlated with diabetic control, VEGF signaling, inflammation, vascular health and targeting VEGF signaling, and may define subclinical CVD. Further prospective studies are necessary to validate our findings in a larger group of patients. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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Review

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14 pages, 1178 KiB

Open AccessReview

Modulation of Endothelial Function by TMAO, a Gut Microbiota-Derived Metabolite

by Giulia Querio, Susanna Antoniotti, Federica Geddo, Renzo Levi and Maria Pia Gallo

Int. J. Mol. Sci. 2023, 24(6), 5806; https://doi.org/10.3390/ijms24065806 - 18 Mar 2023

Cited by 2 | Viewed by 2098

Abstract

Endothelial function is essential in the maintenance of systemic homeostasis, whose modulation strictly depends on the proper activity of tissue-specific angiocrine factors on the physiopathological mechanisms acting at both single and multi-organ levels. Several angiocrine factors take part in the vascular function itself [...] Read more.

Endothelial function is essential in the maintenance of systemic homeostasis, whose modulation strictly depends on the proper activity of tissue-specific angiocrine factors on the physiopathological mechanisms acting at both single and multi-organ levels. Several angiocrine factors take part in the vascular function itself by modulating vascular tone, inflammatory response, and thrombotic state. Recent evidence has outlined a strong relationship between endothelial factors and gut microbiota-derived molecules. In particular, the direct involvement of trimethylamine N-oxide (TMAO) in the development of endothelial dysfunction and its derived pathological outcomes, such as atherosclerosis, has come to light. Indeed, the role of TMAO in the modulation of factors strictly related to the development of endothelial dysfunction, such as nitric oxide, adhesion molecules (ICAM-1, VCAM-1, and selectins), and IL-6, has been widely accepted. The aim of this review is to present the latest studies that describe a direct role of TMAO in the modulation of angiocrine factors primarily involved in the development of vascular pathologies. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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13 pages, 2632 KiB

Open AccessReview

Morphological and Functional Remodeling of Vascular Endothelium in Cardiovascular Diseases

by Ghassan Bkaily and Danielle Jacques

Int. J. Mol. Sci. 2023, 24(3), 1998; https://doi.org/10.3390/ijms24031998 - 19 Jan 2023

Cited by 10 | Viewed by 2319

Abstract

The vascular endothelium plays a vital role during embryogenesis and aging and is a cell monolayer that lines the blood vessels. The immune system recognizes the endothelium as its own. Therefore, an abnormality of the endothelium exposes the tissues to the immune system [...] Read more.

The vascular endothelium plays a vital role during embryogenesis and aging and is a cell monolayer that lines the blood vessels. The immune system recognizes the endothelium as its own. Therefore, an abnormality of the endothelium exposes the tissues to the immune system and provokes inflammation and vascular diseases such as atherosclerosis. Its secretory role allows it to release vasoconstrictors and vasorelaxants as well as cardio-modulatory factors that maintain the proper functioning of the circulatory system. The sealing of the monolayer provided by adhesion molecules plays an important role in cardiovascular physiology and pathology. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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42 pages, 10708 KiB

Open AccessReview

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

by Juan A. De Pablo-Moreno, Luis Javier Serrano, Luis Revuelta, María José Sánchez and Antonio Liras

Int. J. Mol. Sci. 2022, 23(15), 8283; https://doi.org/10.3390/ijms23158283 - 27 Jul 2022

Cited by 26 | Viewed by 7461

Abstract

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation [...] Read more.

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin. Full article

(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease 2.0)

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