10th Anniversary of Biomedicines—Advances in Endothelial Dysfunction

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 40088

Special Issue Editors


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Guest Editor
U.O.C. of Internal Medicine—Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
Interests: endothelial dysfunction; obesity; insulin resistance; diabetic nephropathy; metabolic syndrome; adipokines
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Guest Editor
Department of Translational Medicine and Surgery, Catholic University, Rome, Italy
Interests: obesity; metabolic syndrome; endothelial function; hypertension

Special Issue Information

Dear Colleagues,

The year 2023 marks the 10th anniversary of Biomedicines, a peer-reviewed open access journal in the biomedical field. Thus far, Biomedicines has published more than 2700 papers from more than 17,000 authors. We appreciate each author, reviewer, and academic editor whose support has brought us to where we are today. To celebrate this significant milestone, we aim to publish a Special Issue entitled “10th Anniversary of Biomedicines—Advances in Endothelial Dysfunction".

Endothelial dysfunction is an early marker of atherosclerosis. Under normal conditions, vascular endothelium maintains blood vessels and keeps them in good shape though synthesis and release of several vasodilatory, anti-inflammatory, and antithombotic substances. Principal among these substances is nitric oxide (NO), which plays a central role in the maintenance of vascular homeostasis. When endothelial dysfunction is induced by pathological stresses, such as hyperlipidemia, hypertension, and hyperglycemia, among others, NO production is impaired and the protective effect of endothelium is disrupted, with consequent vasoconstriction and “activation” of endothelial cells that trigger a cascade of events, resulting in the formation of the atherosclerotic lesion.

Changes in adipose tissue related to obesity result in derangement in the main vascular homeostatic mechanisms, the NO pathway, and the endothelin-1 (ET-1) system, thereby leading to a vasoconstrictor and proatherogenic profile. Derangement of insulin signaling seems to play a central role in the pathophysiology of vascular dysfunction associated with obesity and metabolic syndrome; moreover, the vascular alterations associated with insulin resistance and obesity do not seem to be limited to the endothelium, but also involve other layers of the vessel wall, such as vascular smooth muscle and adventitial/perivascular fat. Perivascular adipose tissue (PVAT) is a potential source of the mediators that lead to obesity-related vascular damage, and conformational changes in perivascular fat have been shown to associate with a loss of anticontractile properties, likely due to inflammatory, vasoconstrictor, and oxidative mechanisms.

For this Special Issue, we are seeking research articles that will improve our knowledge on these topics. Both original research and review articles are welcome.

Prof. Dr. Manfredi Tesauro
Prof. Dr. Carmine Cardillo
Guest Editors

Manuscript Submission Information

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Keywords

  • endothelial dysfunction
  • atherosclerosis
  • nitric oxide (NO)
  • hyperlipidemia
  • hypertension
  • hyperglycemia
  • vasodilation
  • perivascular adipose tissue (PVAT)
  • insulin resistance

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Published Papers (15 papers)

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Research

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11 pages, 470 KiB  
Article
Cortisol Reactivity to Acute Psychosocial Stress in Physician Burnout
by Claudia Zuccarella-Hackl, Mary Princip, Sarah A. Holzgang, Sinthujan Sivakumar, Alexa Kuenburg, Aju P. Pazhenkottil, Diego Gomez Vieito and Roland von Känel
Biomedicines 2024, 12(2), 335; https://doi.org/10.3390/biomedicines12020335 - 01 Feb 2024
Viewed by 708
Abstract
Background: Physician burnout, characterized by chronic job-related stress leading to emotional exhaustion, depersonalization, and reduced personal accomplishment. This cross-sectional study investigates cortisol reactivity in male physicians with burnout compared to healthy controls during an acute psychosocial stress test. Methods: Sixty male physicians (30 [...] Read more.
Background: Physician burnout, characterized by chronic job-related stress leading to emotional exhaustion, depersonalization, and reduced personal accomplishment. This cross-sectional study investigates cortisol reactivity in male physicians with burnout compared to healthy controls during an acute psychosocial stress test. Methods: Sixty male physicians (30 burnout, 30 healthy controls) participated between September 2019 and December 2021 to investigate the impact of burnout on cardiovascular health. Salivary cortisol levels were measured before and after a Trier Social Stress Test (TSST). Burnout was assessed with the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). Covariates included age, BMI, and physical activity. Data were analyzed using repeated measures analysis and area under the curve analysis. Results: Male physicians with burnout exhibited significantly greater cortisol reactivity during the TSST, notably post-stress to 15 min post-stress. Emotional exhaustion correlated with reduced cortisol increase from pre-stress and smaller post-stress to 15- and 45-min declines. Discussion: Findings suggest heightened cortisol reactivity in male physicians with burnout, possibly reflecting initial chronic stress stages. This study highlights the necessity for long-term research on cortisol’s influence on cardiovascular health and stress responses across diverse groups. Conclusions: The findings contribute to comprehending physiological responses in burnout-afflicted physicians, emphasizing cortisol reactivity’s pivotal role in stress-related research and its potential health implications, particularly within the burnout context. Full article
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17 pages, 4015 KiB  
Article
The Regulation of Endothelin-1 in Pregnancies Complicated by Gestational Diabetes: Uncovering the Vascular Effects of Insulin
by Bianca R. Fato, Sally Beard, Natalie K. Binder, Natasha Pritchard, Tu’uhevaha J. Kaitu’u-Lino, Natasha de Alwis and Natalie J. Hannan
Biomedicines 2023, 11(10), 2660; https://doi.org/10.3390/biomedicines11102660 - 28 Sep 2023
Cited by 1 | Viewed by 979
Abstract
Gestational diabetes mellitus (GDM) is a condition of pregnancy defined by new-onset hyperglycemia. GDM is associated with impaired maternal endothelial and vascular reactivity. Endothelin-1 (ET-1) is a potent vasoconstrictor that contributes to endothelial dysfunction, however, its abundance and actions in GDM are unclear. [...] Read more.
Gestational diabetes mellitus (GDM) is a condition of pregnancy defined by new-onset hyperglycemia. GDM is associated with impaired maternal endothelial and vascular reactivity. Endothelin-1 (ET-1) is a potent vasoconstrictor that contributes to endothelial dysfunction, however, its abundance and actions in GDM are unclear. Maternal plasma was obtained from pregnancies complicated by GDM (n = 24) and gestation-matched controls (n = 42); circulating ET-1 levels were assessed by ELISA. Human omental arteries from healthy pregnancies and those complicated by GDM were dissected from omental fat biopsies and collected at cesarean section. mRNA expression of ET-1 and its receptors, ETA and ETB, in addition to vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) were assessed by qPCR (n = 28). Using wire myography, we investigated vascular constriction to ET-1 (10−11–10−4 M) in omental arteries from pregnancies complicated by GDM, compared to gestation-matched controls (n = 7). GDM cases were stratified by clinical management, diet intervention (n = 5), or insulin treatment (n = 6). Additionally, arteries from healthy pregnancies were treated with insulin (1 mU/mL (n = 7) and 10 mU/mL (n = 5)) or vehicle control. Vasoactive response to ET-1 was measured via wire myography. Circulating ET-1 levels and mRNA expression of the ET-1 system in omental arteries were not found to be significantly different between pregnancies complicated by GDM compared to healthy controls. However, we found insulin treatment during pregnancy and in ex vivo models reduced ET-1 vasoconstriction of maternal vasculature in GDM. These data suggest insulin may improve vascular function in GDM, however, further investigation is needed to define the role of ET-1 in pregnancy. Full article
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17 pages, 2864 KiB  
Article
Mannose-Binding Lectin Reduces Oxidized Low-Density Lipoprotein Induced Vascular Endothelial Cells Injury by Inhibiting LOX1-ox-LDL Binding and Modulating Autophagy
by Xuelian Zhou, Xuefeng Chen, Li Zhang, Jinna Yuan, Hu Lin, Mingqiang Zhu, Xiaoqin Xu, Guanping Dong, Junfen Fu and Wei Wu
Biomedicines 2023, 11(6), 1743; https://doi.org/10.3390/biomedicines11061743 - 17 Jun 2023
Cited by 1 | Viewed by 985
Abstract
Objective: To investigate the role of mannose-binding lectin (MBL) in modulating autophagy and protecting endothelial cells (ECs) from oxidized low-density lipoprotein (ox-LDL)-induced injury. Methods: Serum MBL concentration and carotid intima-media thickness (cIMT) were measured in 94 obese and 105 healthy children. ECs were [...] Read more.
Objective: To investigate the role of mannose-binding lectin (MBL) in modulating autophagy and protecting endothelial cells (ECs) from oxidized low-density lipoprotein (ox-LDL)-induced injury. Methods: Serum MBL concentration and carotid intima-media thickness (cIMT) were measured in 94 obese and 105 healthy children. ECs were transfected with MBL over-expression plasmid, LOX1 was knocked-down to explore the protective role of MBL in ox-LDL induced ECs injury. Dendritic cells (DCs) were co-cultured with ECs, and inflammatory factors, DC maturation, and autophagy was assessed. WT and ApoE−/− mice were fed with a high fat diet (HFD) with or without MBL-adenovirus injection for 16 weeks and aortic vascular endothelial tissue was isolated, then atherosclerotic plaque, cell injury and autophagy were analyzed. Results: Serum MBL concentration in obese children was lower than healthy controls and was negatively correlated with cIMT. The uptake of ox-LDL was decreased in LOX1 knock-down ECs. MBL over-expression in vitro inhibited LOX1-ox-LDL binding. Both LOX1 knock-down and MBL over-expression can ameliorate EC autophagy and cell injury. MBL over-expression in vivo alleviated atherosclerotic plaque formation, influenced DC maturation and down-regulated IL-6, IL-12, and TNF-a levels. Conclusions: MBL exerts a protective role in ox-LDL-induced EC injury by modulating DC maturation and EC autophagy via inhibiting LOX1-ox-LDL binding. Full article
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17 pages, 1640 KiB  
Article
Endothelial Function and Hypoxic–Hyperoxic Preconditioning in Coronary Surgery with a Cardiopulmonary Bypass: Randomized Clinical Trial
by Irina A. Mandel, Yuriy K. Podoksenov, Sergey L. Mikheev, Irina V. Suhodolo, Yulia S. Svirko, Vladimir M. Shipulin, Anastasia V. Ivanova, Andrey G. Yavorovskiy and Andrey I. Yaroshetskiy
Biomedicines 2023, 11(4), 1044; https://doi.org/10.3390/biomedicines11041044 - 28 Mar 2023
Viewed by 1245
Abstract
A hypoxic–hyperoxic preconditioning (HHP) may be associated with cardioprotection by reducing endothelial damage and a beneficial effect on postoperative outcome in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Patients (n = 120) were randomly assigned to an HHP and a control [...] Read more.
A hypoxic–hyperoxic preconditioning (HHP) may be associated with cardioprotection by reducing endothelial damage and a beneficial effect on postoperative outcome in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Patients (n = 120) were randomly assigned to an HHP and a control group. A safe, inhaled oxygen fraction for the hypoxic preconditioning phase (10–14% oxygen for 10 min) was determined by measuring the anaerobic threshold. At the hyperoxic phase, a 75–80% oxygen fraction was used for 30 min. The cumulative frequency of postoperative complications was 14 (23.3%) in the HHP vs. 23 (41.1%), p = 0.041. The nitrate decreased after surgery by up to 20% in the HHP group and up to 38% in the control group. Endothelin-1 and nitric oxide metabolites were stable in HHP but remained low for more than 24 h in the control group. The endothelial damage markers appeared to be predictors of postoperative complications. The HHP with individual parameters based on the anaerobic threshold is a safe procedure, and it can reduce the frequency of postoperative complications. The endothelial damage markers appeared to be predictors of postoperative complications. Full article
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18 pages, 4978 KiB  
Article
The Long-Term Effects of Prenatal Hypoxia on Coronary Artery Function of the Male and Female Offspring
by Nataliia Hula, Ricky Liu, Floor Spaans, Mazhar Pasha, Anita Quon, Raven Kirschenman, Christy-Lynn M. Cooke and Sandra T. Davidge
Biomedicines 2022, 10(12), 3019; https://doi.org/10.3390/biomedicines10123019 - 23 Nov 2022
Cited by 2 | Viewed by 1638
Abstract
Prenatal hypoxia predisposes the offspring to the development of cardiovascular (CV) dysfunction in adult life. Using a rat model, we assessed the effect of prenatal hypoxia on vasoconstrictive and vasodilative mechanisms in left anterior descending coronary arteries of 4- and 9.5-month-old offspring. Endothelium-dependent [...] Read more.
Prenatal hypoxia predisposes the offspring to the development of cardiovascular (CV) dysfunction in adult life. Using a rat model, we assessed the effect of prenatal hypoxia on vasoconstrictive and vasodilative mechanisms in left anterior descending coronary arteries of 4- and 9.5-month-old offspring. Endothelium-dependent relaxation to methylcholine and vasoconstriction responses to endothelin-1 (ET-1) were assessed by wire myography. Prenatal hypoxia impaired endothelium-dependent vasodilation in 4- and 9.5-month-old offspring. Inhibition of nitric oxide (NO) synthase prevented coronary artery relaxation in all groups. Inhibition of prostaglandin H synthase (PGHS) improved relaxation in prenatally hypoxic males and tended to improve vasorelaxation in females, suggesting that impaired vasodilation was mediated via increased PGHS-dependent vasoconstriction. An enhanced contribution of endothelium-dependent hyperpolarization to coronary artery vasodilation was observed in prenatally hypoxic males and females. No changes in endothelial NO synthase (eNOS) and PGHS-1 expressions were observed, while PGHS-2 expression was decreased in only prenatally hypoxic males. At 4 months, ET-1 responses were similar between groups, while ETB inhibition (with BQ788) tended to decrease ET-1-mediated responses in only prenatally hypoxic females. At 9.5 months, ET-1-mediated responses were decreased in only prenatally hypoxic females. Our data suggest that prenatal hypoxia has long-term similar effects on the mechanisms of impaired endothelium-dependent vasodilation in coronary arteries from adult male and female offspring; however, coronary artery contractile capacity is impaired only in prenatally hypoxic females. Understanding the mechanistic pathways involved in the programming of CV disease may allow for the development of therapeutic interventions. Full article
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21 pages, 2652 KiB  
Article
Circulating Serum Cystatin C as an Independent Risk Biomarker for Vascular Endothelial Dysfunction in Patients with COVID-19-Associated Multisystem Inflammatory Syndrome in Children (MIS-C): A Prospective Observational Study
by Marcela Kreslová, Petr Jehlička, Aneta Sýkorová, Daniel Rajdl, Eva Klásková, Pavel Prokop, Sabina Kaprálová, Jan Pavlíček, Romana Kaslová, Alžběta Palátová, Veronika Mohylová and Josef Sýkora
Biomedicines 2022, 10(11), 2956; https://doi.org/10.3390/biomedicines10112956 - 17 Nov 2022
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Abstract
Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a new clinical entity that has emerged in the context of the COVID-19 pandemic. Despite the less severe course of the disease, varying degrees of cardiovascular events may occur in MIS-C; however, data on vascular [...] Read more.
Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a new clinical entity that has emerged in the context of the COVID-19 pandemic. Despite the less severe course of the disease, varying degrees of cardiovascular events may occur in MIS-C; however, data on vascular changes occurring in MIS-C are still lacking. Endothelial dysfunction (ED) is thought to be one of the key risk factors contributing to MIS-C. Background: We conducted a prospective observational study. We investigated possible manifestations of cardiac and endothelial involvement in MIS-C after the treatment of the acute stage and potential predictive biomarkers in patients with MIS-C. Methods: Twenty-seven consecutive pediatric subjects (≥9 years), at least three months post-treated MIS-C of varying severity, in a stable condition, and twenty-three age- and sex-matched healthy individuals (HI), were enrolled. A combined non-invasive diagnostic approach was used to assess endothelial function as well as markers of organ damage using cardiac examination and measurement of the reactive hyperemia index (RHI), by recording the post- to pre-occlusion pulsatile volume changes and biomarkers related to ED and cardiac disease. Results: MIS-C patients exhibited a significantly lower RHI (indicative of more severe ED) than those in HI (1.32 vs. 1.80; p = 0.001). The cutoff of RHI ≤ 1.4 was independently associated with a higher cardiovascular risk. Age and biomarkers significantly correlated with RHI, while serum cystatin C (Cys C) levels were independently associated with a diminished RHI, suggesting Cys C as a surrogate marker of ED in MIS-C. Conclusions: Patients after MIS-C display evidence of ED, as shown by a diminished RHI and altered endothelial biomarkers. Cys C was identified as an independent indicator for the development of cardiovascular disease. The combination of these factors has the potential to better predict the cardiovascular consequences of MIS-C. Our study suggests that ED may be implicated in the pathophysiology of this disease. Full article
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16 pages, 4079 KiB  
Article
Metformin Prevents Endothelial Dysfunction in Endometriosis through Downregulation of ET-1 and Upregulation of eNOS
by Ana Filipa Martins, Ana Catarina Neto, Adriana Raquel Rodrigues, Sandra Marisa Oliveira, Cláudia Sousa-Mendes, Adelino Leite-Moreira, Alexandra Maria Gouveia, Henrique Almeida and Delminda Neves
Biomedicines 2022, 10(11), 2782; https://doi.org/10.3390/biomedicines10112782 - 01 Nov 2022
Cited by 1 | Viewed by 1899
Abstract
This study aimed to evaluate if the treatment with metformin affects the morphologic structure, endothelial function, angiogenesis, inflammation and oxidation-responsive pathways in the heart of mice with surgically induced endometriosis. B6CBA/F1 mice (n = 37) were divided into four groups; Sham (S), Metformin [...] Read more.
This study aimed to evaluate if the treatment with metformin affects the morphologic structure, endothelial function, angiogenesis, inflammation and oxidation-responsive pathways in the heart of mice with surgically induced endometriosis. B6CBA/F1 mice (n = 37) were divided into four groups; Sham (S), Metformin (M), Endometriosis (E) and Metformin/Endometriosis (ME). The cross-sectional area of cardiomyocytes was assessed after Hematoxylin–Eosin staining and fibrosis after Picrosirius-Red staining. ET-1, nitric oxide synthases-iNOS and eNOS, and VEGF and VEGFR-2 were detected by immunofluorescence. Semi-quantification of ET-1, eNOS, VEGF, NF-kB, Ikβα and KEAP-1 was performed by Western blotting. MIR199a, MIR16-1, MIR18a, MIR20a, MIR155, MIR200a, MIR342, MIR24-1 and MIR320a were quantified by Real-Time qPCR. The interaction of endometriosis and metformin effects was assessed by a two-way ANOVA test. Compared with the other groups, M-treated mice presented a higher cross-sectional area of cardiomyocytes. Heart fibrosis increased with endometriosis. Treatment of endometriosis with metformin in the ME group downregulates ET-1 and upregulates eNOS expression comparatively with the E group. However, metformin failed to mitigate NF-kB expression significantly incremented by endometriosis. The expression of MIR199a, MIR16-1 and MIR18a decreased with endometriosis, whereas MIR20a showed an equivalent trend, altogether reducing cardioprotection. In summary, metformin diminished endometriosis-associated endothelial dysfunction but did not mitigate the increase in NF-kB expression and cardiac fibrosis in mice with endometriosis. Full article
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17 pages, 1031 KiB  
Article
Bronchial Asthma as a Cardiovascular Risk Factor: A Prospective Observational Study
by Marcela Kreslová, Olga Kirchnerová, Daniel Rajdl, Vendula Sudová, Jiří Blažek, Aneta Sýkorová, Petr Jehlička, Ladislav Trefil, Jan Schwarz, Renata Pomahačová and Josef Sýkora
Biomedicines 2022, 10(10), 2614; https://doi.org/10.3390/biomedicines10102614 - 18 Oct 2022
Cited by 5 | Viewed by 7012
Abstract
Introduction: Asthma as a chronic inflammatory disorder has been suggested as a risk factor for endothelial dysfunction (ED), but studies on the association between asthma and cardiovascular disease (CVD) risk are limited. Background: We assessed associations of ED with the severity of asthma, [...] Read more.
Introduction: Asthma as a chronic inflammatory disorder has been suggested as a risk factor for endothelial dysfunction (ED), but studies on the association between asthma and cardiovascular disease (CVD) risk are limited. Background: We assessed associations of ED with the severity of asthma, eosinophilic inflammation, lung function, and asthma control. Methods: 52 young asthmatics (median age of 25.22 years) and 45 healthy individuals were included. Demographic, clinical, and laboratory findings were recorded. We evaluated microvascular responsiveness by recording the reactive hyperemia index (RHI) indicating post-occlusive peripheral endothelium-dependent changes in vascular tone using the Itamar Medical EndoPAT2000. VCAM-1, ADMA, high-sensitive CRP (hsCRP), and E-selectin were measured. Results: Asthmatics had considerably lower RHI values (p < 0.001) with a dynamic decreasing trend by asthma severity and higher hsCRP levels (p < 0.001). A substantial increase in hsCRP and E-selectin with asthma severity (p < 0.05) was also observed. We confirmed a higher body mass index (BMI) in asthmatics (p < 0.001), especially in women and in severe asthma. Conclusions: We demonstrated the progression of CVD in asthmatics and the association of the ongoing deterioration of ED with the inflammatory severity, suggesting that the increased risk of CVD in young asthmatics is dependent on disease severity. The underlying mechanisms of risk factors for CVD and disease control require further study. Full article
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Review

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14 pages, 313 KiB  
Review
Endothelial Dysfunction and Pregnant COVID-19 Patients with Thrombophilia: A Narrative Review
by Metodija Sekulovski, Niya Mileva, Lyubomir Chervenkov, Monika Peshevska-Sekulovska, Georgi Vasilev Vasilev, Georgi Hristov Vasilev, Dimitrina Miteva, Latchezar Tomov, Snezhina Lazova, Milena Gulinac and Tsvetelina Velikova
Biomedicines 2023, 11(9), 2458; https://doi.org/10.3390/biomedicines11092458 - 04 Sep 2023
Viewed by 1229
Abstract
Pregnancy with SARS-CoV-2 infection can raise the risk of many complications, including severe COVID-19 and maternal–fetal adverse outcomes. Additionally, endothelial damage occurs as a result of direct SARS-CoV-2 infection, as well as immune system, cardiovascular, and thrombo-inflammatory reactions. In this narrative review, we [...] Read more.
Pregnancy with SARS-CoV-2 infection can raise the risk of many complications, including severe COVID-19 and maternal–fetal adverse outcomes. Additionally, endothelial damage occurs as a result of direct SARS-CoV-2 infection, as well as immune system, cardiovascular, and thrombo-inflammatory reactions. In this narrative review, we focus on endothelial dysfunction (ED) in pregnancy, associated with obstetric complications, such as preeclampsia, fetal growth retardation, gestational diabetes, etc., and SARS-CoV-2 infection in pregnant women that can cause ED itself and overlap with other pregnancy complications. We also discuss some shared mechanisms of SARS-CoV-2 pathophysiology and ED. Full article
33 pages, 1990 KiB  
Review
Immunological and Metabolic Causes of Infertility in Polycystic Ovary Syndrome
by Aleksandra Maria Kicińska, Radoslaw B. Maksym, Magdalena A. Zabielska-Kaczorowska, Aneta Stachowska and Anna Babińska
Biomedicines 2023, 11(6), 1567; https://doi.org/10.3390/biomedicines11061567 - 28 May 2023
Cited by 6 | Viewed by 4871
Abstract
Infertility has been recognized as a civilizational disease. One of the most common causes of infertility is polycystic ovary syndrome (PCOS). Closely interrelated immunometabolic mechanisms underlie the development of this complex syndrome and lead to infertility. The direct cause of infertility in PCOS [...] Read more.
Infertility has been recognized as a civilizational disease. One of the most common causes of infertility is polycystic ovary syndrome (PCOS). Closely interrelated immunometabolic mechanisms underlie the development of this complex syndrome and lead to infertility. The direct cause of infertility in PCOS is ovulation and implantation disorders caused by low-grade inflammation of ovarian tissue and endometrium which, in turn, result from immune and metabolic system disorders. The systemic immune response, in particular the inflammatory response, in conjunction with metabolic disorders, insulin resistance (IR), hyperadrenalism, insufficient secretion of progesterone, and oxidative stress lead not only to cardiovascular diseases, cancer, autoimmunity, and lipid metabolism disorders but also to infertility. Depending on the genetic and environmental conditions as well as certain cultural factors, some diseases may occur immediately, while others may become apparent years after an infertility diagnosis. Each of them alone can be a significant factor contributing to the development of PCOS and infertility. Further research will allow clinical management protocols to be established for PCOS patients experiencing infertility so that a targeted therapy approach can be applied to the factor underlying and driving the “vicious circle” alongside symptomatic treatment and ovulation stimulation. Hence, therapy of fertility for PCOS should be conducted by interdisciplinary teams of specialists as an in-depth understanding of the molecular relationships and clinical implications between the immunological and metabolic factors that trigger reproductive system disorders is necessary to restore the physiology and homeostasis of the body and, thus, fertility, among PCOS patients. Full article
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15 pages, 637 KiB  
Review
Erectile Dysfunction: Pharmacological Pathways with Understudied Potentials
by Doaa R. Adam and Manal M. Alem
Biomedicines 2023, 11(1), 46; https://doi.org/10.3390/biomedicines11010046 - 25 Dec 2022
Cited by 4 | Viewed by 3794
Abstract
Erectile dysfunction (ED) is a public health concern worldwide. In the past, it was perceived as a phenomenon attributed to age advancement. However, more individuals are affected every year that do not fall under that age criterion. Epidemiological research revealed that this abnormality [...] Read more.
Erectile dysfunction (ED) is a public health concern worldwide. In the past, it was perceived as a phenomenon attributed to age advancement. However, more individuals are affected every year that do not fall under that age criterion. Epidemiological research revealed that this abnormality has an association with endothelial dysfunction connected to several cardiovascular (CV) risk factors. Currently, ED is interpreted as a clinical marker for future adverse events and not only as a present health issue that negatively affects the quality of life. The management of ED involves lifestyle modifications, therapeutic optimization for comorbid conditions, and pharmacological and psychosexual therapy. Phosphodiesterase type 5 (PDE5) inhibitors are the first-line pharmacological agents to be prescribed for such a condition. Nonetheless, other pharmacological pathways and agents remain underinvestigated or were investigated at some stage. This review aimed to present to future researchers interested in this field with some pharmacological agents that showed favorable effects on a limited number of studies on human subjects or experimental models. Full article
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16 pages, 660 KiB  
Review
Endothelial Progenitor Cells in Neurovascular Disorders—A Comprehensive Overview of the Current State of Knowledge
by Ewa Rudnicka-Drożak, Paulina Drożak, Grzegorz Mizerski and Martyna Drożak
Biomedicines 2022, 10(10), 2616; https://doi.org/10.3390/biomedicines10102616 - 18 Oct 2022
Cited by 3 | Viewed by 2231
Abstract
Endothelial progenitor cells (EPCs) are a population of cells that circulate in the blood looking for areas of endothelial or vascular injury in order to repair them. Endothelial dysfunction is an important component of disorders with neurovascular involvement. Thus, the subject of involvement [...] Read more.
Endothelial progenitor cells (EPCs) are a population of cells that circulate in the blood looking for areas of endothelial or vascular injury in order to repair them. Endothelial dysfunction is an important component of disorders with neurovascular involvement. Thus, the subject of involvement of EPCs in such conditions has been gaining increasing scientific interest in recent years. Overall, decreased levels of EPCs are associated with worse disease outcome. Moreover, their functionalities appear to decline with severity of disease. These findings inspired the application of EPCs as therapeutic targets and agents. So far, EPCs appear safe and promising based on the results of pre-clinical studies conducted on their use in the treatment of Alzheimer’s disease and ischemic stroke. In the case of the latter, human clinical trials have recently started to be performed in this subject and provided optimistic results thus far. Whereas in the case of migraine, existing findings pave the way for testing EPCs in in vitro studies. This review aims to thoroughly summarize current knowledge on the role EPCs in four disorders with neurovascular involvement, which are Alzheimer’s disease, cerebral small vessel disease, ischemic stroke and migraine, with a particular focus on the potential practical use of these cells as a treatment remedy. Full article
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36 pages, 969 KiB  
Review
Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options
by Teresa Salvatore, Raffaele Galiero, Alfredo Caturano, Erica Vetrano, Giuseppe Loffredo, Luca Rinaldi, Christian Catalini, Klodian Gjeloshi, Gaetana Albanese, Anna Di Martino, Giovanni Docimo, Celestino Sardu, Raffaele Marfella and Ferdinando Carlo Sasso
Biomedicines 2022, 10(9), 2274; https://doi.org/10.3390/biomedicines10092274 - 14 Sep 2022
Cited by 23 | Viewed by 3440
Abstract
Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of [...] Read more.
Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of this microvascular complication is complex and not completely known, involving several alterations among which hyperglycemia and insulin resistance play particularly central roles leading to oxidative stress, inflammatory activation and altered barrier function of endothelium. CMD significantly contributes to cardiac events such as angina or infarction without obstructive coronary artery disease, as well as heart failure, especially the phenotype associated with preserved ejection fraction, which greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target this vascular damage, but recent experimental studies and some clinical investigations have produced data in favor of potential beneficial effects on coronary micro vessels caused by two classes of glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy and inhibitors of sodium-glucose cotransporter-2 (SGLT2). The purpose of this review is to describe pathophysiological mechanisms, clinical manifestations of CMD with particular reference to diabetes, and to summarize the protective effects of antidiabetic drugs on the myocardial microvascular compartment. Full article
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13 pages, 947 KiB  
Review
Endothelial Dysfunction, Erectile Deficit and Cardiovascular Disease: An Overview of the Pathogenetic Links
by Federico De Leonardis, Gaia Colalillo, Enrico Finazzi Agrò, Roberto Miano, Andrea Fuschi and Anastasios D. Asimakopoulos
Biomedicines 2022, 10(8), 1848; https://doi.org/10.3390/biomedicines10081848 - 01 Aug 2022
Cited by 8 | Viewed by 2237
Abstract
Erectile dysfunction (ED) is a condition with multifactorial pathogenesis, quite common among men, especially those above 60 years old. A vascular etiology is the most common cause. The interaction between chronic inflammation, androgens, and cardiovascular risk factors determines macroscopically invisible alterations such as [...] Read more.
Erectile dysfunction (ED) is a condition with multifactorial pathogenesis, quite common among men, especially those above 60 years old. A vascular etiology is the most common cause. The interaction between chronic inflammation, androgens, and cardiovascular risk factors determines macroscopically invisible alterations such as endothelial dysfunction and subsequent atherosclerosis and flow-limiting stenosis that affects both penile and coronary arteries. Thus, ED and cardiovascular disease (CVD) should be considered two different manifestations of the same systemic disorder, with a shared aetiological factor being endothelial dysfunction. Moreover, the penile arteries have a smaller size compared with coronary arteries; thus, for the same level of arteriopathy, a more significant blood flow reduction will occur in erectile tissue compared with coronary circulation. As a result, ED often precedes CVD by 2–5 years, and its diagnosis offers a time window for cardiovascular risk mitigation. Growing evidence suggests, in fact, that patients presenting with ED should be investigated for CVD even if they have no symptoms. Early detection could facilitate prompt intervention and a reduction in long-term complications. In this review, we provide an overview of the pathogenetic mechanisms behind arteriogenic ED and CVD, focusing on the role of endothelial dysfunction as the common denominator of the two disorders. Developed algorithms that may help identify those patients complaining of ED who should undergo detailed cardiologic assessment and receive intensive treatment for risk factors are also analyzed. Full article
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16 pages, 1082 KiB  
Review
The Role of KLF2 in the Regulation of Atherosclerosis Development and Potential Use of KLF2-Targeted Therapy
by Siarhei A. Dabravolski, Vasily N. Sukhorukov, Vladislav A. Kalmykov, Andrey V. Grechko, Nikolay K. Shakhpazyan and Alexander N. Orekhov
Biomedicines 2022, 10(2), 254; https://doi.org/10.3390/biomedicines10020254 - 24 Jan 2022
Cited by 17 | Viewed by 4795
Abstract
Kruppel like factor 2 (KLF2) is a mechanosensitive transcription factor participating in the regulation of vascular endothelial cells metabolism. Activating KLF2 in endothelial cells induces eNOS (endothelial nitric oxide synthase) expression, subsequent NO (nitric oxide) release, and vasodilatory effect. In addition, many KLF2-regulated [...] Read more.
Kruppel like factor 2 (KLF2) is a mechanosensitive transcription factor participating in the regulation of vascular endothelial cells metabolism. Activating KLF2 in endothelial cells induces eNOS (endothelial nitric oxide synthase) expression, subsequent NO (nitric oxide) release, and vasodilatory effect. In addition, many KLF2-regulated genes participate in the anti-thrombotic, antioxidant, and anti-inflammatory activities, thereby preventing atherosclerosis development and progression. In this review, we summarise recent evidence suggesting that KLF2 plays a major role in regulating atheroprotective effects in endothelial cells. We also discuss several recently identified repurposed drugs and natural plant-based bioactive compounds with KLF2-mediated atheroprotective activities. Herein, we present a comprehensive overview of the role of KLF2 in atherosclerosis and as a pharmacological target for different drugs and natural compounds and highlight the potential application of these phytochemicals for the treatment of atherosclerosis. Full article
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