Biomedicines

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Open AccessEditorial

Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target

by Pasquale Ambrosino, Guido Grassi and Mauro Maniscalco

Biomedicines 2022, 10(1), 78; https://doi.org/10.3390/biomedicines10010078 - 31 Dec 2021

Cited by 11 | Viewed by 1633

Abstract

The endothelium is considered the largest organ of the body, composed of a monolayer of endothelial cells (ECs) lining the interior surface of blood and lymphatic vessels [...] Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

Research

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23 pages, 6506 KiB

Open AccessArticle

Vascular Effects of Low-Dose ACE2 Inhibitor MLN-4760—Benefit or Detriment in Essential Hypertension?

by Andrea Berenyiova, Iveta Bernatova, Anna Zemancikova, Magdalena Drobna, Martina Cebova, Samuel Golas, Peter Balis, Silvia Liskova, Zuzana Valaskova, Katarina Krskova, Stefan Zorad, Ezgi Dayar and Sona Cacanyiova

Biomedicines 2022, 10(1), 38; https://doi.org/10.3390/biomedicines10010038 - 24 Dec 2021

Cited by 12 | Viewed by 3456

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1–7 (Ang 1–7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the [...] Read more.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1–7 (Ang 1–7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had (1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1–7 in plasma, (2) negative effects on ACE1 inhibitor (captopril) action, (3) detrimental effects on the small arteries function and (4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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12 pages, 3343 KiB

Open AccessArticle

Angiotensin-Converting Enzyme 2 Protein Is Overexpressed in a Wide Range of Human Tumour Types: A Systematic Tissue Microarray Study on >15,000 Tumours

by Jan Meiners, Kristina Jansen, Natalia Gorbokon, Franziska Büscheck, Andreas M. Luebke, Martina Kluth, Claudia Hube-Magg, Doris Höflmayer, Sören Weidemann, Christoph Fraune, Katharina Möller, Christian Bernreuther, Patrick Lebok, Anne Menz, Frank Jacobsen, Till Clauditz, Guido Sauter, Ria Uhlig, Waldemar Wilczak, Jakob Izbicki, Daniel Perez, Sarah Minner, Eike Burandt, Till Krech, Andreas Marx, Ronald Simon and Stefan Steurer Show full author list Hide full author list

Biomedicines 2021, 9(12), 1831; https://doi.org/10.3390/biomedicines9121831 - 3 Dec 2021

Cited by 7 | Viewed by 2601

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a regulator in the renin-angiotensin system. ACE2 expression was analysed immunohistochemically in 15,306 samples from 119 tumour types and in 608 samples of 76 normal tissue types. In normal tissue, ACE2 was most abundant in testis and corpus [...] Read more.

Angiotensin-converting enzyme 2 (ACE2) is a regulator in the renin-angiotensin system. ACE2 expression was analysed immunohistochemically in 15,306 samples from 119 tumour types and in 608 samples of 76 normal tissue types. In normal tissue, ACE2 was most abundant in testis and corpus luteum, kidney, small intestine and capillaries of selected organs. At least an occasional weak ACE2 positivity of tumour cells was seen in 83 of 119 (70%) tumour types. ACE2 tumour cell positivity was particularly frequent in papillary (94%) and clear cell (86%) renal cell carcinoma, colorectal adenocarcinoma (81%), mucinous ovarian cancer (61%), cholangiocarcinoma (58%), hepatocellular carcinoma (56%), and in adenocarcinomas of the stomach (47%), pancreas (42%), and the lung (35%). ACE2-positive capillaries were found in 409/12,644 (3%) of analysable tumours, most frequently in tumours with endocrine/neuroendocrine activity. Presence of ACE2-positive capillaries was linked to low stage in papillary thyroid cancer and low grade in neuroendocrine neoplasms. In conclusion, ACE2 expression can occur both in tumour cells and tumour-associated capillaries in a broad variety of different tumour types at highly variable frequencies. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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17 pages, 5717 KiB

Open AccessEditor’s ChoiceArticle

Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients

by Paolo Macor, Paolo Durigutto, Alessandro Mangogna, Rossana Bussani, Luca De Maso, Stefano D’Errico, Martina Zanon, Nicola Pozzi, Pier Luigi Meroni and Francesco Tedesco

Biomedicines 2021, 9(8), 1003; https://doi.org/10.3390/biomedicines9081003 - 12 Aug 2021

Cited by 50 | Viewed by 3715

Abstract

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to [...] Read more.

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG, and spike protein of SARS-CoV-2. Lung deposits of C1q, C4, C3, and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. FB deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on the hepatic artery and portal vein of the liver. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease and the contribution of the complement system to inflammation and tissue damage. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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9 pages, 692 KiB

Open AccessArticle

Endothelial Progenitor Cells: Relevant Players in the Vasculopathy and Lung Fibrosis Associated with the Presence of Interstitial Lung Disease in Systemic Sclerosis Patients

by Verónica Pulito-Cueto, Sara Remuzgo-Martínez, Fernanda Genre, Belén Atienza-Mateo, Víctor M. Mora-Cuesta, David Iturbe-Fernández, Leticia Lera-Gómez, Raquel Pérez-Fernández, Diana Prieto-Peña, Virginia Portilla, Ricardo Blanco, Alfonso Corrales, Oreste Gualillo, José M. Cifrián, Raquel López-Mejías and Miguel A. González-Gay

Biomedicines 2021, 9(7), 847; https://doi.org/10.3390/biomedicines9070847 - 20 Jul 2021

Cited by 11 | Viewed by 3060

Abstract

Endothelial progenitor cells (EPC), which are key effectors in the physiologic vascular network, have been described as relevant players in autoimmune diseases. We previously showed that EPC frequency may help to identify the presence of interstitial lung disease (ILD) in rheumatoid arthritis patients. [...] Read more.

Endothelial progenitor cells (EPC), which are key effectors in the physiologic vascular network, have been described as relevant players in autoimmune diseases. We previously showed that EPC frequency may help to identify the presence of interstitial lung disease (ILD) in rheumatoid arthritis patients. Given that ILD constitutes the main cause of mortality in systemic sclerosis (SSc) patients, we aimed to determine the EPC contribution to the pathogenic processes of vasculopathy and lung fibrosis in SSc-ILD⁺. EPC quantification was performed by flow cytometry on blood from 83 individuals: 21 SSc-ILD⁺ patients and subjects from comparative groups (20 SSc-ILD⁻ and 21 idiopathic pulmonary fibrosis (IPF) patients and 21 healthy controls (HC)). EPC were considered as CD34⁺, CD45^low, CD309⁺, and CD133⁺. A significant increase in EPC frequency was found in SSc-ILD⁺ patients when compared to HC (p < 0.001). SSc-ILD⁺ patients exhibited a higher EPC frequency than SSc-ILD⁻ patients (p = 0.012), whereas it was markedly reduced compared to IPF patients (p < 0.001). EPC frequency was higher in males (p = 0.04) and negatively correlated to SSc duration (p = 0.04) in SSc-ILD⁺ patients. Our results indicate a role of EPC in the processes of vasculopathy and lung fibrosis in SSc-ILD⁺. EPC frequency may be considered as a biomarker of ILD in SSc patients. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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16 pages, 5360 KiB

Open AccessArticle

Biphasic Effects of Blue Light Irradiation on Human Umbilical Vein Endothelial Cells

by Kejia Kan, Yifei Mu, Marielle Bouschbacher, Carsten Sticht, Natalia Kuch, Martin Sigl, Nuh Rahbari, Norbert Gretz, Prama Pallavi and Michael Keese

Biomedicines 2021, 9(7), 829; https://doi.org/10.3390/biomedicines9070829 - 16 Jul 2021

Cited by 6 | Viewed by 2972

Abstract

Blue light regulates biological function in various cells, such as proliferation, oxidative stress, and cell death. We employed blue light illumination on human umbilical vein endothelial cells utilizing a LED device at 453 nm wavelength and revealed a novel biphasic response on human [...] Read more.

Blue light regulates biological function in various cells, such as proliferation, oxidative stress, and cell death. We employed blue light illumination on human umbilical vein endothelial cells utilizing a LED device at 453 nm wavelength and revealed a novel biphasic response on human umbilical vein endothelial cells (HUVECs). The results showed that low fluence blue light irradiation promoted the fundamental cell activities, including cell viability, migration and angiogenesis by activating the angiogenic pathways such as the VEGF signaling pathway. In contrast, high fluence illumination caused the opposite effect on those activities by upregulating pro-apoptotic signaling cascades like ferroptosis, necroptosis and the p53 signaling pathways. Our results provide an underlying insight into photobiomodulation by blue light and may help to implement potential treatment strategies for treating angiogenesis-dependent diseases. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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11 pages, 853 KiB

Open AccessArticle

New-Onset Diabetes, Endothelial Dysfunction, and Cardiovascular Outcomes in Hypertensive Patients: An Illness-Event Model Analysis

by Raffaele Maio, Edoardo Suraci, Benedetto Caroleo, Cristina Politi, Simona Gigliotti, Angela Sciacqua, Francesco Andreozzi, Francesco Perticone and Maria Perticone

Biomedicines 2021, 9(7), 721; https://doi.org/10.3390/biomedicines9070721 - 23 Jun 2021

Cited by 5 | Viewed by 1992

Abstract

Background. Insulin resistance and endothelial dysfunction are common findings in hypertensives, both predisposing to a higher risk of diabetes and cardiovascular events. We designed this study to evaluate the role of endothelial dysfunction in three pathogenetic pathways: (1) from baseline to cardiovascular events, [...] Read more.

Background. Insulin resistance and endothelial dysfunction are common findings in hypertensives, both predisposing to a higher risk of diabetes and cardiovascular events. We designed this study to evaluate the role of endothelial dysfunction in three pathogenetic pathways: (1) from baseline to cardiovascular events, (2) from baseline to diabetes, and (3) from new-onset diabetes to cardiovascular events. Methods. We enrolled 653 Caucasian never-treated hypertensives. Endothelial dysfunction was investigated by strain-gauge plethysmography; incident diabetes and cardiovascular events were evaluated by an illness-event model analysis. Results. During the follow-up (median 113 months), we documented 191 new cardiovascular events and 92 new cases of diabetes. In a multiple Cox regression analysis, acetylcholine-stimulated forearm blood flow [100% decrease, hazard ratio: 2.42 (95% confidence interval = 1.72–3.40)] and serum high-sensitivity C-reactive protein [hazard ratio: 1.30 (95% confidence interval = 1.21–1.40)] had an independent association with cardiovascular outcomes. The incidence rate of cardiovascular outcomes in diabetes-developer patients was higher than in the diabetes-free ones (34.9 vs. 2.5 events per 100 persons-year). In an illness-event model, a 100% decrease in forearm blood flow was associated with a 55.5% hazard ratio increase (hazard ratio: 1.56, 95% confidence interval: 1.33–1.82) of transition 1 (from baseline status to cardiovascular events) and to an almost doubled increase (hazard ratio: 2.54, 95% CI: 2.00–3.25) of the risk of transition 2 (from baseline status to diabetes). No such effects were found in transition 3 (from diabetes to cardiovascular events). Conclusions. Endothelial dysfunction plays a primary role in the pathways leading to diabetes and cardiovascular events in hypertensives. When diabetes is overt, endothelial dysfunction has no predictive value for subsequent cardiovascular events. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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16 pages, 1984 KiB

Open AccessEditor’s ChoiceArticle

Clinical Assessment of Endothelial Function in Convalescent COVID-19 Patients Undergoing Multidisciplinary Pulmonary Rehabilitation

by Pasquale Ambrosino, Antonio Molino, Ilenia Calcaterra, Roberto Formisano, Silvia Stufano, Giorgio Alfredo Spedicato, Andrea Motta, Antimo Papa, Matteo Nicola Dario Di Minno and Mauro Maniscalco

Biomedicines 2021, 9(6), 614; https://doi.org/10.3390/biomedicines9060614 - 28 May 2021

Cited by 30 | Viewed by 4278

Abstract

Background: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). Methods: After swab test negativization, [...] Read more.

Background: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). Methods: After swab test negativization, convalescent COVID-19 patients referring to a post-acute care facility for PR were consecutively screened for inclusion. Study procedures were performed at the time of hospitalization and discharge. Results: We enrolled 82 convalescent COVID-19 patients (85.4% males, mean age 60.4 years). After PR, a significant improvement in most pulmonary function tests and exercise capacity was documented. FMD changed from 2.48% ± 2.01 to 4.24% ± 2.81 (p < 0.001), corresponding to a 70.9% increase. Significantly higher changes in FMD were found in patients without a history of vascular events as compared to those with (+2.04% ± 2.30 vs. +0.61% ± 1.83, p = 0.013). Values of forced expiratory volume in 1 s (FEV₁%), forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLCO%) significantly and directly correlated with FMD both at baseline and after PR. Patients with normal FEV₁% (≥80% predicted) during the overall study period or those normalizing FEV₁% after PR showed a more significant FMD change as compared to patients with persistently impaired FEV₁% (<80% predicted) (p for trend = 0.029). This finding was confirmed in a multivariate analysis. Conclusions: Clinically evaluated endothelial function improves after PR in convalescent COVID-19 patients. A direct and persistent association between the severity of pulmonary and vascular disease can be hypothesized. Endothelial function testing may be useful in the follow-up of convalescent COVID-19 patients. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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16 pages, 1264 KiB

Open AccessArticle

Endocan and Circulating Progenitor Cells in Women with Systemic Sclerosis: Association with Inflammation and Pulmonary Hypertension

by Alberto Lo Gullo, Giuseppe Mandraffino, Javier Rodríguez-Carrio, Michele Scuruchi, Davide Sinicropi, Maria Postorino, Carmela Morace, Clemente Giuffrida, Davide Sciortino, Romina Gallizzi, Saverio Loddo, Concetta Zito and Giovanni Squadrito

Biomedicines 2021, 9(5), 533; https://doi.org/10.3390/biomedicines9050533 - 11 May 2021

Cited by 16 | Viewed by 3087

Abstract

Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. [...] Read more.

Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls; ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: −0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p < 0.001), tricuspid annular plane excursion (TAPSE) (r: −0.311, p < 0.01), and E/A ratio (r: −0.487, p < 0.001), but not with ejection fraction (r: −0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: −0.619, p < 0.001), sPAP (r: −0.404, p = 0.011), E/A (r: 0.470, p < 0.005 in SSc. CONCLUSION: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc; endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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Review

Jump to: Editorial, Research

12 pages, 953 KiB

Open AccessReview

Role of Adropin in Cardiometabolic Disorders: From Pathophysiological Mechanisms to Therapeutic Target

by Josko Bozic, Marko Kumric, Tina Ticinovic Kurir, Ivan Males, Josip A. Borovac, Dinko Martinovic and Marino Vilovic

Biomedicines 2021, 9(10), 1407; https://doi.org/10.3390/biomedicines9101407 - 7 Oct 2021

Cited by 19 | Viewed by 2814

Abstract

Although a large amount of data supports the crucial role of endothelial dysfunction (ED) in cardiovascular diseases (CVDs), there is a large bench-to-bedside chasm between basic and clinical research of ED, limiting the implementation of these findings in everyday clinical settings. Hence, it [...] Read more.

Although a large amount of data supports the crucial role of endothelial dysfunction (ED) in cardiovascular diseases (CVDs), there is a large bench-to-bedside chasm between basic and clinical research of ED, limiting the implementation of these findings in everyday clinical settings. Hence, it is important to further investigate the pathophysiological mechanisms underlying ED and find modalities that will alleviate its clinical implementation. Adropin, a highly conserved peptide hormone secreted primarily by the liver, recently emerged as an important regulatory component of the vascular endothelium. Specifically, the vasoprotective role of adropin is achieved mainly by affecting endothelial NO synthesis. Thus, in this review, we aimed to summarize the current knowledge regarding the role of adropin in physiological processes and address the protective role of adropin in endothelium with consequent implications to CV pathologies. We focused on data regarding the role of adropin in the clinical setting, with concurrent implications to future clinical use of adropin. Studies suggest that plasma levels of adropin correlate with indices of ED in various pathologies and enhanced disease progression, implying that adropin may serve as a useful biomarker of ED in the upcoming future. On the other hand, despite notable results with respect to therapeutic potential of adropin in preliminary experiments, further well-designed studies are warranted in order to establish if adropin might be beneficial in this setting. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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21 pages, 2071 KiB

Open AccessEditor’s ChoiceReview

Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function

by Teresa Salvatore, Alfredo Caturano, Raffaele Galiero, Anna Di Martino, Gaetana Albanese, Erica Vetrano, Celestino Sardu, Raffaele Marfella, Luca Rinaldi and Ferdinando Carlo Sasso

Biomedicines 2021, 9(10), 1356; https://doi.org/10.3390/biomedicines9101356 - 29 Sep 2021

Cited by 56 | Viewed by 5760

Abstract

Type 2 diabetes mellitus (T2DM) is a known independent risk factor for atherosclerotic cardiovascular disease (CVD) and solid epidemiological evidence points to heart failure (HF) as one of the most common complications of diabetes. For this reason, it is imperative to consider the [...] Read more.

Type 2 diabetes mellitus (T2DM) is a known independent risk factor for atherosclerotic cardiovascular disease (CVD) and solid epidemiological evidence points to heart failure (HF) as one of the most common complications of diabetes. For this reason, it is imperative to consider the prevention of CV outcomes as an effective goal for the management of diabetic patients, as important as lowering blood glucose. Endothelial dysfunction (ED) is an early event of atherosclerosis involving adhesion molecules, chemokines, and leucocytes to enhance low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. This abnormal vascular phenotype represents an important risk factor for the genesis of any complication of diabetes, contributing to the pathogenesis of not only macrovascular disease but also microvascular damage. Gliflozins are a novel class of anti-hyperglycemic agents used for the treatment of Type 2 diabetes mellitus (T2DM) that selectively inhibit the sodium glucose transporter 2 (SGLT2) in the kidneys and have provoked large interest in scientific community due to their cardiovascular beneficial effects, whose underlying pathophysiology is still not fully understood. This review aimed to analyze the cardiovascular protective mechanisms of SGLT2 inhibition in patients T2DM and their impact on endothelial function. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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8 pages, 791 KiB

Open AccessReview

Clinical Relevance of the Sympathetic–Vascular Interactions in Health and Disease

by Fosca Quarti-Trevano, Gino Seravalle and Guido Grassi

Biomedicines 2021, 9(8), 1007; https://doi.org/10.3390/biomedicines9081007 - 13 Aug 2021

Cited by 13 | Viewed by 2347

Abstract

The sympathetic nervous system is known to play a pivotal role in the short- and long-term regulation of different cardiovascular functions. In recent decades, increasing evidence has demonstrated that sympathetic neural influences are involved not only in the vasomotor modulation of small resistance [...] Read more.

The sympathetic nervous system is known to play a pivotal role in the short- and long-term regulation of different cardiovascular functions. In recent decades, increasing evidence has demonstrated that sympathetic neural influences are involved not only in the vasomotor modulation of small resistance arteries but also in the control of large arteries. Sympathetic activity and vascular function, which are key factors in the pathophysiology and prognosis of cardiovascular disease, are linked by a close relationship. Evidence from experimental studies indicates that the sympathetic nervous system is critically influenced, at the central and also at the peripheral level, by the most relevant factors regulating vascular function, namely nitric oxide, reactive oxygen species and endothelin. Additionally, there is evidence of a reciprocal influence between endothelial function and sympathetic mechanisms. This paper will provide an overview of the relationships between endothelial function and the sympathetic nervous system characterizing physiological states. It will also briefly mention the alterations described in cardiovascular disease, with particular emphasis on essential hypertension and congestive heart failure, i.e., the two pathological states in which endothelial dysfunction and neuroadrenergic activation appear to be relevant factors for determining cardiovascular prognosis. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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16 pages, 1883 KiB

Open AccessReview

Well-Known and Novel Players in Endothelial Dysfunction: Updates on a Notch(ed) Landscape

by Francesca Fortini, Francesco Vieceli Dalla Sega, Luisa Marracino, Paolo Severi, Claudio Rapezzi, Paola Rizzo and Roberto Ferrari

Biomedicines 2021, 9(8), 997; https://doi.org/10.3390/biomedicines9080997 - 11 Aug 2021

Cited by 19 | Viewed by 4696

Abstract

Endothelial dysfunction characterizes every aspect of the so-called cardiovascular continuum, a series of events ranging from hypertension to the development of atherosclerosis and, finally, to coronary heart disease, thrombus formation, myocardial infarction, and heart failure. Endothelial dysfunction is the main prognostic factor for [...] Read more.

Endothelial dysfunction characterizes every aspect of the so-called cardiovascular continuum, a series of events ranging from hypertension to the development of atherosclerosis and, finally, to coronary heart disease, thrombus formation, myocardial infarction, and heart failure. Endothelial dysfunction is the main prognostic factor for the progression of vascular disorders, which responds to drug intervention and lifestyle changes. Virtually all of the drugs used to prevent cardiovascular disorders, such as long-used and new antilipidemic agents and inhibitors of angiotensin enzyme (ACEi), exert an important effect on the endothelium. Endothelial dysfunction is a central feature of coronavirus disease -19 (COVID-19), and it is now clear that life-risk complications of the disease are prompted by alterations of the endothelium induced by viral infection. As a consequence, the progression of COVID-19 is worse in the subjects in whom endothelial dysfunction is already present, such as elderly, diabetic, obese, and hypertensive patients. Importantly, circulating biomarkers of endothelial activation and injury predict the severity and mortality of the disease and can be used to evaluate the efficacy of treatments. The purpose of this review is to provide updates on endothelial function by discussing its clinical relevance in the cardiovascular continuum, the latest insights from molecular and cellular biology, and their implications for clinical practice, with a focus on new actors, such as the Notch signaling and emerging therapies for cardiovascular disease. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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21 pages, 1971 KiB

Open AccessReview

Inflammatory Mechanisms Contributing to Endothelial Dysfunction

by Panagiotis Theofilis, Marios Sagris, Evangelos Oikonomou, Alexios S. Antonopoulos, Gerasimos Siasos, Costas Tsioufis and Dimitris Tousoulis

Biomedicines 2021, 9(7), 781; https://doi.org/10.3390/biomedicines9070781 - 6 Jul 2021

Cited by 256 | Viewed by 15342

Abstract

Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is [...] Read more.

Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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9 pages, 532 KiB

Open AccessReview

Endothelial Dysfunction and Cardiovascular Disease: History and Analysis of the Clinical Utility of the Relationship

by Peter J. Little, Christopher D. Askew, Suowen Xu and Danielle Kamato

Biomedicines 2021, 9(6), 699; https://doi.org/10.3390/biomedicines9060699 - 20 Jun 2021

Cited by 44 | Viewed by 4755

Abstract

The endothelium is the single-cell monolayer that lines the entire vasculature. The endothelium has a barrier function to separate blood from organs and tissues but also has an increasingly appreciated role in anti-coagulation, vascular senescence, endocrine secretion, suppression of inflammation and beyond. In [...] Read more.

The endothelium is the single-cell monolayer that lines the entire vasculature. The endothelium has a barrier function to separate blood from organs and tissues but also has an increasingly appreciated role in anti-coagulation, vascular senescence, endocrine secretion, suppression of inflammation and beyond. In modern times, endothelial cells have been identified as the source of major endocrine and vaso-regulatory factors principally the dissolved lipophilic vosodilating gas, nitric oxide and the potent vascular constricting G protein receptor agonists, the peptide endothelin. The role of the endothelium can be conveniently conceptualized. Continued investigations of the mechanism of endothelial dysfunction will lead to novel therapies for cardiovascular disease. In this review, we discuss the impact of endothelial dysfunction on cardiovascular disease and assess the clinical relevance of endothelial dysfunction. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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