Diabetes is a vascular disease: the role of endothelial dysfunction in pathophysiology of cardiovascular disease in diabetes

Gender plays a pivotal role in the onset as well as in the progression of the cardiovascular disease with a higher morbidity and mortality being detected in men with respect to women. Type 2 Diabetes Mellitus (T2DM) may reduce gender-related differences in the prevalence of cardiovascular disease by fading the vascular protective effects afforded by estrogen in females. This article will discuss the role of sex and sex hormones on the incidence and mechanisms involved in vascular dysfunction associated to T2DM, which might explain why women with T2DM lack the vascular protection.

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Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

International Journal of Molecular Sciences ◽

10.3390/ijms20153775 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3775 ◽

Cited By ~ 23

Author(s):

Cesar A. Meza ◽

Justin D. La Favor ◽

Do-Houn Kim ◽

Robert C. Hickner

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Blood Flow ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Vascular Dysfunction ◽

Vascular Complications ◽

Enzymatic Production

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

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

Biomedicines ◽

10.3390/biomedicines9060699 ◽

2021 ◽

Vol 9 (6) ◽

pp. 699

Author(s):

Peter J. Little ◽

Christopher D. Askew ◽

Suowen Xu ◽

Danielle Kamato

Keyword(s):

Cardiovascular Disease ◽

Endothelial Dysfunction ◽

Cell Monolayer ◽

Modern Times ◽

Protein Receptor ◽

Endocrine Secretion ◽

The Impact ◽

The Relationship ◽

Vascular Senescence

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.

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Interactions between Epac1 and ezrin in the control of endothelial barrier function

Biochemical Society Transactions ◽

10.1042/bst20130271 ◽

2014 ◽

Vol 42 (2) ◽

pp. 274-278 ◽

Cited By ~ 9

Author(s):

Euan Parnell ◽

Stephen J. Yarwood

Keyword(s):

Cardiovascular Disease ◽

Endothelial Dysfunction ◽

Barrier Function ◽

Endothelial Barrier ◽

Endothelial Barrier Function ◽

Growing Body ◽

Cytoskeletal Dynamics ◽

Inflammatory Signalling ◽

Kinase A

Loss of barrier function in the vasculature promotes inflammatory signalling which in turn contributes to the progression of cardiovascular disease. cAMP can protect against endothelial dysfunction through the effectors PKA (protein kinase A) and Epac (exchange protein directly activated by cAMP). The present review outlines the role of Epac1 signalling within the endothelium and, in particular, the role of Epac1 in cytoskeletal dynamics and the control of cell morphology. The actin/cytoskeleton linker ezrin will be described in terms of the growing body of evidence placing it downstream of cAMP signalling as a mediator of altered cellular morphology.

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Pathophysiological Role of Adiponectin, Leptin and Asymmetric Dimethylarginine in the Process of Atherosclerosis

Folia Medica ◽

10.1515/folmed-2016-0039 ◽

2016 ◽

Vol 58 (4) ◽

pp. 234-240 ◽

Cited By ~ 8

Author(s):

Daniela Iv. Koleva ◽

Maria M. Orbetzova ◽

Julia G. Nikolova ◽

Tanya I. Deneva

Keyword(s):

Cardiovascular Disease ◽

Adipose Tissue ◽

Endothelial Dysfunction ◽

Proinflammatory Cytokines ◽

Asymmetric Dimethylarginine ◽

Serum Levels ◽

Reactive Protein ◽

Proinflammatory Mediators ◽

Pathophysiological Role

Abstract Adipose tissue is recognized as a rich source of proinflammatory mediators that may directly contribute to vascular injury, insulin resistance, and atherogenesis. Many studies have shown that adiponectin has antiatherogenic and anti-inflammatory properties. Adiponectin acts not only as a factor increasing insulin sensitivity, and the protective effect may result from its ability to suppress production of proinflammatory cytokines. It negatively regulates the expression of TNF-alpha and C-reactive protein (CRP) in adipose tissue; reduces expression of vascular and intracellular adhesion molecules (VCAM-1, ICAM-1), E-selectin, interleukin-8 (IL-8). Hyperleptinemia has been linked with the development of hypertension and endothelial dysfunction/atherosclerosis, two main pathophysiological conditions associated with cardiovascular disease development. Leptin-mediated increases in sympathetic nervous system activity may be among the principal mechanisms evoking obesity related hypertension. Leptin stimulates the secretion of proinflammatory cytokines, and increases the release of endothelin-1 (ET-1), which may promote hypertension. Increased serum levels of asymmetric dimethylarginine (ADMA), a physiological regulator of the biosynthesis of nitric oxide (NO), promote the process of atherosclerosis, leading to the occurrence of endothelial dysfunction and cardiovascular disease.

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The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00397.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. R1288-R1295 ◽

Cited By ~ 107

Author(s):

Stephane L. Bourque ◽

Sandra T. Davidge ◽

Michael A. Adams

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Vascular Disease ◽

Vascular Remodeling ◽

Vascular Function ◽

No Synthase ◽

Endothelin 1 ◽

No Signaling ◽

No Bioavailability

Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.

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Abstract 610: Context-Dependent Effects of Suppressor of Cytokine Signaling 3 (SOCS3) in Angiotensin II-Induced Vascular Dysfunction: Mechanisms and Role of Bone Marrow-Derived Cells

Hypertension ◽

10.1161/hyp.64.suppl_1.610 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Ying Li ◽

Dale Kinzenbaw ◽

Mary Modrick ◽

Lecia Epping ◽

John T Harty ◽

...

Keyword(s):

Bone Marrow ◽

Angiotensin Ii ◽

Endothelial Dysfunction ◽

Vascular Disease ◽

Vascular Dysfunction ◽

Pressor Response ◽

Ang Ii ◽

Bone Marrow Derived Cells ◽

The Impact

Angiotensin II (Ang II) promotes vascular disease and hypertension, in part, by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Although SOCS3 regulates this pathway in the immune system, its role in vascular disease and hypertension is unknown. In this study, we investigated the role of SOCS3 in a model of Ang II-induced vascular disease. To exam direct effects, carotid arteries from wild-type (WT) and SOCS3 haplodeficient (SOCS3 +/- ) mice were incubated with Ang II for 22 hrs, followed by examination of endothelial function using acetylcholine (Ach). Relaxation to Ach was similar in all arteries incubated with vehicle. A low concentration of Ang II (1 nmol/L) did not affect Ach-induced vasodilation in WT mice, but reduced that of SOCS3 +/- mice by ~50% (P<0.05). Ang II-induced impairment was prevented by inhibitors of STAT3, IL-6, NF-κB, or a scavenger of superoxide. Responses to nitroprusside were similar in all groups. We also tested the impact of SOCS3 in vivo by systemically infusing Ang II (1.4 mg/kg per day) for 14 days via osmotic mini-pumps. Ach-induced vasodilation in carotid and resistance arteries in brain from WT mice was reduced by ~60% (P<0.05). Surprisingly, deficiency in SOCS3 prevented the majority of Ang II-induced endothelial dysfunction without affecting the pressor response to Ang II. Lethally irradiated WT mice reconstituted with SOCS3 +/- bone marrow were protected from Ang II-induced endothelial dysfunction (P<0.05), while reconstitution of irradiated SOCS3 +/- mice with WT bone marrow exacerbated Ang II-induced vascular dysfunction (P<0.05). WT into WT and SOCS3 +/- into SOCS3 +/- bone marrow chimeras exhibited vascular function consistent with non-irradiated controls. The pressor response to Ang II was reduced by ~50% in WT mice reconstituted with bone marrow from SOCS3 +/- mice (P<0.05). These data suggest SOCS3 exerts divergent local versus systemic effects on Ang II-induced vascular dysfunction. In the face of SOCS3 deficiency, bone marrow-derived cells protect against Ang II-induced vascular dysfunction and hypertension.

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