scholarly journals Endothelium-Dependent Hyperpolarization (EDH) in Diabetes: Mechanistic Insights and Therapeutic Implications

2019 ◽  
Vol 20 (15) ◽  
pp. 3737 ◽  
Author(s):  
Kenichi Goto ◽  
Takanari Kitazono
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Current Knowledge ◽  
Microvascular Complications ◽  
Vascular Complications ◽  
Muscle Cells ◽  
Diabetes In Animals ◽  
Diabetic Vascular Complications

Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes.

Altered L-type Ca2+ channel currents in vascular smooth muscle cells from experimental diabetic rats

2000 ◽  
Vol 278 (3) ◽  
pp. H714-H722 ◽  
Author(s):  
Rui Wang ◽  
Yuejin Wu ◽  
Guanghua Tang ◽  
Lingyun Wu ◽  
Salma Toma Hanna
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Complications ◽  
Muscle Cells ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
High Concentration ◽  
Voltage Dependent

Vascular complications of diabetes are associated with abnormal Ca2+ handling by vascular smooth muscle cells (SMCs) in which the alteration in L-type voltage-dependent Ca2+ channel (VDCC) currents may play an important role. In the present study, the characteristics of L-type VDCC currents in tail artery SMCs from streptozotocin-induced diabetic rats were examined. The densities, but not the voltage dependence, of L-type VDCC currents were reduced as diabetes progressed from 1 wk to 3 mo. The inhibitory effect of dibutyryl-cAMP on L-type VDCC currents was greater in diabetic SMCs than in age-matched control cells ( P < 0.01). Both the stimulatory effect of BAY K 8644 and the inhibitory effect of nifedipine on L-type VDCC currents were significantly enhanced in diabetic cells. The diabetes-related abnormalities in L-type VDCC currents were mimicked by culturing SMCs with a high concentration of glucose. Our results suggest that the properties of L-type VDCC in diabetic vascular SMCs were significantly altered, partially related to the increased L-type VDCC sensitivity to cAMP and hyperglycemia.

scholarly journals Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

2008 ◽  
Vol 295 (4) ◽  
pp. E810-E819 ◽  
Author(s):  
Jiandong Zhang ◽  
Nancy A. Noble ◽  
Wayne A. Border ◽  
Rick T. Owens ◽  
Yufeng Huang
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Tissue ◽  
Microvascular Complications ◽  
Muscle Cells ◽  
Diabetic Patients ◽  
Ang Ii ◽  
Pai 1

Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10−7 M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.

scholarly journals Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy

2018 ◽  
Vol 50 (2) ◽  
pp. 745-756 ◽  
Author(s):  
Xing-Rong An ◽  
Xin Li ◽  
Wei Wei ◽  
Xiao-Xue Li ◽  
Ming Xu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Prostaglandin E1 ◽  
Vascular Complications ◽  
Muscle Cells ◽  
In Vivo Study ◽  
Phenotype Switching

Background/Aims: The phenotype switching of vascular smooth muscle cells (VSMCs) was associated with the onset or progression of the atherogenic process in type 2 diabetes mellitus (T2DM). Alprostadil (Prostaglandin E1, PGE1) as a bioactive drug had a protective effect on vascular function. However, it is unknown whether PGE1 inhibited the phenotype switching in VSMCs via autophagy, which played a protective role in the vascular complications of diabetes. Methods: The phenotype switching was induced by high glucose (HG, 25mM) in VSMCs, the protein expression was measured by western blot analysis and immunofluorescent staining. In vivo study, vascular lesion and dysfunction were produced in the rats fed with high fat diet (HFD) combined with low dose streptozotocin (STZ) administration. Results: The decrease of α-SMA and the increase of vimentin, collagen I and proliferating cell nuclear antigen (PCNA) were found in HG-treated VSMCs. Along with more abundance of p62, autophagy markers LC3B and Beclin-1 significantly decreased in VSMCs exposed to HG. Such abnormal changes were significantly reversed by PGE1, which mimicked the role of autophagy activator rapamycin and was dramatically counteracted by 3-methyladenine, an autophagy inhibitor. Furthermore, PGE1 suppressed the phosphorylation of AKT and mTOR, which negatively regulated autophagy level in VSMCs. In vivo study, PGE1 remarkably improved the endothelium-independent contraction of thoracic aorta and restored the expression of α-SMA, osteopontin, LC3B, phosphorylated mTOR in the artery media of T2DM rats. Conclusion: These results demonstrated that PGE1 maintained the phenotype of VSMCs via the AKT/mTOR-dependent autophagy, which prevented diabetes-induced vascular complications.

scholarly journals TRPC and TRPV Channels’ Role in Vascular Remodeling and Disease

2020 ◽  
Vol 21 (17) ◽  
pp. 6125
Author(s):  
Marta Martín-Bórnez ◽  
Isabel Galeano-Otero ◽  
Raquel del Toro ◽  
Tarik Smani
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Trp Channels ◽  
Current Knowledge ◽  
Wide Spectrum ◽  
Human Subjects ◽  
Muscle Cells

Transient receptor potentials (TRPs) are non-selective cation channels that are widely expressed in vascular beds. They contribute to the Ca2+ influx evoked by a wide spectrum of chemical and physical stimuli, both in endothelial and vascular smooth muscle cells. Within the superfamily of TRP channels, different isoforms of TRPC (canonical) and TRPV (vanilloid) have emerged as important regulators of vascular tone and blood flow pressure. Additionally, several lines of evidence derived from animal models, and even from human subjects, highlighted the role of TRPC and TRPV in vascular remodeling and disease. Dysregulation in the function and/or expression of TRPC and TRPV isoforms likely regulates vascular smooth muscle cells switching from a contractile to a synthetic phenotype. This process contributes to the development and progression of vascular disorders, such as systemic and pulmonary arterial hypertension, atherosclerosis and restenosis. In this review, we provide an overview of the current knowledge on the implication of TRPC and TRPV in the physiological and pathological processes of some frequent vascular diseases.

scholarly journals Cardiovascular Actions of Neurotrophins

2009 ◽  
Vol 89 (1) ◽  
pp. 279-308 ◽  
Author(s):  
Andrea Caporali ◽  
Costanza Emanueli
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Therapeutic Potential ◽  
Microvascular Complications ◽  
Muscle Cells ◽  
Cardiovascular Development ◽  
Molecular Signaling

Neurotrophins were christened in consideration of their actions on the nervous system and, for a long time, they were the exclusive interest of neuroscientists. However, more recently, this family of proteins has been shown to possess essential cardiovascular functions. During cardiovascular development, neurotrophins and their receptors are essential factors in the formation of the heart and critical regulator of vascular development. Postnatally, neurotrophins control the survival of endothelial cells, vascular smooth muscle cells, and cardiomyocytes and regulate angiogenesis and vasculogenesis, by autocrine and paracrine mechanisms. Recent studies suggest the capacity of neurotrophins, via their tropomyosin-kinase receptors, to promote therapeutic neovascularization in animal models of hindlimb ischemia. Conversely, the neurotrophin low-affinity p75NTRreceptor induces apoptosis of endothelial cells and vascular smooth muscle cells and impairs angiogenesis. Finally, nerve growth factor looks particularly promising in treating microvascular complications of diabetes or reducing cardiomyocyte apoptosis in the infarcted heart. These seminal discoveries have fuelled basic and translational research and thus opened a new field of investigation in cardiovascular medicine and therapeutics. Here, we review recent progress on the molecular signaling and roles played by neurotrophins in cardiovascular development, function, and pathology, and we discuss therapeutic potential of strategies based on neurotrophin manipulation.

scholarly journals Vascular Adventitia is a Suitable Compartment to Transplant Transduced Vascular Smooth Muscle Cells for Ex Vivo Gene Expression

2002 ◽  
Vol 11 (6) ◽  
pp. 583-592 ◽  
Author(s):  
Patricia C. B. Beltrão-Braga ◽  
Ivan H. J. Koh ◽  
Maria R. R. Silva ◽  
Paulo S. Gutierrez ◽  
Sang W. Han
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Simple Procedure ◽  
Vascular Complications ◽  
Muscle Cells ◽  
Retroviral Vectors ◽  
Growth Hormone Gene

Vascular smooth muscle cells (VSMC) are ideal for systemic gene therapy because of their proximity to blood vessels and they have demonstrated long-term exogenous gene expression in vivo. However, the procedure generally followed to seed the transduced VSMC onto arteries denuded of endothelial cells usually induces stenosis and thrombosis, with a consequent high risk for use in humans. We demonstrate here that the vascular adventitia is a suitable place to introduce transduced VSMC and to secrete therapeutic proteins into the blood stream by a simple procedure, avoiding postoperative vascular complications. Transduced VSMC, with the retroviral vectors carrying the human growth hormone gene (hGH), were seeded into the adventitia of the rat abdominal aorta by single injection of a cell suspension. Based on the hGH and anti-hGH production in serum and on histological analysis of the removed aortas, we demonstrated hGH production over the 2-month experimental period. None of the animals used in the experiment showed stenosis, thrombosis, or other vascular or visible physiological abnormalities.

scholarly journals Molecular Interactions Between Vascular Smooth Muscle Cells and Macrophages in Atherosclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Jahnic Beck-Joseph ◽  
Stephanie Lehoux
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Molecular Interactions ◽  
Current Knowledge ◽  
Muscle Cells ◽  
Cell Types ◽  
Physical Contact ◽  
Life Threatening

Atherosclerosis is the largest contributor toward life-threatening cardiovascular events. Cellular activity and cholesterol accumulation lead to vascular remodeling and the formation of fatty plaques. Complications arise from blood clots, forming at sites of plaque development, which may detach and result in thrombotic occlusions. Vascular smooth muscle cells and macrophages play dominant roles in atherosclerosis. A firm understanding of how these cells influence and modulate each other is pivotal for a better understanding of the disease and the development of novel therapeutics. Recent studies have investigated molecular interactions between both cell types and their impact on disease progression. Here we aim to review the current knowledge. Intercellular communications through soluble factors, physical contact, and extracellular vesicles are discussed. We also present relevant background on scientific methods used to study the disease, the general pathophysiology and intracellular factors involved in phenotypic modulation of vascular smooth muscle cells. We conclude this review with a discussion of the current state, shortcomings and potential future directions of the field.

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