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1.
Biomolecules ; 11(7)2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34356605

RESUMO

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The initial stage of CVDs is characterized by endothelial dysfunction, defined as the limited bioavailability of nitric oxide (NO). Thus, any factors that interfere with the synthesis or metabolism of NO in endothelial cells are involved in CVD pathogenesis. It is well established that hypoxia is both the triggering factor as well as the accompanying factor in cardiovascular disease, and diminished tissue oxygen levels have been reported to influence endothelial NO bioavailability. In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS) from L-Arg, with tetrahydrobiopterin (BH4) as an essential cofactor. Here, we discuss the mechanisms by which hypoxia affects NO bioavailability, including regulation of eNOS expression and activity. What is particularly important is the fact that hypoxia contributes to the depletion of cofactor BH4 and deficiency of substrate L-Arg, and thus elicits eNOS uncoupling-a state in which the enzyme produces superoxide instead of NO. eNOS uncoupling and the resulting oxidative stress is the major driver of endothelial dysfunction and atherogenesis. Moreover, hypoxia induces impairment in mitochondrial respiration and endothelial cell activation; thus, oxidative stress and inflammation, along with the hypoxic response, contribute to the development of endothelial dysfunction.


Assuntos
Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Hipóxia/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Animais , Aterosclerose/patologia , Disponibilidade Biológica , Células Endoteliais/patologia , Endotélio Vascular/patologia , Humanos , Hipóxia/patologia , Estresse Oxidativo
2.
Biomolecules ; 11(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34356618

RESUMO

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood-brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.


Assuntos
Trifosfato de Adenosina/metabolismo , Doenças de Pequenos Vasos Cerebrais/metabolismo , Endotélio Vascular/metabolismo , AVC Isquêmico/metabolismo , Transdução de Sinais , Trombose/metabolismo , Animais , Doenças de Pequenos Vasos Cerebrais/patologia , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , AVC Isquêmico/patologia , Trombose/patologia
3.
Nutrients ; 13(7)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34371816

RESUMO

(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry.


Assuntos
Arginina/análogos & derivados , Arginina/sangue , Diabetes Mellitus Tipo 2/sangue , Endotélio Vascular/metabolismo , Eritrócitos/metabolismo , Óxido Nítrico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Citrulina/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade
4.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445652

RESUMO

Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-ß/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.


Assuntos
Endoglina/fisiologia , Endotélio Vascular/patologia , Mutação , Telangiectasia Hemorrágica Hereditária/complicações , Doenças Vasculares/patologia , Animais , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo
5.
Life Sci ; 283: 119868, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34358551

RESUMO

AIMS: In this study, we investigated the vasodilatory effects of trelagliptin (a dipeptidyl peptidase-4 inhibitor) and its related mechanisms using rabbit aortic rings. MAIN METHODS: Arterial tone measurement was performed in rabbit thoracic aortic rings. KEY FINDINGS: Trelagliptin induced vasodilation in a dose-dependent manner. Pretreatment with the ATP-sensitive K+ channel inhibitor glibenclamide, large-conductance Ca2+-activated K+ channel inhibitor paxilline, and inwardly rectifying K+ channel inhibitor Ba2+ did not affect the vasodilatory effect of trelagliptin. However, pretreatment with the voltage-dependent K+ (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly attenuated the vasodilatory effect of trelagliptin, suggesting that the vasodilatory effect of trelagliptin is associated with Kv channel activation. Although pretreatment with Kv1.5 and Kv2.1 subtype inhibitors did not affect the response to trelagliptin, pretreatment with a Kv7.X subtype inhibitor effectively reduced the vasodilatory effect of trelagliptin. Furthermore, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors also significantly attenuated the vasodilatory effect of trelagliptin. These effects, however, were not affected by pretreatment with Ca2+ channel inhibitors, adenylyl cyclase/PKA inhibitors, guanylyl cyclase/PKG inhibitors, or removal of the endothelium. SIGNIFICANCE: From these results, we concluded that the vasodilatory effect of trelagliptin was associated with the activation of Kv channels (primary the Kv7.X subtype) and SERCA pump regardless of other K+ channels, Ca2+ channels, cAMP/PKA-related or cGMP/PKG-related signaling pathways, and the endothelium. Therefore, caution is required when prescribing trelagliptin to the patients with hypotension and diabetes.


Assuntos
Aorta/metabolismo , Endotélio Vascular/metabolismo , Hipoglicemiantes/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Uracila/análogos & derivados , Vasodilatação/efeitos dos fármacos , Animais , Masculino , Coelhos , Uracila/farmacologia
6.
Nutrients ; 13(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34444906

RESUMO

Diabetic kidney disease (DKD) has become a global health concern, with about 40% of people living with type 1 and type 2 diabetes mellitus developing DKD. Upregulation of vascular endothelial growth factor (VEGF) in the kidney is a significant pathology of DKD associated with increased glomerular vascular permeability. To date, however, current anti-VEGF therapies have demonstrated limited success in treating DKD. Recent studies have shown that artificial sweeteners exhibit anti-VEGF potential. The aim of this study was therefore to assess the effects of aspartame, saccharin, and sucralose on VEGF-induced leak using an in vitro model of the glomerular endothelium. Saccharin and sucralose but not aspartame protected against VEGF-induced permeability. Whilst the sweeteners had no effect on traditional VEGF signalling, GC-MS analysis demonstrated that the sweetener sucralose was not able to enter the glomerular endothelial cell to exert the protective effect. Chemical and molecular inhibition studies demonstrated that sweetener-mediated protection of the glomerular endothelium against VEGF is dependent on the sweet taste receptor, T1R3. These studies demonstrate the potential for sweeteners to exert a protective effect against VEGF-induced increased permeability to maintain a healthy endothelium and protect against vascular leak in the glomerulus in settings of DKD.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Substâncias Protetoras/farmacocinética , Sacarina/farmacocinética , Sacarose/análogos & derivados , Edulcorantes/farmacologia , Aspartame/farmacocinética , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Células Endoteliais , Endotélio Vascular/metabolismo , Humanos , Técnicas In Vitro , Rim/irrigação sanguínea , Microvasos/metabolismo , Sacarose/farmacocinética , Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
Molecules ; 26(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34299400

RESUMO

The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein-kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.


Assuntos
Bradicinina/metabolismo , Camellia/química , Endotélio Vascular/efeitos dos fármacos , Fator XII/antagonistas & inibidores , Sistema Calicreína-Cinina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Artéria Pulmonar/metabolismo
8.
Arterioscler Thromb Vasc Biol ; 41(9): 2357-2369, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34196216

RESUMO

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent endothelial properties and take on mesenchymal cell behaviors. To begin the process, endothelial cells loosen their cell-cell junctions, degrade the basement membrane, and migrate out into the perivascular surroundings. These initial endothelial behaviors reflect a transient modulation of cellular phenotype, that is, a phenotypic modulation, that is sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening of endothelial junctions and migration are also seen in inflammatory and angiogenic settings such that endothelial cells initiating endothelial-to-mesenchymal transition have overlapping behaviors and gene expression with endothelial cells responding to inflammatory signals or sprouting to form new blood vessels. Reduced endothelial junctions increase permeability, which facilitates leukocyte trafficking, whereas endothelial migration precedes angiogenic sprouting and neovascularization; both endothelial barriers and quiescence are restored as inflammatory and angiogenic stimuli subside. Complete endothelial-to-mesenchymal transition proceeds beyond phenotypic modulation such that mesenchymal characteristics become prominent and endothelial functions diminish. In proadaptive, regenerative settings the new mesenchymal cells produce extracellular matrix and contribute to tissue integrity whereas in maladaptive, pathologic settings the new mesenchymal cells become fibrotic, overproducing matrix to cause tissue stiffness, which eventually impacts function. Here we will review what is known about how TGF (transforming growth factor) ß influences this continuum from junctional loosening to cellular migration and its relevance to cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/patologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Transição Epitelial-Mesenquimal , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Movimento Celular , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Permeabilidade , Fenótipo , Transdução de Sinais
9.
Molecules ; 26(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299486

RESUMO

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.


Assuntos
Berberina/análogos & derivados , Diabetes Mellitus Experimental/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Berberina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Vasculares/metabolismo
10.
JCI Insight ; 6(17)2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34314391

RESUMO

Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.


Assuntos
COVID-19/metabolismo , Endotélio Vascular/metabolismo , Ácido Hialurônico/metabolismo , Idoso , COVID-19/sangue , COVID-19/patologia , Citocinas/sangue , Endotélio Vascular/patologia , Feminino , Glicocálix/metabolismo , Glicocálix/patologia , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/sangue , Hialuronoglucosaminidase/sangue , Hialuronoglucosaminidase/metabolismo , Masculino , Pessoa de Meia-Idade , Quinases Associadas a rho/metabolismo
11.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199319

RESUMO

Inflammation is an old concept that has started to be considered as an important factor in infection and chronic diseases. The role of leukocytes, the plasmatic components, then of the mediators such as prostaglandins, cytokines, and, in recent decades, of the endothelium has completed the concept of the inflammation process. The function of the endothelium appeared to be crucial as a regulator or the initiator of the inflammatory process. Culture of human endothelial cells and experimental systems made it possible to define the molecular basis of inflammation in vascular diseases, in diabetes mellitus, atherosclerosis, vasculitis and thromboembolic complications. Advanced glycation end product receptor (RAGE), present on endothelial cells (ECs) and monocytes, participates in the activation of these cells in inflammatory conditions. Inflammasome is a cytosolic multiprotein that controls the response to diverse microorganisms. It is positively regulated by stimulator of interferon response CGAMP interactor-1 (STING1). Angiogenesis and thrombotic events are dysregulated during inflammation. ECs appear to be a protector, but also a possible initiator of thrombosis.


Assuntos
Aterosclerose/patologia , Endotélio Vascular/metabolismo , Trombose/patologia , Aterosclerose/metabolismo , Endotélio Vascular/citologia , Humanos , Inflamassomos/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica , Óxido Nítrico/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Trombose/metabolismo
12.
J Neuroinflammation ; 18(1): 167, 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325716

RESUMO

BACKGROUND: Neurological complications are common in patients affected by COVID-19 due to the ability of SARS-CoV-2 to infect brains. While the mechanisms of this process are not fully understood, it has been proposed that SARS-CoV-2 can infect the cells of the neurovascular unit (NVU), which form the blood-brain barrier (BBB). The aim of the current study was to analyze the expression pattern of the main SARS-CoV-2 receptors in naïve and HIV-1-infected cells of the NVU in order to elucidate a possible pathway of the virus entry into the brain and a potential modulatory impact of HIV-1 in this process. METHODS: The gene and protein expression profile of ACE2, TMPRSS2, ADAM17, BSG, DPP4, AGTR2, ANPEP, cathepsin B, and cathepsin L was assessed by qPCR, immunoblotting, and immunostaining, respectively. In addition, we investigated if brain endothelial cells can be affected by the exposure to the S1 subunit of the S protein, the domain responsible for the direct binding of SARS-CoV-2 to the ACE2 receptors. RESULTS: The receptors involved in SARS-CoV-2 infection are co-expressed in the cells of the NVU, especially in astrocytes and microglial cells. These receptors are functionally active as exposure of endothelial cells to the SARS CoV-2 S1 protein subunit altered the expression pattern of tight junction proteins, such as claudin-5 and ZO-1. Additionally, HIV-1 infection upregulated ACE2 and TMPRSS2 expression in brain astrocytes and microglia cells. CONCLUSIONS: These findings provide key insight into SARS-CoV-2 recognition by cells of the NVU and may help to develop possible treatment of CNS complications of COVID-19.


Assuntos
Vasos Sanguíneos/metabolismo , COVID-19/complicações , Infecções por HIV/metabolismo , HIV-1 , Neurônios/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Astrócitos/metabolismo , Encefalopatias/etiologia , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Microglia/metabolismo , Doenças do Sistema Nervoso/etiologia , Cultura Primária de Células , Receptor Tipo 2 de Angiotensina , Replicação Viral
13.
Science ; 373(6554)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326210

RESUMO

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, "inflammaging" (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.


Assuntos
Envelhecimento/fisiologia , Envelhecimento Saudável , Longevidade , Fator A de Crescimento do Endotélio Vascular/metabolismo , Tecido Adiposo , Animais , Vasos Sanguíneos/fisiologia , Composição Corporal , Distribuição da Gordura Corporal , Metabolismo dos Carboidratos , Carcinogênese , Endotélio Vascular/metabolismo , Fígado Gorduroso/patologia , Feminino , Inflamação/prevenção & controle , Fígado/patologia , Masculino , Camundongos , Densidade Microvascular , Microvasos/fisiologia , Osteoporose/prevenção & controle , Consumo de Oxigênio , Sarcopenia/prevenção & controle , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/sangue
14.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205118

RESUMO

During metastasis, cancer cells that originate from the primary tumor circulate in the bloodstream, extravasate, and form micrometastases at distant locations. Several lines of evidence suggest that specific interactions between cancer cells and endothelial cells, in particular tumor cell adhesion to the endothelium and transendothelial migration, play a crucial role in extravasation. Here we have studied the role of vascular endothelial (VE)-cadherin which is expressed aberrantly by breast cancer cells and might promote such interactions. By comparing different human breast cancer cell lines, we observed that the number of cancer cells that adhered to endothelium correlated with VE-cadherin expression levels. VE-cadherin silencing experiments confirmed that VE-cadherin enhances cancer cell adhesion to endothelial cells. However, in contrast, the number of cancer cells that incorporated into the endothelium was not dependent on VE-cadherin. Thus, it appears that cancer cell adhesion and incorporation are distinct processes that are governed by different molecular mechanisms. When cancer cells incorporated into the endothelial monolayer, they formed VE-cadherin positive contacts with endothelial cells. On the other hand, we also observed tumor cells that had displaced endothelial cells, reflecting either different modes of incorporation, or a temporal sequence where cancer cells first form contact with endothelial cells and then displace them to facilitate transmigration. Taken together, these results show that VE-cadherin promotes the adhesion of breast cancer cells to the endothelium and is involved in the initial phase of incorporation, but not their transmigration. Thus, VE-cadherin might be of relevance for therapeutic strategies aiming at preventing the metastatic spread of breast cancer cells.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , Adesão Celular/genética , Endotélio Vascular/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Cocultura , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Imagem Molecular/métodos , Metástase Neoplásica
15.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207234

RESUMO

Filamin A (FLNA) is a large actin-binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C-terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells. Localized FLNA mutations associate with cardiovascular malformations in humans. A lack of FLNA in experimental animal models disrupts cell migration during embryogenesis and causes anomalies, including heart and vessels, similar to human malformations. More recently, it was shown that FLNA mediates the progression of myocardial infarction and atherosclerosis. Thus, these latest findings identify FLNA as an important novel mediator of cardiovascular development and remodeling, and thus a potential target for therapy. In this update, we summarized the literature on filamin biology with regard to cardiovascular cell function.


Assuntos
Doenças Cardiovasculares/genética , Filaminas/genética , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Filaminas/metabolismo , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
16.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299157

RESUMO

Curcumin, a yellow polyphenol extracted from the turmeric root is used as a diet supplement. It exhibits anti-inflammatory, antioxidant, and antitumor properties by modulating different intracellular mechanisms. Due to their low solubility in water, the curcumin molecules must be encapsulated into liposomes to improve the bioavailability and biomedical potential. For the periodontal tissue and systemic health, it is essential to regulate the local inflammatory response. In this study, the possible beneficial effect of liposomes loaded with curcumin (CurLIP) in neural crest-derived human periodontal ligament stem cells (hPDLSCs) and in endothelial-differentiated hPDLSCs (e-hPDLSCs) induced with an inflammatory stimulus (lipopolysaccharide obtained from Porphyromonas gingivalis, LPS-G) was evaluated. The CurLIP formulation exhibited a significant anti-inflammatory effect by the downregulation of Toll-like receptor-4 (TLR4)/Myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa light chain enhancer of activated B cells (NFkB)/NLR Family Pyrin Domain Containing 3 (NLRP3)/Caspase-1/Interleukin (IL)-1ß inflammation cascade and reactive oxygen species (ROS) formation. Moreover, the exposure to LPS-G caused significant alterations in the expression of epigenetic modifiers, such as DNA Methyltransferase 1 (DNMT1) and P300, while the CurLIP treatment showed physiological expression. Overall, our in vitro study provides novel mechanistic insights into the intracellular pathway exert by CurLIP in the regulation of inflammation and epigenetic modifications.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Curcumina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Crista Neural/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Diferenciação Celular , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Lipossomos/administração & dosagem , Lipossomos/química , Crista Neural/citologia , Crista Neural/metabolismo , Ligamento Periodontal/citologia , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Porphyromonas gingivalis/química , Espécies Reativas de Oxigênio , Células-Tronco/citologia , Células-Tronco/metabolismo
17.
Medicine (Baltimore) ; 100(28): e24004, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260518

RESUMO

ABSTRACT: We aim to investigate the association between plasma endothelial microparticles (EMPs) and contrast-induced nephropathy of patients underwent coronary angiography.The patients were divided into normal renal function group and renal dysfunction group based on the estimated glomerular filtration rate (eGFR). Among the 180 cases, 117 received determination of EMP and serum creatinine after percutaneous coronary intervention (PCI) and/or coronary angiography. The patients were divided into contrast-induced-nephropathy (CIN) group and non-CIN group. EMPs collection and determination were performed, together with biochemical analysis and digital subtraction angiography (DSA) analysis.Spearman correlation showed that the expression of EMP was negatively correlated with eGFR (r = -0.201, P < .01). The serum hypersensitive C-reactive protein (hs-CRP), cystatin C (Cys-C), uric acid (UA) were significantly higher in CIN group than that in the non CIN group. Spearman correlation showed that the expression of EMP was positively correlated with serum interleukin-6 (IL-6, r = 0.393, P < .01). The expression of EMP was positively correlated with serum hs-CRP (r = 0.360, P < .01). Logistic regression analysis showed that the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), eGFR, UA, and Cys-C were correlated with the incidence of contrast induced nephropathy.In patients with contrast-induced-nephropathy, the plasma EMPs were significantly increased after coronary angiography. The expression of plasma EMPs may play a role in the occurrence of contrast-induced-nephropathy.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Meios de Contraste/efeitos adversos , Endotélio Vascular/metabolismo , Nefropatias/sangue , Nefropatias/induzido quimicamente , Idoso , Proteína C-Reativa/análise , Angiografia Coronária/efeitos adversos , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade
18.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200377

RESUMO

High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J mice and cultured human endothelial cells (EA.hy926) were stimulated with Aldo (100 nM) in the presence of tiron [reactive oxygen species (ROS) scavenger, eplerenone [mineralocorticoid receptor (MR) antagonist], and L-sulforaphane (SFN; Nrf2 activator). Thoracic aortas were also isolated from mice infused with Aldo (600 µg/kg per day) for 14 days. Aldo decreased endothelium-dependent vasorelaxation and increased ROS generation, effects prevented by tiron and MR blockade. Pharmacological activation of Nrf2 with SFN abrogated Aldo-induced vascular dysfunction and ROS generation. In EA.hy926 cells, Aldo increased ROS generation, which was prevented by eplerenone, tiron, and SFN. At short times, Aldo-induced ROS generation was linked to increased Nrf2 activation. However, after three hours, Aldo decreased the nuclear accumulation of Nrf2. Increased Keap1 protein expression, but not activation of p38 MAPK, was linked to Aldo-induced reduced Nrf2 activity. Arteries from Aldo-infused mice also exhibited decreased nuclear Nrf2 and increased Keap1 expression. Our findings suggest that Aldo reduces vascular Nrf2 transcriptional activity by Keap1-dependent mechanisms, contributing to mineralocorticoid-induced vascular dysfunction.


Assuntos
Aldosterona/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores de Mineralocorticoides/química , Doenças Vasculares/patologia , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Fator 2 Relacionado a NF-E2/genética , Espécies Reativas de Oxigênio/metabolismo , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/metabolismo
19.
J Dermatol Sci ; 103(1): 25-32, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34148739

RESUMO

BACKGROUND: Mucopolysaccharide polysulfate (MPS) is a heparinoid and MPS-containing formulations are widely used as moisturizers for dry skin and to treat peripheral vascular insufficiency. Although MPS has therapeutic effects in skin diseases with microvascular abnormalities, the effects of MPS on microvascular function remain incompletely understood. OBJECTIVE: The aim of this study was to evaluate the functional activities of MPS on human pericytes (HPC) and human dermal microvascular endothelial cells (HDMEC) in vitro, and on microvascular permeability of the skin. METHODS: The protein expression of angiopoietin (Ang)-1 in HPC, and platelet-derived growth factor-BB (PDGF-BB) and phosphorylated tyrosine-protein kinase receptor 2 (Tie2) in HDMEC were measured in the presence or absence of MPS. The vascular barrier was evaluated by the expressions of claudin-5 and vascular endothelial (VE)-cadherin, and transendothelial electrical resistance (TEER). RESULTS: In HPC, MPS dose-dependently enhanced Ang-1 secretion, which activated Tie2 in HDMEC. In HDMEC, MPS significantly increased the production of PDGF-BB, which is important for the recruitment of HPC to the vascular endothelium, and significantly increased the phosphorylation of Tie2, which results in the activation of the Ang-1/Tie2 signaling . MPS significantly increased the expression of tight junction protein claudin-5 and TEER in the HDMEC. Moreover, the intradermal injection of MPS prevented vascular endothelial growth factor-induced increase in vascular permeability in mouse skin. CONCLUSION: We found that MPS promoted microvascular stabilization and barrier integrity in HDMEC via Ang-1/Tie2 activation. These results suggest that MPS might improve microvascular abnormalities in various diseases accompanied by disturbances in Ang-1/Tie2 signaling.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Emolientes/farmacologia , Endotélio Vascular/efeitos dos fármacos , Glicosaminoglicanos/farmacologia , Microvasos/efeitos dos fármacos , Angiopoietina-1/metabolismo , Animais , Becaplermina/metabolismo , Células Endoteliais , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Injeções Intradérmicas , Camundongos , Microvasos/citologia , Microvasos/metabolismo , Modelos Animais , Pericitos , Fosforilação/efeitos dos fármacos , Receptor TIE-2/metabolismo , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/metabolismo , Dermatopatias Vasculares/tratamento farmacológico
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