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1.
Front Immunol ; 12: 773352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745149

RESUMO

Anti-MDA5 dermatomyositis is a rare systemic autoimmune disease, historically described in Japanese patients with clinically amyopathic dermatomyositis and life-threatening rapidly progressive interstitial lung disease. Subsequently, the complete clinical spectrum of the disease was enriched by skin, articular and vascular manifestations. Depending on the predominance of these symptoms, three distinct clinical phenotypes with different prognosis are now defined. To date, the only known molecular component shared by the three entities are specific antibodies targeting MDA5, a cytosolic protein essential for antiviral host immune responses. Several biological tools have emerged to detect these antibodies, with drawbacks and limitations for each of them. However, the identification of this highly specific serological marker of the disease raises the question of its role in the pathogenesis. Although current knowledge on the pathogenic mechanisms that take place in the disease are still in their enfancy, several lines of evidence support a central role of interferon-mediated vasculopathy in the development of skin and lung lesions, as well as a possible pathogenic involvement of anti-MDA5 antibodies. Here, we review the clinical and biological evidences in favor of these hypothesis, and we discuss the contribution of emerging therapies that shed some light on the pathogenesis of the disease.


Assuntos
Autoanticorpos/imunologia , Vasos Sanguíneos/patologia , Dermatomiosite/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Doenças Pulmonares Intersticiais/imunologia , Pele/patologia , Animais , Dermatomiosite/terapia , Humanos , Interferons/metabolismo , Doenças Pulmonares Intersticiais/terapia , Fenótipo
2.
Hamostaseologie ; 41(5): 347-348, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34695851

RESUMO

The COVID-19 pandemic is still threatening us, our patients, and the global health care system. Since the first outbreak at the end of 2019 in China, it became rapidly clear that a new variant of a SARS virus, SARS-CoV-2, is threatening our human society worldwide. Since then, the scientific community has accumulated an incredibly large amount of knowledge about the pathophysiology of this virus, primarily affecting the respiratory tract and, in severe cases, subsequently resulting in acute respiratory distress syndrome and multiple organ failure due to uncontrolled systemic inflammatory response syndrome.1 2.


Assuntos
COVID-19/fisiopatologia , SARS-CoV-2 , Biomarcadores/metabolismo , Vasos Sanguíneos/fisiopatologia , COVID-19/complicações , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Coração/fisiopatologia , Humanos , Pulmão/fisiopatologia , Pandemias , SARS-CoV-2/patogenicidade
3.
PLoS One ; 16(10): e0257859, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34679094

RESUMO

PURPOSE: To assess the repeatability of multiple automatic vessel density (VD) measurements and the effect of image averaging on vessel detection by optical coherence tomography angiography (OCTA). METHODS: An observational study was conducted in a series of healthy volunteers and patients with macular oedema. Five sequential OCTA images were acquired for each eye using the OptoVue HD device. The effect of the averaging of the 5 acquisitions on vessel detection was analysed quantitatively using a pixel-by-pixel automated analysis. In addition, two independent retina experts qualitatively assessed the change in vessel detection in averaged images segmented in 9 boxes and compared to the first non-averaged image. RESULTS: The automatic VD measurement in OCTA images showed a good repeatability with an overall mean intra-class correlation coefficient (ICC) of 0.924. The mean ICC was higher in healthy eyes compared to eyes with macular oedema (0.877 versus 0.960; p < 0.001) and in the superficial vascular plexus versus the deep vascular complex (0.967 versus 0.888; p = 0.001). The quantitative analysis of the effect of the averaging showed that averaged images had a mean gain of 790.4 pixels/box, located around or completing interruptions in the vessel walls, and a mean loss of 727.2 pixels/box. The qualitative analysis of the averaged images showed that 99.6% of boxes in the averaged images had a gain in vessel detection (i.e., vessels detected in the averaged image but not in the non-averaged image). The loss of pixels was due to a reduction in background noise and motion artifacts in all cases and no case of loss of vessel detection was observed. CONCLUSION: The automatic VD measurement using the OptoVue HD device showed a good repeatability in 5 acquisitions in a row setting. Averaging images increased vessel detection, and in about a third of boxes, decreased the background noise, both in healthy eyes and, in a greater proportion, in eyes with macular oedema.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Olho/diagnóstico por imagem , Edema Macular/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Adulto , Idoso , Olho/irrigação sanguínea , Feminino , Angiofluoresceinografia , Voluntários Saudáveis , Humanos , Macula Lutea/diagnóstico por imagem , Macula Lutea/patologia , Edema Macular/patologia , Masculino , Retina/diagnóstico por imagem , Retina/patologia , Vasos Retinianos/patologia , Tomografia de Coerência Óptica , Adulto Jovem
4.
Nat Commun ; 12(1): 6011, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650057

RESUMO

Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind this is poorly studied. Herein, we develop a method that combines magnetic beads and flow cytometry cell sorting to isolate pericytes from tumors and normal adjacent tissues from patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). Pericytes from tumors show defective blood vessel supporting functions when comparing to those obtained from normal tissues. Mechanistically, combined proteomics and metabolic flux analysis reveals elevated hexokinase 2(HK2)-driven glycolysis in tumor pericytes, which up-regulates their ROCK2-MLC2 mediated contractility leading to impaired blood vessel supporting function. Clinically, high percentage of HK2 positive pericytes in blood vessels correlates with poor patient overall survival in NSCLC and HCC. Administration of a HK2 inhibitor induces pericyte-MLC2 driven tumor vasculature remodeling leading to enhanced drug delivery and efficacy against tumor growth. Overall, these data suggest that glycolysis in tumor pericytes regulates their blood vessel supporting role.


Assuntos
Vasos Sanguíneos/anormalidades , Glicólise , Hexoquinase/metabolismo , Neoplasias de Tecido Vascular/metabolismo , Pericitos/metabolismo , Células A549 , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Hexoquinase/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/metabolismo , Neoplasias/metabolismo , Neoplasias de Tecido Vascular/tratamento farmacológico , Neoplasias de Tecido Vascular/genética , Neoplasias de Tecido Vascular/patologia , Microambiente Tumoral/fisiologia , Regulação para Cima , Quinases Associadas a rho
5.
Life Sci ; 284: 119925, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480933

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction and is frequent in people with type 2 diabetes mellitus. In diabetic patients, increased levels of the eicosanoid 12-hydroxyeicosatetraenoic acid (12-HETE) are linked to vascular dysfunction. Here, we aimed to identify the importance of 12-HETE in type 2 diabetic patients exhibiting diastolic dysfunction, and mice exhibiting HFpEF and whether targeting 12-HETE is a means to ameliorate HFpEF progression by improving vascular function in diabetes. MATERIAL AND METHODS: Subjects with diagnosed type 2 diabetes mellitus and reported diastolic dysfunction or healthy controls were recruited and 12(S)-HETE levels determined by ELISA. 12(S)-HETE levels were determined in type 2 diabetic, leptin receptor deficient mice (LepRdb/db) and HFpEF verified by echocardiography. Mitochondrial function, endothelial function and capillary density were assessed using Seahorse technique, pressure myography and immunohistochemistry in LepRdb/db or non-diabetic littermate controls. 12/15Lo generation was inhibited using ML351 and 12(S)-HETE action by using the V1-cal peptide. KEY FINDINGS: Endothelium-dependent vasodilation and mitochondrial functional capacity both improved in response to either application of ML351 or the V1-cal peptide. Correlating to improved vascular function, mice treated with either pharmacological agent exhibited improved diastolic filling and left ventricular relaxation that correlated with increased myocardial capillary density. SIGNIFICANCE: Our results suggest that 12-HETE may serve as a biomarker indicating endothelial dysfunction and the resulting cardiovascular consequences such as HFpEF in type 2 diabetic patients. Antagonizing 12-HETE is a potent means to causally control HFpEF development and progression in type 2 diabetes by preserving vascular function.


Assuntos
Vasos Sanguíneos/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Volume Sistólico/fisiologia , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Idoso , Animais , Diástole , Células Endoteliais/metabolismo , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Camundongos , Mitocôndrias/metabolismo , Canais de Cátion TRPV/metabolismo , Vasodilatação
6.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502102

RESUMO

Every cell in the body requires oxygen for its functioning, in virtually every animal, and a tightly regulated system that balances oxygen supply and demand is therefore fundamental. The vascular network is one of the first systems to sense oxygen, and deprived oxygen (hypoxia) conditions automatically lead to a cascade of cellular signals that serve to circumvent the negative effects of hypoxia, such as angiogenesis associated with inflammation, tumor development, or vascular disorders. This vascular signaling is driven by central transcription factors, namely the hypoxia inducible factors (HIFs), which determine the expression of a growing number of genes in endothelial cells and pericytes. HIF functions are tightly regulated by oxygen sensors known as the HIF-prolyl hydroxylase domain proteins (PHDs), which are enzymes that hydroxylate HIFs for eventual proteasomal degradation. HIFs, as well as PHDs, represent attractive therapeutic targets under various pathological settings, including those involving vascular (dys)function. We focus on the characteristics and mechanisms by which vascular cells respond to hypoxia under a variety of conditions.


Assuntos
Proteínas Angiogênicas/metabolismo , Vasos Sanguíneos/metabolismo , Hipóxia Celular , Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/metabolismo , Proteínas Angiogênicas/genética , Animais , Vasos Sanguíneos/crescimento & desenvolvimento , Vasos Sanguíneos/fisiologia , Redes Reguladoras de Genes , Humanos , Fator 1 Induzível por Hipóxia/genética , Neovascularização Fisiológica
7.
Cells ; 10(9)2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34571851

RESUMO

Solid tumors in advanced cancer often feature a structurally and functionally abnormal vasculature through tumor angiogenesis, which contributes to cancer progression, metastasis, and therapeutic resistances. Hypoxia is considered a major driver of angiogenesis in tumor microenvironments. However, there remains a lack of in vitro models that recapitulate both the vasculature and hypoxia in the same model with physiological resemblance to the tumor microenvironment, while allowing for high-content spatiotemporal analyses for mechanistic studies and therapeutic evaluations. We have previously constructed a hypoxia microdevice that utilizes the metabolism of cancer cells to generate an oxygen gradient in the cancer cell layer as seen in solid tumor sections. Here, we have engineered a new composite microdevice-microfluidics platform that recapitulates a vascularized hypoxic tumor. Endothelial cells were seeded in a collagen channel formed by viscous fingering, to generate a rounded vascular lumen surrounding a hypoxic tumor section composed of cancer cells embedded in a 3-D hydrogel extracellular matrix. We demonstrated that the new device can be used with microscopy-based high-content analyses to track the vascular phenotypes, morphology, and sprouting into the hypoxic tumor section over a 7-day culture, as well as the response to different cancer/stromal cells. We further evaluated the integrity/leakiness of the vascular lumen in molecular delivery, and the potential of the platform to study the movement/trafficking of therapeutic immune cells. Therefore, our new platform can be used as a model for understanding tumor angiogenesis and therapeutic delivery/efficacy in vascularized hypoxic tumors.


Assuntos
Microfluídica/instrumentação , Neoplasias/irrigação sanguínea , Microambiente Tumoral/fisiologia , Vasos Sanguíneos/fisiologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Matriz Extracelular/metabolismo , Humanos , Hipóxia/patologia , Microfluídica/métodos , Modelos Biológicos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Oxigênio/metabolismo , Células Estromais/metabolismo
8.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576086

RESUMO

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2α. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca2+-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC/cGMP/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC/cGMP axis in VSMCs to increase myofilament Ca2+ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents.


Assuntos
Pressão Sanguínea , Vasos Sanguíneos/fisiologia , GMP Cíclico/metabolismo , Proteínas com Domínio LIM/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Feminino , Masculino , Camundongos Knockout , Modelos Biológicos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Norepinefrina/farmacologia , Transdução de Sinais , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores/farmacologia
9.
J Mech Behav Biomed Mater ; 124: 104835, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34530301

RESUMO

Fibrin is used successfully as a biological matrix in various bioengineering approaches. Its unique combination of autologous availability, hemocompatibility and biological activity makes it an almost ideal matrix material for vascular tissue engineering. However, clinical application of fibrin-based bioartificial blood vessels is still limited due to insufficient mechanical stability and stiffness of fibrin matrices. Biomechanical properties of fibrin-based constructs can potentially be modified by adjusting matrix density. Thus, as an attempt to optimize strength and elasticity of fibrin matrices for vascular tissue engineering applications, we developed a simple and reproducible method for transluminal compression of small-diameter fibrin-based vessels: After initial polymerization of high-concentration fibrin matrices in a vascular mold, vessels were compressed using an intraluminal angioplasty balloon. Vessels compacted with different pressures were compared for ultimate strength, elastic and structural properties and cellularization capacity. Transluminal compression increased fibrin network density and facilitated rapid production of homogenous vessels with a length of 10 cm. Compared to non-compressed controls, compacted fibrin vessels showed superior maximal burst pressure (199.8 mmHg vs. 94.0 mmHg), physiological elastic properties similar to the elastic behavior of natural arteries and higher luminal endothelial cell coverage (98.6% vs. 34.6%). Thus, transluminal compaction represents a suitable technique to enhance biomechanical properties of fibrin-based bioartificial vessels while preserving the biological advantages of this promising biomaterial.


Assuntos
Fibrina , Tecidos Suporte , Materiais Biocompatíveis , Prótese Vascular , Vasos Sanguíneos , Engenharia Tecidual
10.
Cells ; 10(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34440838

RESUMO

A current hypothesis is that transforming growth factor-ß signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.


Assuntos
Ativinas/metabolismo , Vasos Sanguíneos/metabolismo , Miostatina/metabolismo , Calcificação Vascular/patologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Humanos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Calcificação Vascular/metabolismo , Remodelação Vascular
11.
Viruses ; 13(7)2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34372552

RESUMO

The SARS-CoV-2 virus causing COVID-19 disease has emerged expeditiously in the world and has been declared pandemic since March 2020, by World Health Organization (WHO). The destructive effects of SARS-CoV-2 infection are increased among the patients with pre-existing chronic conditions and, in particular, this review focuses on patients with underlying cardiovascular complications. The expression pattern and potential functions of SARS-CoV-2 binding receptors and the attributes of SARS-CoV-2 virus tropism in a physio-pathological state of heart and blood vessel are precisely described. Of note, the atheroprotective role of ACE2 receptors is reviewed. A detailed description of the possible detrimental role of SARS-CoV-2 infection in terms of vascular leakage, including endothelial glycocalyx dysfunction and bradykinin 1 receptor stimulation is concisely stated. Furthermore, the potential molecular mechanisms underlying SARS-CoV-2 induced clot formation in association with host defense components, including activation of FXIIa, complements and platelets, endothelial dysfunction, immune cell responses with cytokine-mediated action are well elaborated. Moreover, a brief clinical update on patient with COVID-19 disease with underlying cardiovascular complications and those who had new onset of cardiovascular complications post-COVID-19 disease was also discussed. Taken together, this review provides an overview of the mechanistic aspects of SARS-CoV-2 induced devastating effects, in vital organs such as the heart and vessels.


Assuntos
COVID-19/imunologia , COVID-19/metabolismo , Doenças Cardiovasculares/virologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Vasos Sanguíneos/virologia , Doenças Cardiovasculares/metabolismo , Coração/virologia , Humanos , Pandemias
12.
Nat Commun ; 12(1): 4872, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381052

RESUMO

The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B's necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.


Assuntos
Apoptose , Vasos Sanguíneos/crescimento & desenvolvimento , Receptores de Netrina/metabolismo , Isoformas de RNA/metabolismo , Processamento Alternativo , Animais , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/metabolismo , Células Endoteliais , Humanos , Morfogênese , Neovascularização Patológica/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de Netrina/genética , Netrina-1/metabolismo , Isoformas de RNA/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Análise de Sobrevida , Peixe-Zebra
13.
Cells ; 10(7)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34359937

RESUMO

Chronic kidney disease is associated with extremely high cardiovascular mortality. The circadian rhythms (CR) have an impact on vascular function. The disruption of CR causes serious health problems and contributes to the development of cardiovascular diseases. Uremia may affect the master pacemaker of CR in the hypothalamus. A molecular circadian clock is also expressed in peripheral tissues, including the vasculature, where it regulates the different aspects of both vascular physiology and pathophysiology. Here, we address the impact of CKD on the intrinsic circadian clock in the vasculature. The expression of the core circadian clock genes in the aorta is disrupted in CKD. We propose a novel concept of the disruption of the circadian clock system in the vasculature of importance for the pathology of the uremic vasculopathy.


Assuntos
Vasos Sanguíneos/fisiopatologia , Relógios Circadianos , Insuficiência Renal Crônica/fisiopatologia , Animais , Relógios Circadianos/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Insuficiência Renal Crônica/genética , Doenças Vasculares/genética , Doenças Vasculares/fisiopatologia
14.
Cells ; 10(8)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34440805

RESUMO

Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to interact with other somatic cell types, which is distinct from developing vascular cells in vivo. Recently, it was demonstrated that blood vessel organoids (BVOs) recreate the structure and functions of developing human blood vessels. However, the tissue-specific adaptability of BVOs had not been assessed in somatic tissues. Herein, we investigated whether BVOs infiltrate human cerebral organoids and form a blood-brain barrier. As a result, vascular cells arising from BVOs penetrated the cerebral organoids and developed a vessel-like architecture composed of CD31+ endothelial tubes coated with SMA+ or PDGFR+ mural cells. Molecular markers of the blood-brain barrier were detected in the vascularized cerebral organoids. We revealed that BVOs can form neural-specific blood-vessel networks that can be maintained for over 50 days.


Assuntos
Vasos Sanguíneos/fisiologia , Encéfalo/irrigação sanguínea , Neovascularização Fisiológica/fisiologia , Organoides/irrigação sanguínea , Vasos Sanguíneos/citologia , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/metabolismo , Encéfalo/citologia , Técnicas de Cocultura , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio/citologia , Endotélio/metabolismo , Humanos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Organoides/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo
15.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198654

RESUMO

Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.


Assuntos
Vasos Sanguíneos/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Vasos Linfáticos/metabolismo , Transdução de Sinais , Animais , Humanos
16.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204949

RESUMO

Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , MAP Quinase Quinase 4/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Vasos Sanguíneos/enzimologia , Vasos Sanguíneos/crescimento & desenvolvimento , Fibroblastos/enzimologia , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/embriologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/genética , Macrófagos/enzimologia
17.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34203038

RESUMO

Heavy metals are toxic environmental pollutants associated with severe ecological and human health risks. Among them is mercury (Hg), widespread in air, soil, and water, due to its peculiar geo-biochemical cycle. The clinical consequences of Hg exposure include neurotoxicity and nephrotoxicity. Furthermore, increased risk for cardiovascular diseases is also reported due to a direct effect on cardiovascular tissues, including endothelial cells, recently identified as important targets for the harmful action of heavy metals. In this review, we will discuss the rationale for the potential use of erythrocytes as a surrogate model to study Hg-related toxicity on the cardiovascular system. The toxic effects of Hg on erythrocytes have been amply investigated in the last few years. Among the observed alterations, phosphatidylserine exposure has been proposed as an underlying mechanism responsible for Hg-induced increased proatherogenic and prothrombotic activity of these cells. Furthermore, following Hg-exposure, a decrease in NOS activity has also been reported, with consequent lowering of NO bioavailability, thus impairing endothelial function. An additional mechanism that may induce a decrease in NO availability is the generation of an oxidative microenvironment. Finally, considering that chronic Hg exposure mainly occurs through contaminated foods, the protective effect of dietary components is also discussed.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiopatologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Metais Pesados/toxicidade , Animais , Vasos Sanguíneos/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Suscetibilidade a Doenças , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Poluentes Ambientais/efeitos adversos , Humanos , Mercúrio/toxicidade , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
18.
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
19.
J Exp Med ; 218(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34269788

RESUMO

Necrotizing enterocolitis (NEC) is a severe gastrointestinal complication of prematurity. Using suspension and imaging mass cytometry coupled with single-cell RNA sequencing, we demonstrate severe inflammation in patients with NEC. NEC mucosa could be subtyped by an influx of three distinct neutrophil phenotypes (immature, newly emigrated, and aged). Furthermore, CD16+CD163+ monocytes/Mϕ, correlated with newly emigrated neutrophils, were specifically enriched in NEC mucosa, found adjacent to the blood vessels, and increased in circulation of infants with surgical NEC, suggesting trafficking from the periphery to areas of inflammation. NEC-specific monocytes/Mϕ transcribed inflammatory genes, including TREM1, IL1A, IL1B, and calprotectin, and neutrophil recruitment genes IL8, CXCL1, CXCL2, CXCL5 and had enrichment of gene sets in pathways involved in chemotaxis, migration, phagocytosis, and reactive oxygen species generation. In summary, we identify a novel subtype of inflammatory monocytes/Mϕ associated with NEC that should be further evaluated as a potential biomarker of surgical NEC and a target for the development of NEC-specific therapeutics.


Assuntos
Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Enterocolite Necrosante/patologia , Mucosa Gástrica/patologia , Monócitos/patologia , Receptores de Superfície Celular , Receptores de IgG , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Vasos Sanguíneos/patologia , Estudos de Casos e Controles , Quimiotaxia , Enterocolite Necrosante/cirurgia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Lactente , Recém-Nascido , Intestino Delgado/irrigação sanguínea , Intestino Delgado/patologia , Monócitos/imunologia , Neutropenia/etiologia , Neutropenia/patologia , Neutrófilos/patologia , Fagocitose/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Análise de Sequência de RNA , Análise de Célula Única
20.
Cells ; 10(6)2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204799

RESUMO

Studies of adipose tissue biology have demonstrated that adipose tissue should be considered as both passive, energy-storing tissue and an endocrine organ because of the secretion of adipose-specific factors, called adipokines. Adiponectin is a well-described homeostatic adipokine with metabolic properties. It regulates whole-body energy status through the induction of fatty acid oxidation and glucose uptake. Adiponectin also has anti-inflammatory and antidiabetic properties, making it an interesting subject of biomedical studies. Perivascular adipose tissue (PVAT) is a fat depot that is conterminous to the vascular wall and acts on it in a paracrine manner through adipokine secretion. PVAT-derived adiponectin can act on the vascular wall through endothelial cells and vascular smooth muscle cells. The present review describes adiponectin's structure, receptors, and main signaling pathways. We further discuss recent studies of the extent and nature of crosstalk between PVAT-derived adiponectin and endothelial cells, vascular smooth muscle cells, and atherosclerotic plaques. Furthermore, we argue whether adiponectin and its receptors may be considered putative therapeutic targets.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Vasos Sanguíneos/metabolismo , Homeostase/fisiologia , Animais , Aterosclerose/metabolismo , Vasos Sanguíneos/patologia , Células Endoteliais/metabolismo , Humanos , Músculo Liso Vascular/metabolismo
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