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1.
Biomater Adv ; 163: 213938, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38959650

RESUMO

Endothelial cells are constantly exposed to mechanical stimuli, of which mechanical stretch has shown various beneficial or deleterious effects depending on whether loads are within physiological or pathological levels, respectively. Vascular properties change with age, and on a cell-scale, senescence elicits changes in endothelial cell mechanical properties that together can impair its response to stretch. Here, high-rate uniaxial stretch experiments were performed to quantify and compare the stretch-induced damage of monolayers consisting of young, senescent, and aged endothelial populations. The aged and senescent phenotypes were more fragile to stretch-induced damage. Prominent damage was detected by immunofluorescence and scanning electron microscopy as intercellular and intracellular void formation. Damage increased proportionally to the applied level of deformation and, for the aged and senescent phenotype, induced significant detachment of cells at lower levels of stretch compared to the young counterpart. Based on the phenotypic difference in cell-substrate adhesion of senescent cells indicating more mature focal adhesions, a discrete network model of endothelial cells being stretched was developed. The model showed that the more affine deformation of senescent cells increased their intracellular energy, thus enhancing the tendency for cellular damage and impending detachment. Next to quantifying for the first-time critical levels of endothelial stretch, the present results indicate that young cells are more resilient to deformation and that the fragility of senescent cells may be associated with their stronger adhesion to the substrate.

2.
Pulm Circ ; 14(3): e12379, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38962184

RESUMO

Acute kidney injury (AKI) causes distant organ dysfunction through yet unknown mechanisms, leading to multiorgan failure and death. The lungs are one of the most common extrarenal organs affected by AKI, and combined lung and kidney injury has a mortality as high as 60%-80%. One mechanism that has been implicated in lung injury after AKI involves molecules released from injured kidney cells (DAMPs, or damage-associated molecular patterns) that promote a noninfectious inflammatory response by binding to pattern recognition receptors (PRRs) constitutively expressed on the pulmonary endothelium. To date there are limited data investigating the role of PRRs and DAMPs in the pulmonary endothelial response to AKI. Understanding these mechanisms holds great promise for therapeutics aimed at ameliorating the devastating effects of AKI. In this study, we stimulate primary human microvascular endothelial cells with DAMPs derived from injured primary renal tubular epithelial cells (RTECs) as an ex-vivo model of lung injury following AKI. We show that DAMPs derived from injured RTECs cause activation of Toll-Like Receptor and NOD-Like Receptor signaling pathways as well as increase human primary pulmonary microvascular endothelial cell (HMVEC) cytokine production, cell signaling activation, and permeability. We further show that cytokine production in HMVECs in response to DAMPs derived from RTECs is reduced by the inhibition of NOD1 and NOD2, which may have implications for future therapeutics. This paper adds to our understanding of PRR expression and function in pulmonary HMVECs and provides a foundation for future work aimed at developing therapeutic strategies to prevent lung injury following AKI.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38949891

RESUMO

Purpose: To protect the corneal endothelium, various ophthalmical viscoelastic devices (OVDs) are used during cataract surgery. In this study, we compared two sodium hyaluronate-based OVD, the bacteria-derived FIDIAL PLUS OVD (test) with the animal-derived IAL®-F OVD (reference) during the surgical procedure. Methods: Fifty patients with bilateral cataract participated in the study: 50 eyes randomly received FIDIAL PLUS and 50 eyes received IAL®-F (ratio 1:1). Noninferior efficacy of FIDIAL PLUS compared with reference OVD (first objective) was evaluated using a paired t-test comparing the mean percent loss of corneal endothelial cells (CECs) with FIDIAL PLUS against the mean percent loss with IAL®-F. Corneal endothelial protection during cataract surgery with FIDIAL PLUS without significant (≥30 mmHg) postoperative intraocular pressure (IOP) increase (main secondary objective) was assessed using a repeated measures logistic model comparing the incidence of significant postoperative IOP elevation between the two groups. Safety, tolerability, and efficacy were also evaluated by assessing secondary endpoints before and after surgery. Results: FIDIAL PLUS showed a statistically noninferior efficacy compared with IAL®-F; there was no significant increase in IOP in either group or different trends of the secondary endpoints were observed between the OVD groups. The safety profile was similar in both OVD groups and no adverse device effects were reported. Conclusions: This study demonstrates the equivalent efficacy, tolerability, and safety of the bacteria-derived FIDIAL PLUS compared with the animal-derived IAL®-F, confirming the clinical value of this product.

4.
World J Diabetes ; 15(6): 1122-1141, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38983824

RESUMO

Endothelial function plays a pivotal role in cardiovascular health, and dysfunction in this context diminishes vasorelaxation concomitant with endothelial activity. The nitric oxide-cyclic guanosine monophosphate pathway, prostacyclin-cyclic adenosine monophosphate pathway, inhibition of phosphodiesterase, and the opening of potassium channels, coupled with the reduction of calcium levels in the cell, constitute critical mechanisms governing vasorelaxation. Cardiovascular disease stands as a significant contributor to morbidity and mortality among individuals with diabetes, with adults afflicted by diabetes exhibiting a heightened cardiovascular risk compared to their non-diabetic counterparts. A plethora of medicinal plants, characterized by potent pharmacological effects and minimal side effects, holds promise in addressing these concerns. In this review, we delineate various medicinal plants and their respective biochemical constituents, showcasing concurrent vasorelaxant and anti-diabetic activities.

5.
Transfusion ; 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38973502

RESUMO

BACKGROUND: Septic shock is associated with high morbidity and mortality, the endothelium plays an important role. Crystalloids is standard of care to maintain intravascular volume. Plasma is associated with improved endothelial integrity and restoration of the glycocalyx layer. We evaluated the efficacy and safety aspects of cell-free and pathogen inactivated pooled plasma (OctaplasLG®) as resuscitation in septic shock patients. STUDY DESIGN AND METHODS: This randomized, investigator-initiated phase IIa trial ran at a Danish single center intensive care unit, from 2017 to 2019. Patients were 18 years of age or older with septic shock and randomized to fluid optimization with OctaplasLG® or Ringer-acetate in the first 24 h. The primary endpoints were changes in biomarkers indicative of endothelial activation, damage, and microvascular perfusion from baseline to 24 h. Safety events and mortality were assessed during 90 days. RESULTS: Forty-four patients were randomized, 20 to OctaplasLG versus 24 to Ringer-acetate. The median age was 69, and 55% were men. Median Sequential Organ Failure Assessment score was 13. Baseline differences favoring the Ringer-acetate group were observed. The OctaplasLG® group was resuscitated with 740 mL plasma and the Ringer-acetate group with 841 mL crystalloids. There was no significant change in the microvascular perfusion or five biomarkers except VEGFR1 change, which was higher in patients receiving OctaplasLG® 0.12(SD 0.37) versus Ringer-acetate -0.24 (SD 0.39), with mean difference 0.36 (95% CI, 0.13-0.59, p = .003) in favor of Ringer-acetate. DISCUSSION: This study found that fluid resuscitation with OctaplasLG® in critically ill septic shock patients is feasible. Baseline confounding prevented assessment of the potential effect of OctaplasLG®.

7.
Semin Immunopathol ; 46(1-2): 3, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38990363

RESUMO

Sustained tumor angiogenesis, i.e., the induction and maintenance of blood vessel growth by tumor cells, is one of the hallmarks of cancer. The vascularization of malignant tissues not only facilitates tumor growth and metastasis, but also contributes to immune evasion. Important players in all these processes are the endothelial cells which line the luminal side of blood vessel. In the tumor vasculature, these cells are actively involved in angiogenesis as well in the hampered recruitment of immune cells. This is the result of the abnormal tumor microenvironment which triggers both angiostimulatory and immune inhibitory gene expression profiles in endothelial cells. In recent years, it has become evident that galectins constitute a protein family that is expressed in the tumor endothelium. Moreover, several members of this glycan-binding protein family have been found to facilitate tumor angiogenesis and stimulate immune suppression. All this has identified galectins as potential therapeutic targets to simultaneously hamper tumor angiogenesis and alleviate immune suppression. The current review provides a brief introduction in the human galectin protein family. The current knowledge regarding the expression and regulation of galectins in endothelial cells is summarized. Furthermore, an overview of the role that endothelial galectins play in tumor angiogenesis and tumor immunomodulation is provided. Finally, some outstanding questions are discussed that should be addressed by future research efforts. This will help to fully understand the contribution of endothelial galectins to tumor progression and to exploit endothelial galectins for cancer therapy.


Assuntos
Galectinas , Neoplasias , Neovascularização Patológica , Microambiente Tumoral , Humanos , Neoplasias/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/irrigação sanguínea , Galectinas/metabolismo , Galectinas/imunologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/imunologia , Animais , Microambiente Tumoral/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/imunologia , Imunomodulação , Angiogênese
8.
bioRxiv ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38948838

RESUMO

Endothelial tissues are essential mechanosensors in the vasculature and facilitate adaptation to various blood flow-induced mechanical cues. Defects in endothelial mechanoresponses can perturb tissue remodelling and functions leading to cardiovascular disease progression. In this context, the precise mechanisms of endothelial mechanoresponses contributing to normal and diseased tissue functioning remain elusive. Here, we sought to uncover how flow-mediated transcriptional regulation drives endothelial mechanoresponses in healthy and atherosclerotic-prone tissues. Using bulk RNA sequencing, we identify novel mechanosensitive genes in response to healthy unidirectional flow (UF) and athero-prone disturbed flow (DF). We find that the transcription as well as protein expression of Four-and-a-half LIM protein 2 (FHL2) are enriched in athero-prone DF both in vitro and in vivo. We then demonstrate that the exogenous expression of FHL2 is necessary and sufficient to drive discontinuous adherens junction morphology and increased tissue permeability. This athero-prone phenotype requires the force-sensitive binding of FHL2 to actin. In turn, the force-dependent localisation of FHL2 to stress fibres promotes microtubule dynamics to release the RhoGEF, GEF-H1, and activate the Rho-ROCK pathway. Thus, we unravelled a novel mechanochemical feedback wherein force-dependent FHL2 localisation promotes hypercontractility. This misregulated mechanoresponse creates highly permeable tissues, depicting classic hallmarks of atherosclerosis progression. Overall, we highlight crucial functions for the FHL2 force-sensitivity in tuning multi-scale endothelial mechanoresponses.

9.
Nutrients ; 16(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38999899

RESUMO

Background: Hypertension poses a significant global health burden and is associated with cardiovascular morbidity. Chios mastic gum (CMG), derived from Pistacia lentiscus var. Chia, shows potential as a phytotherapeutic agent, due to its multifaceted beneficial effects. However, its anti-hypertensive effects and vascular, circulatory, and renal-related dysfunction, have not been thoroughly investigated. Herein, we aimed to explore the antihypertensive potential of CMG, focusing on vascular and renal endothelium, in vivo. Methods: Two models of hypertension in male rats, induced by Angiotensin II and Deoxycorticosterone acetate (DOCA)-high-salt administration, were utilized. CMG was administered at 220 mg/kg daily for four weeks after hypertension onset and blood pressure was measured non-invasively. Whole blood RNA sequencing, metabolomics, real-time PCR, and Western blot analyses of kidney and aorta tissues were additionally performed. Results: CMG significantly lowered systolic, diastolic, and mean blood pressure in both models. RNA sequencing revealed that CMG modulated immunity in the Angiotensin II model and metabolism in the DOCA-HS model. CMG downregulated genes related to oxidative stress and endothelial dysfunction and upregulated endothelial markers such as Vegfa. Metabolomic analysis indicated improved endothelial homeostasis via lysophosphatidylinositol upregulation. Conclusions: CMG emerges as a potent natural antihypertensive therapy, demonstrating beneficial effects on blood pressure and renal endothelial function.


Assuntos
Anti-Hipertensivos , Pressão Sanguínea , Hipertensão , Pistacia , Animais , Pistacia/química , Masculino , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ratos , Rim/efeitos dos fármacos , Rim/metabolismo , Resina Mástique , Modelos Animais de Doenças , Angiotensina II , Ratos Sprague-Dawley , Acetato de Desoxicorticosterona , Estresse Oxidativo/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Extratos Vegetais/farmacologia
10.
Acta Physiol (Oxf) ; : e14201, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39007513

RESUMO

AIM: We aimed to test the hypothesis that a high-salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)-dependent mechanism. METHODS: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. RESULTS: We found HS-induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS-fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma-derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. CONCLUSION: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.

11.
Rom J Ophthalmol ; 68(2): 128-134, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006342

RESUMO

Aim: To compare corneal parameters in diabetics versus age-group-matched non-diabetics; also, to correlate these parameters with the duration of diabetes, glycated haemoglobin (HbA1c) levels, and severity levels of diabetic retinopathy (DR). Materials and methods: A comparative study was conducted at a tertiary eye-care center from January 2020 to December 2020. Two-hundred patients (400 eyes) with type-2 diabetes (100) and age-sex-matched non-diabetics (100) were included. Corneal morphological parameters like central corneal thickness (CCT), endothelial cell density (ECD), coefficient of variance (CoV), hexagonality (6A), and average cell area were recorded by specular microscopy. These parameters were correlated with the duration of diabetes, severity of disease based upon fasting blood glucose levels, HbA1c, and grade of DR. Mean and standard deviation were calculated, and regular distribution of continuous data was tested using independent sample t-test and ANOVA. Results: Mean ECD (2447.32 ± 269.89/mm2), 6A (45.03 ± 6.71%), and IOP (15.47 ± 2.02 mmHg) changed in diabetic cases and were significantly low in diabetics, whereas, mean average cell area (413 ± 50.19 mm2), standard deviation (167.05 ± 77.91), CCT (525.81 ± 36.69) and CoV (39.84 ± 15.59%), were significantly high in diabetics. Mean CCT had insignificant variation. Subgroup analysis within diabetics showed a statistically significant reduction of ECD, cell count, and 6A with increased duration of diabetes, poor glycaemic control, and raised HbA1c. Discussion: The corneal endothelial analysis is vital in daily clinical practice and provides valuable evidence concerning the viability of corneal endothelium in various intraocular surgeries. Uncontrolled DM harms the cornea with 70% of diabetics resulting in complications like keratopathy. The study highlighted that the increased duration of diabetes raised HbA1c, and poor glycemic control negatively affected corneal morphology. Our study showed a definite reduction in ECD and 6A in diabetics compared to non-diabetics. Conclusion: A definite reduction in the corneal endothelial counts, cell density, and hexagonality was found in type-2 diabetics compared to non-diabetics. Abbreviations: DM = Diabetes Mellitus, CCT = central corneal thickness, ECC = endothelial cell counts, ECD = endothelial cell density, CoV = coefficient of variance, 6A = hexagonality, DR = Diabetic retinopathy, SD = Standard of deviation, IOP = Intraocular pressure.


Assuntos
Glicemia , Córnea , Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Endotélio Corneano , Hemoglobinas Glicadas , Humanos , Feminino , Masculino , Glicemia/metabolismo , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Córnea/patologia , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/sangue , Endotélio Corneano/patologia , Contagem de Células , Idoso , Adulto , Paquimetria Corneana , Estudos Retrospectivos
12.
Chin Med J Pulm Crit Care Med ; 2(2): 80-87, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39006829

RESUMO

Endothelial cells (ECs) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. Pulmonary endothelial barrier integrity is maintained through coordinated cellular processes involving receptors, signaling molecules, junctional complexes, and protein-regulated cytoskeletal reorganization. In acute lung injury (ALI) or its more severe form acute respiratory distress syndrome (ARDS), the loss of endothelial barrier integrity secondary to endothelial dysfunction caused by severe pulmonary inflammation and/or infection leads to pulmonary edema and hypoxemia. Pro-inflammatory agonists such as histamine, thrombin, bradykinin, interleukin 1ß, tumor necrosis factor α, vascular endothelial growth factor, angiopoietin-2, and platelet-activating factor, as well as bacterial toxins and reactive oxygen species, cause dynamic changes in cytoskeletal structure, adherens junction disorganization, and detachment of vascular endothelial cadherin (VE-cadherin) from the actin cytoskeleton, leading to an increase in endothelial permeability. Endothelial interactions with leukocytes, platelets, and coagulation enhance the inflammatory response. Moreover, inflammatory infiltration and the associated generation of pro-inflammatory cytokines during infection cause EC death, resulting in further compromise of the structural integrity of lung endothelial barrier. Despite the use of potent antibiotics and aggressive intensive care support, the mortality of ALI is still high, because the mechanisms of pulmonary EC barrier disruption are not fully understood. In this review, we summarized recent advances in the studies of endothelial cytoskeletal reorganization, inter-endothelial junctions, endothelial inflammation, EC death, and endothelial repair in ALI and ARDS, intending to shed some light on the potential diagnostic and therapeutic targets in the clinical management of the disease.

13.
Bull Exp Biol Med ; 177(1): 115-123, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38963596

RESUMO

The cardiac perivascular niche is a cellular microenvironment of a blood vessel. The principles of niche regulation are still poorly understood. We studied the effect of TGFß1 on cells forming the cardiac perivascular niche using 3D cell culture (cardiospheres). Cardiospheres contained progenitor (c-Kit), endothelial (CD31), and mural (αSMA) cells, basement membrane proteins (laminin) and extracellular matrix proteins (collagen I, fibronectin). TGFß1 treatment decreased the length of CD31+ microvasculature, VE cadherin protein level, and proportion of NG2+ cells, and increased proportion of αSMA+ cells and transgelin/SM22α protein level. We supposed that this effect is related to the stabilizing function of TGFß1 on vascular cells: decreased endothelial cell proliferation, as shown for HUVEC, and activation of mural cell differentiation.


Assuntos
Diferenciação Celular , Proliferação de Células , Fator de Crescimento Transformador beta1 , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Diferenciação Celular/efeitos dos fármacos , Humanos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Animais , Proteínas dos Microfilamentos/metabolismo , Proteínas dos Microfilamentos/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Caderinas/metabolismo , Laminina/metabolismo , Laminina/farmacologia , Proteínas Musculares/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/citologia , Fibronectinas/metabolismo , Fibronectinas/farmacologia , Antígenos CD/metabolismo , Miocárdio/metabolismo , Miocárdio/citologia , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/fisiologia , Colágeno Tipo I/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/citologia , Técnicas de Cultura de Células em Três Dimensões/métodos
14.
J Clin Med ; 13(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38999352

RESUMO

Background: Age and sex are the most significant risk of factors for advanced Fuchs dystrophy. Nevertheless, few data are available on the hormone's receptor pattern expressed in adult and advanced fuchs endothelial corneal dystrophy (FECD). We investigated the impact of gender, growth factors and extracellular matrix (ECM) regulatory proteins expressed by the dystrophic endothelia. Methods: Ten dystrophic endothelial tissues and 10 normal endothelial sheets (corneoscleral specimens; Eye Bank) were used for this characterization study. Hormones' receptors (ERα, AR, PR, SHBG), few growth factors (VEGFA, ßNGF, TGFß1), some ECM regulators (MMP1, MMP7) and few inflammatory cytokines (IFNγ, IL10) were analyzed by real-time RT-PCR. Results: ERα transcripts were significantly increased, AR and SHBG transcripts were decreased in Fuchs endothelia from female patients, and no changes were detected for PR transcripts. VEGFA, ßNGF and TGFß1 transcripts were upregulated in Fuchs' endothelia, but not significantly linked to gender. High MMP1 and low MMP7 transcripts' expression were detected in Fuchs' specimens, mainly in males than females. An increased IFNγ (Th1) transcript expression was observed in females than males, and a trend to increase for IL10 (Th2) transcripts was detected in males than females. Conclusions: Our findings clearly indicate that hormone receptors, growth factors and matrix mediators as well as a Th1 pathway are predominant in Fuchs' dystrophy, displaying a pattern of expression specific for the female phenotype. The differential expression of hormones' receptors and the Th1/Th2 ratio might prompt to new theories to be tested in vitro and in vivo models, such as the use of hormonal substitute for counteracting this endothelial cell lost.

15.
Int J Mol Sci ; 25(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39000380

RESUMO

Endothelial dysfunction often precedes the development of cardiovascular diseases, including heart failure. The cardioprotective benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2is) could be explained by their favorable impact on the endothelium. In this review, we summarize the current knowledge on the direct in vitro effects of SGLT2is on endothelial cells, as well as the systematic observations in preclinical models. Four putative mechanisms are explored: oxidative stress, nitric oxide (NO)-mediated pathways, inflammation, and endothelial cell survival and proliferation. Both in vitro and in vivo studies suggest that SGLT2is share a class effect on attenuating reactive oxygen species (ROS) and on enhancing the NO bioavailability by increasing endothelial nitric oxide synthase activity and by reducing NO scavenging by ROS. Moreover, SGLT2is significantly suppress inflammation by preventing endothelial expression of adhesion receptors and pro-inflammatory chemokines in vivo, indicating another class effect for endothelial protection. However, in vitro studies have not consistently shown regulation of adhesion molecule expression by SGLT2is. While SGLT2is improve endothelial cell survival under cell death-inducing stimuli, their impact on angiogenesis remains uncertain. Further experimental studies are required to accurately determine the interplay among these mechanisms in various cardiovascular complications, including heart failure and acute myocardial infarction.


Assuntos
Inibidores do Transportador 2 de Sódio-Glicose , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Humanos , Animais , Estresse Oxidativo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Inflamação/metabolismo , Inflamação/tratamento farmacológico
16.
Front Immunol ; 15: 1405364, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39021568

RESUMO

Introduction: As the body's first line of defense against disease and infection, neutrophils must efficiently navigate to sites of inflammation; however, neutrophil dysregulation contributes to the pathogenesis of numerous diseases that leave people susceptible to infections. Many of these diseases are also associated with changes to the protein composition of the extracellular matrix. While it is known that neutrophils and endothelial cells, which play a key role in neutrophil activation, are sensitive to the mechanical and structural properties of the extracellular matrix, our understanding of how protein composition in the matrix affects the neutrophil response to infection is incomplete. Methods: To investigate the effects of extracellular matrix composition on the neutrophil response to infection, we used an infection-on-a-chip microfluidic device that replicates a portion of a blood vessel endothelium surrounded by a model extracellular matrix. Model blood vessels were fabricated by seeding human umbilical vein endothelial cells on 2, 4, or 6 mg/mL type I collagen hydrogels. Primary human neutrophils were loaded into the endothelial lumens and stimulated by adding the bacterial pathogen Pseudomonas aeruginosa to the surrounding matrix. Results: Collagen concentration did not affect the cell density or barrier function of the endothelial lumens. Upon infectious challenge, we found greater neutrophil extravasation into the 4 mg/mL collagen gels compared to the 6 mg/mL collagen gels. We further found that extravasated neutrophils had the highest migration speed and distance in 2mg/mL gels and that these values decreased with increasing collagen concentration. However, these phenomena were not observed in the absence of an endothelial lumen. Lastly, no differences in the percent of extravasated neutrophils producing reactive oxygen species were observed across the various collagen concentrations. Discussion: Our study suggests that neutrophil extravasation and migration in response to an infectious challenge are regulated by collagen concentration in an endothelial cell-dependent manner. The results demonstrate how the mechanical and structural aspects of the tissue microenvironment affect the neutrophil response to infection. Additionally, these findings underscore the importance of developing and using microphysiological systems for studying the regulatory factors that govern the neutrophil response.


Assuntos
Movimento Celular , Células Endoteliais da Veia Umbilical Humana , Neutrófilos , Humanos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/fisiologia , Matriz Extracelular/metabolismo , Colágeno/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/imunologia , Dispositivos Lab-On-A-Chip , Ativação de Neutrófilo , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Células Cultivadas
17.
Angiogenesis ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38955953

RESUMO

The proliferation of the endothelium is a highly coordinated process to ensure the emergence, expansion, and homeostasis of the vasculature. While Bone Morphogenetic Protein (BMP) signaling fine-tunes the behaviors of endothelium in health and disease, how BMP signaling influences the proliferation of endothelium and therefore, modulates angiogenesis remains largely unknown. Here, we evaluated the role of Activin A Type I Receptor (ACVR1/ALK2), a key BMP receptor in the endothelium, in modulating the proliferation of endothelial cells. We show that ACVR1/ALK2 is a key modulator for the proliferation of endothelium in the retinal vessels. Loss of endothelial ALK2 leads to a significant reduction in endothelial proliferation and results in fewer branches/endothelial cells in the retinal vessels. Interestingly, venous endothelium appears to be more susceptible to ALK2 deletion. Mechanistically, ACVR1/ALK2 inhibits the expression of CDKN1A/p21, a critical negative regulator of cell cycle progression, in a SMAD1/5-dependent manner, thereby enabling the venous endothelium to undergo active proliferation by suppressing CDKN1A/p21. Taken together, our findings show that BMP signaling mediated by ACVR1/ALK2 provides a critical yet previously underappreciated input to modulate the proliferation of venous endothelium, thereby fine-tuning the context of angiogenesis in health and disease.

18.
Alzheimers Dement ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958537

RESUMO

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.

20.
Geroscience ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38980632

RESUMO

As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction.

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