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Pulmonary hypertension (PH) is a chronic progressive vascular disease characterized by abnormal pulmonary vascular resistance and pulmonary artery pressure. The major structural alteration during PH is pulmonary vascular remodelling, which is mainly caused by the imbalance between proliferation and apoptosis of pulmonary vascular cells. Previously, it was thought that apoptosis was the only type of programmed cell death (PCD). Soon afterward, other types of PCD have been identified, including autophagy, pyroptosis, ferroptosis and necroptosis. In this review, we summarize the role of the above five forms of PCD in mediating pulmonary vascular remodelling, and discuss their guiding significance for PH treatment. The current review could provide a better understanding of the correlation between PCD and pulmonary vascular remodelling, contributing to identify new PCD-associated drug targets for PH.
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Apoptose , Hipertensão Pulmonar , Remodelação Vascular , Humanos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Animais , Necroptose , Transdução de Sinais , Autofagia , Ferroptose , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , PiroptoseRESUMO
AIMS: Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with development of vascular calcification (VC) in chronic kidney disease (CKD). Although recent studies have been focusing on associations of CPPs with presence of VC in CKD, insights in the underlying processes and mechanisms by which CPPs might aggravate VC and vascular dysfunction in vivo are currently lacking. Here, we assessed overall burden of abdominal VC in healthy kidney donors and CKD patients, and subsequently performed transcriptome profiling in vascular tissue obtained from these subjects, linking outcome to CPP counts and calcification propensity. METHODS AND RESULTS: Calcification scores were quantified in renal arteries, iliac arteries and abdominal aorta, using computed tomography (CT) scans of kidney donors and CKD patients. Vascular tissue was collected from kidney donors (renal artery) and CKD patients (iliac artery), after which bulk RNA sequencing and gene set enrichment analysis (GSEA) was performed on a subset of patients. Calcification propensity (crystallization time, T50) was measured using nephelometry, and CPP counts with microparticle flow cytometric analysis. Increased calcification scores (based on CT) were found in CKD patients compared to kidney donors. Transcriptome profiling revealed enrichment for processes related to endothelial activation, inflammation, extracellular matrix (ECM) remodelling and ossification in CKD vascular biopsies compared to kidney donors. Calcification propensity was increased in CKD, as well as CPP counts, of which the latter significantly associated with markers of vascular remodelling. CONCLUSIONS: Our findings reveal that CKD is characterized by systemic VC with increased calcification propensity and CPP counts. Transcriptome profiling showed altered vascular gene expression with enrichment for endothelial activation, inflammation, ECM remodelling and ossification. Moreover, we demonstrate for the first time that vascular remodelling processes are associated with increased circulating CPP counts. Interventions targeting CPPs are promising avenues for alleviating vascular remodelling and VC in CKD.
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We previously reported pulmonary arterial remodelling and active endothelial to mesenchymal transition (EndMT) in smokers and patients with early COPD. In this study, we aimed to evaluate the role of different drivers of EndMT. Immunohistochemical staining for EndMT drivers, TGF-ß1, pSMAD-2/3, SMAD-7, and ß-catenin, was performed on lung resections from 46 subjects. Twelve were non-smoker-controls (NC), six normal lung function smokers (NLFS), nine patients with small-airway diseases (SAD), nine mild-moderate COPD-current smokers (COPD-CS) and ten COPD-ex-smokers (COPD-ES). Histopathological measurements were done using Image ProPlus softwarev7.0. We observed lower levels of total TGF-ß1 (p<0.05) in all smoking groups than in the non-smoking control (NC). Across arterial sizes, smoking groups exhibited significantly higher (p <0.05) total and individual layer pSMAD-2/3 and SMAD-7 than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared to NC. Total ß-catenin expression was significantly higher in smoking groups across arterial sizes (p <0.05), except for COPD-ES and NLFS groups in small and medium arteries, respectively. Increased total ß-catenin was positively correlated with total S100A4 in small and medium arteries (r= 0.35, 0.50; p=0.02, 0.01, respectively), with vimentin in medium arteries (r=0.42, p=0.07), and with arterial thickness of medium and large arteries (r= 0.34, 0.41, p=0.02, 0.01, respectively). This is the first study uncovering active endothelial SMAD pathway independent of TGF-ß1 in smokers, SAD, and COPD patients. Increased expression of ß-catenin indicates its potential interaction with SMAD pathway, warranting further research to identify the deviation of this classical pathway.
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Hypoxic pulmonary hypertension (HPH) is a serious and life-threatening chronic cardiopulmonary disease characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular remodeling. Mesenchymal stem cell- derived exosomes (MSC-Exos) can relieve HPH by reversing pulmonary vascular remodeling. The HPH model was established in healthy male Sprague-Dawley (SD) rats aged 6 to 8 weeks. The rats were placed in a room with oxygen concentration of (10 ± 1) % for 8 hours a day over 28 days, were then injected intravenously with MSC-Exos (100 ug protein/kg) or equal-volume phosphate buffer saline (PBS) once a day over 1 week. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and pulmonary vascular remodeling were observed after anesthesia. In addition, platelet-derived growth factor BB (PDGF-BB) was used to stimulate rat pulmonary artery smooth muscle cells (PASMCs) to construct HPH pathological cell models. The results showed that MSC-Exos could not only reduce the elevation of RVSP, right ventricular hypertrophy and the degree of pulmonary vascular remodeling in HPH rats, but also reduce the proliferation, migration and apoptosis resistance of PASMCs. Finally, GSE53408 and GSE113439 datasets were analyzed and showed that the expression of Hsp90aa1 and pERK/ERK were significantly increased in HPH, also could be inhibited by MSC-Exos. Meanwhile, inhibition of Hsp90aa1 also reduced PASMCs migration and pERK/ERK protein level. In conclusion, MSC-Exos alleviated HPH by suppressing PASMCs proliferation, migration and apoptosis resistance through inhibiting the Hsp90aa1/ERK/pERK pathway.
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Exossomos , Proteínas de Choque Térmico HSP90 , Hipertensão Pulmonar , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais , Ratos Sprague-Dawley , Animais , Exossomos/metabolismo , Exossomos/transplante , Masculino , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/terapia , Células-Tronco Mesenquimais/metabolismo , Ratos , Proteínas de Choque Térmico HSP90/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Hipóxia/metabolismo , Hipóxia/terapia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologiaRESUMO
Optimal vascular structure and function are essential for maintaining the physiological functions of the cardiovascular system. Vascular remodelling involves changes in vessel structure, including its size, shape, cellular and molecular composition. These changes result from multiple risk factors and may be compensatory adaptations to sustain blood vessel function. They occur in diverse cardiovascular pathologies, from hypertension to heart failure and atherosclerosis. Dynamic changes in the endothelium, fibroblasts, smooth muscle cells, pericytes or other vascular wall cells underlie remodelling. In addition, immune cells, including macrophages and lymphocytes, may infiltrate vessels and initiate inflammatory signalling. They contribute to a dynamic interplay between cell proliferation, apoptosis, migration, inflammation, and extracellular matrix reorganisation, all critical mechanisms of vascular remodelling. Molecular pathways underlying these processes include growth factors (e.g., vascular endothelial growth factor and platelet-derived growth factor), inflammatory cytokines (e.g., interleukin-1ß and tumour necrosis factor-α), reactive oxygen species, and signalling pathways, such as Rho/ROCK, MAPK, and TGF-ß/Smad, related to nitric oxide and superoxide biology. MicroRNAs and long noncoding RNAs are crucial epigenetic regulators of gene expression in vascular remodelling. We evaluate these pathways for potential therapeutic targeting from a clinical translational perspective. In summary, vascular remodelling, a coordinated modification of vascular structure and function, is crucial in cardiovascular disease pathology.
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Doenças Cardiovasculares , Hipertensão , Inflamação , Remodelação Vascular , Humanos , Inflamação/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/metabolismo , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Animais , Estresse Oxidativo , Transdução de Sinais , OxirreduçãoRESUMO
In the seemingly well-researched field of vascular research, there are still many underestimated factors and molecular mechanisms. In recent years, SUMOylation has become increasingly important. SUMOylation is a post-translational modification in which small ubiquitin-related modifiers (SUMO) are covalently attached to target proteins. Sites where these SUMO modification processes take place in the cell nucleus are PML nuclear bodies (PML-NBs) - multiprotein complexes with their essential main component and organizer, the PML protein. PML and SUMO, either alone or as partners, influence a variety of cellular processes, including regulation of transcription, senescence, DNA damage response and defence against microorganisms, and are involved in innate immunity and inflammatory responses. They also play an important role in maintaining homeostasis in the vascular system and in pathological processes leading to the development and progression of cardiovascular diseases. This review summarizes information about the function of SUMO(ylation) and PML(-NBs) in the human vasculature from angiogenesis to disease and highlights their clinical potential as drug targets.
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Proteínas Nucleares , Proteína da Leucemia Promielocítica , Sumoilação , Fatores de Transcrição , Humanos , Proteína da Leucemia Promielocítica/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas Supressoras de Tumor/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologiaRESUMO
PURPOSE: To document vascular changes in eyes with post-fever retinitis (PFR) pre and post treatment demonstrated using optical coherence tomography angiography (OCTA). METHODS: This is a retrospective observational case series wherein patients with PFR were retrospectively evaluated for changes in the retinal vasculature during the course of disease using OCTA. RESULTS: At presentation, OCTA revealed flow void areas in superficial and deep capillary plexus (SCP and DCP) corresponding to the areas of retinitis. Post treatment, OCTA showed a significant decrease in the flow void areas with the appearance of new capillary network in both SCP and DCP. The optical coherence tomography also demonstrated normalization of retinal architecture over time. It is speculated that the good visual outcome in PFR could be attributed to the normalization of retinal architecture and remodelling in retinal vasculature. CONCLUSION: OCTA being non-invasive can be used to understand and quantify the extent of vascular remodelling in PFR.
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BACKGROUND: Intracranial atherosclerosis, a leading cause of stroke, involves arterial plaque formation. This study explores the link between plaque remodelling patterns and diabetes using high-resolution vessel wall imaging (HR-VWI). AIM: To investigate the factors of intracranial atherosclerotic remodelling patterns and the relationship between intracranial atherosclerotic remodelling and diabetes mellitus using HR-VWI. METHODS: Ninety-four patients diagnosed with middle cerebral artery or basilar artery atherosclerosis were enrolled. Their basic clinical data were collected, and HR-VWI was performed. The vascular area at the plaque (VAMLN) and normal reference vessel (VAreference) were delineated and measured using image postprocessing software, and the Remodelling index (RI) was calculated. According to the value of the RI, the patients were divided into a positive remodelling (PR) group, intermediate remodelling (IR) group, negative remodelling (NR) group, PR group and non-PR (N-PR) group. RESULTS: The PR group exhibited a higher prevalence of diabetes and serum cholesterol levels than the IR and NR groups [45.2%, 4.54 (4.16, 5.93) vs 25%, 4.80 ± 1.22 and 16.4%, 4.14 (3.53, 4.75), respectively, P < 0.05]. The diabetes incidence was also significantly greater in the PR group than in the N-PR group (45.2% vs 17.5%, P < 0.05). Furthermore, the PR group displayed elevated serum triglyceride and cholesterol levels compared to the N-PR group [1.64 (1.23, 2.33) and 4.54 (4.16, 5.93) vs 4.54 (4.16, 5.93) and 4.24 (3.53, 4.89), P < 0.05]. Logistic regression analysis revealed diabetes mellitus as an independent influencing factor in plaque-PR [odds ratio (95% confidence interval): 3.718 (1.207-11.454), P < 0.05]. CONCLUSION: HR-VWI can clearly show the morphology and signal characteristics of intracranial vascular walls and plaques. Intracranial atherosclerotic plaques in diabetic patients are more likely to show PR, suggesting poor plaque stability and a greater risk of stroke.
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Diseases of the central nervous system (CNS) are often associated with vascular disturbances or inflammation and frequently both. Consequently, endothelial cells and macrophages are key cellular players that mediate pathology in many CNS diseases. Macrophages in the brain consist of the CNS-associated macrophages (CAMs) [also referred to as border-associated macrophages (BAMs)] and microglia, both of which are close neighbours or even form direct contacts with endothelial cells in microvessels. Recent progress has revealed that different macrophage populations in the CNS and a subset of brain endothelial cells are derived from the same erythromyeloid progenitor cells. Macrophages and endothelial cells share several common features in their life cycle-from invasion into the CNS early during embryonic development and proliferation in the CNS, to their demise. In adults, microglia and CAMs have been implicated in regulating the patency and diameter of vessels, blood flow, the tightness of the blood-brain barrier, the removal of vascular calcification, and the life-time of brain endothelial cells. Conversely, CNS endothelial cells may affect the polarization and activation state of myeloid populations. The molecular mechanisms governing the pas de deux of brain macrophages and endothelial cells are beginning to be deciphered and will be reviewed here.
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Encéfalo , Células Endoteliais , Encéfalo/patologia , Macrófagos , Sistema Nervoso Central/patologia , MicrogliaRESUMO
Background: We have previously reported that endothelial-to-mesenchymal transition (EndMT) is an active process in patients with idiopathic pulmonary fibrosis (IPF) contributing to arterial remodelling. Here, we aim to quantify drivers of EndMT in IPF patients compared to normal controls (NCs). Methods: Lung resections from thirteen IPF patients and eleven NCs were immunohistochemically stained for EndMT drivers, including TGF-ß1, pSmad-2/3, Smad-7, and ß-catenin. Intima, media, and adventitia were analysed for expression of each EndMT driver in pulmonary arteries. Computer- and microscope-assisted Image ProPlus7.0 image analysis software was used for quantifications. Results: Significant TGF-ß1, pSmad-2/3, Smad-7, and ß-catenin expression was apparent across all arterial sizes in IPF (p < 0.05). Intimal TGF-ß1, pSmad-2/3, Smad-7, and ß-catenin were augmented in the arterial range of 100-1000 µm (p < 0.001) compared to NC. Intimal TGF-ß1 and ß-catenin percentage expression showed a strong correlation with the percentage expression of intimal vimentin (r' = 0.54, p = 0.05 and r' = 0.61, p = 0.02, respectively) and intimal N-cadherin (r' = 0.62, p = 0.03 and r' = 0.70, p = 0.001, respectively). Intimal TGF-ß1 and ß-catenin expression were significantly correlated with increased intimal thickness as well (r' = 0.52, p = 0.04; r' = 0.052, p = 0.04, respectively). Moreover, intimal TGF-ß1 expression was also significantly associated with increased intimal elastin deposition (r' = 0.79, p = 0.002). Furthermore, total TGF-ß1 expression significantly impacted the percentage of DLCO (r' = -0.61, p = 0.03). Conclusions: This is the first study to illustrate the involvement of active TGF-ß/Smad-2/3-dependent and ß-catenin-dependent Wnt signalling pathways in driving EndMT and resultant pulmonary arterial remodelling in patients with IPF. EndMT is a potential therapeutic target for vascular remodelling and fibrosis in general in patients with IPF.
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AIMS: Pulmonary arterial hypertension (PAH) is characterized by extensive pulmonary arterial remodelling. Although mesenchymal stem cell (MSC)-derived exosomes provide protective effects in PAH, MSCs exhibit limited senescence during in vitro expansion compared with the induced pluripotent stem cells (iPSCs). Moreover, the exact mechanism is not known. METHODS AND RESULTS: In this study, we used murine iPSCs generated from mouse embryonic fibroblasts with triple factor (Oct4, Klf4, and Sox2) transduction to determine the efficacy and action mechanism of iPSC-derived exosomes (iPSC-Exo) in attenuating PAH in rats with monocrotaline (MCT)-induced pulmonary hypertension. Both early and late iPSC-Exo treatment effectively prevented the wall thickening and muscularization of pulmonary arterioles, improved the right ventricular systolic pressure, and alleviated the right ventricular hypertrophy in MCT-induced PAH rats. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-Exo treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by iPSC-Exo with suppression of PCNA, cyclin D1, MMP-1, and MMP-10, which are mediated via the HIF-1α and P21-activated kinase 1/AKT/Runx2 pathways. CONCLUSION: IPSC-Exo are effective at reversing pulmonary hypertension by reducing pulmonary vascular remodelling and may provide an iPSC-free therapy for the treatment of PAH.
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Exossomos , Hipertensão Pulmonar , Células-Tronco Pluripotentes Induzidas , Hipertensão Arterial Pulmonar , Ratos , Animais , Camundongos , Hipertensão Arterial Pulmonar/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Remodelação Vascular , Exossomos/metabolismo , Fibroblastos/metabolismo , Hipertensão Pulmonar Primária Familiar/metabolismo , Artéria Pulmonar , Monocrotalina/efeitos adversos , Monocrotalina/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismoRESUMO
Hypoxia-induced vasoconstriction and vascular remodelling are the main pathological features of hypoxic pulmonary arterial hypertension (HPAH), and inflammation is participated in the occurrence of pulmonary vascular remodelling (PVR). Matrine is an alkaloid with the effects of anti-inflammation, antifibrosis and antitumour. But, few studies have explored the role of matrine in regulating PVR, and the related mechanisms are still unknown. In this study, we found that hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibited its apoptosis, reduced the expression of ribosomal protein s5 and activated the nuclear factor kappa-B (NF-κB) signalling. Matrine, sildenafil and NF-κB inhibitor Bay 11-7082 could reverse these changes and impel the cell cycle in phase S retardation, and reduced the expression of p50, p65, proliferating cell nuclear antigen (PCNA), Bcl-2. In addition, matrine could lower right ventricular systolic pressure and mean pulmonary artery pressure of rats, α-smooth muscle actin and PCNA expression in pulmonary artery media, the levels of tumor necrosis factor-α and interleuki-1ß, thus improved hypoxia-induced PVR. This study indicated that matrine could alleviate inflammation and improve PVR through reversing the imbalance of proliferation and apoptosis of PASMCs, thus it had a therapeutic effect on HPAH.
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Hidralazina/análogos & derivados , Hipertensão Pulmonar , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Matrinas , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Remodelação Vascular , Proliferação de Células , Hipóxia/complicações , Hipóxia/metabolismo , Inflamação/metabolismo , Miócitos de Músculo Liso/metabolismo , HidrazonasRESUMO
OBJECTIVE: Pressure overload can result in significant changes to the structure of blood vessels, a process known as vascular remodeling. High levels of tension can cause vascular inflammation, fibrosis, and structural alterations to the vascular wall. Prior research from our team has demonstrated that the oral administration of alamandine can promote vasculoprotective effects in mice aorta that have undergone transverse aortic constriction (TAC). Furthermore, changes in local hemodynamics can affect the right and left carotid arteries differently after TAC. Thus, in this study, we aimed to assess the effects of alamandine treatment on right carotid remodeling and the expression of oxidative stress-related substances induced by TAC. METHODS AND RESULTS: Male C57BL/6 mice were categorized into three groups: Sham, TAC, and TAC treated with alamandine (TAC+ALA). Alamandine treatment was administered orally by gavage (30 µg/kg/day), starting three days before the surgery, and continuing for a period of fourteen days. Morphometric analysis of hematoxylin and eosin-stained sections revealed that TAC induced hypertrophic and positive remodeling in the right carotid artery. Picrosirius Red staining also demonstrated an increase in total collagen deposition in the right carotid artery due to TAC-induced vascular changes. Alamandine treatment effectively prevented the increase in reactive oxygen species production and depletion of nitric oxide levels, which were induced by TAC. Finally, alamandine treatment was also shown to prevent the increased expression of nuclear factor erythroid 2-related factor 2 and 3-nitrotyrosine that were induced by TAC. CONCLUSION: Our results suggest that alamandine can effectively attenuate pathophysiological stress in the right carotid artery of animals subjected to TAC.
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Artérias Carótidas , Estresse Oxidativo , Masculino , Camundongos , Animais , Constrição , Camundongos Endogâmicos C57BL , Artérias Carótidas/cirurgia , Remodelação Ventricular , Modelos Animais de DoençasRESUMO
Cerebral vasospasm significantly contributes to poor prognosis and mortality in patients with aneurysmal subarachnoid hemorrhage. Current research indicates that the pathological and physiological mechanisms of cerebral vasospasm may be attributed to the exposure of blood vessels to toxic substances, such as oxyhaemoglobin and inflammation factors. These factors disrupt cerebral vascular homeostasis. Vascular homeostasis is maintained by the extracellular matrix (ECM) and related cell surface receptors, such as integrins, characterised by collagen deposition, collagen crosslinking, and elastin degradation within the vascular ECM. It involves interactions between the ECM and smooth muscle cells as well as endothelial cells. Its biological activities are particularly crucial in the context of cerebral vasospasm. Therefore, regulating ECM homeostasis may represent a novel therapeutic target for cerebral vasospasm. This review explores the potential pathogenic mechanisms of cerebral vasospasm and the impacts of ECM protein metabolism on the vascular wall during ECM remodelling. Additionally, we underscore the significance of an ECM protein imbalance, which can lead to increased ECM stiffness and activation of the YAP pathway, resulting in vascular remodelling. Lastly, we discuss future research directions.
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Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/metabolismo , Vasoespasmo Intracraniano/patologia , Células Endoteliais/metabolismo , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , ColágenoRESUMO
Arteriovenous malformation (AVM) is an anomaly of blood vessel formation. Numerous models have been established to understand the nature of AVM. These models have limitations in terms of the diameter of the vessels used and the impact on the circulatory system. Our goal was to establish an AVM model that does not cause prompt and significant hemodynamic and cardiac alterations but is feasible for follow-up of the AVM's progression. Sixteen female rats were randomly divided into sham-operated and AVM groups. In the AVM group, the saphenous vein and artery were interconnected using microsurgical techniques. The animals were followed up for 12 weeks. Anastomosis patency and the structural and hemodynamic changes of the heart were monitored. The hearts and vessels were histologically analyzed. During the follow-up period, shunts remained unobstructed. Systolic, diastolic, mean arterial pressure, and heart rate values slightly and non-significantly decreased in the AVM group. Echocardiogram results indicated minor systolic function impact, with slight and insignificant changes in aortic pressure and blood velocity, and minimal left ventricular wall enlargement. The small-caliber saphenous AVM model does not cause acute hemodynamic changes. Moderate but progressive alterations and venous dilatation confirmed AVM-like features. The model seems to be suitable for studying further the progression, enlargement, or destabilization of AVM.
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BACKGROUND: The goal of this study was to evaluate macular microvascular changes in patients with Fabry disease (FD) using optical coherence tomography angiography (OCTA) and to explore their correlation with laboratory and ocular findings. METHODS: A total of 76 eyes (38 patients) and 48 eyes of 24 healthy controls were enrolled in this prospective study. Vessel Area Density (VAD) and Foveal Avascular Zone (FAZ) area were calculated on 2.9 × 2.9 mm OCTA images scanned with the Heidelberg Spectralis II (Heidelberg, Germany). VAD was measured in three layers: Superficial Vascular Plexus (SVP), Intermediate Capillary Plexus (ICP), and Deep Capillary Plexus (DCP). All scans were analyzed with the EA-Tool (Version 1.0), which was coded in MATLAB (The MathWorks Inc, R2017b). FAZ area was manually measured in full-thickness, SVP, ICP and DCP scans. RESULTS: Average VAD in SVP, ICP and DCP was higher in Fabry disease patients than in controls (49.4 ± 11.0 vs. 26.5 ± 6.2, 29.6 ± 7.4 vs. 20.2 ± 4.4, 32.3 ± 8.8 vs. 21.7 ± 5.1 respectively, p < 0.001). Patients with cornea verticillata (CV) had a higher VAD in ICP and DCP compared to patients without CV (p < 0.01). Patients with increased lysoGb3 concentration had a higher VAD in DCP when compared to patients with normal lysoGb3 concentration (p < 0.04). There was no difference in VAD in patients with and without vascular tortuosity. However, a significantly higher VAD was observed in patients with vascular tortuosity compared to controls (p < 0.03). CONCLUSIONS: Increased lysoGb3 and VAD in DCP could be reliable biomarkers of disease activity. Cornea verticillata could be adopted as a predictive biomarker for VAD changes and disease progression. The combination of cornea verticillata and increased VAD may serve as a diagnostic biomarker for Fabry disease, however due to the discrepancies in VAD values in various studies, further research has to be done to address this claim.
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Distrofias Hereditárias da Córnea , Doença de Fabry , Humanos , Angiofluoresceinografia/métodos , Vasos Retinianos , Estudos Prospectivos , Doença de Fabry/diagnóstico , Acuidade Visual , BiomarcadoresRESUMO
Vascular remodelling is an adaptive response to physiological and pathological stimuli that leads to structural and functional changes in the vascular intima, media, and adventitia. Pathological vascular remodelling is a hallmark feature of numerous vascular diseases, including atherosclerosis, hypertension, abdominal aortic aneurysm, pulmonary hypertension and preeclampsia. Autophagy is critical in maintaining cellular homeostasis, and its dysregulation has been implicated in the pathogenesis of various diseases, including vascular diseases. However, despite emerging evidence, the role of autophagy and its dual effects on vascular remodelling has garnered limited attention. Autophagy can exert protective and detrimental effects on the vascular intima, media and adventitia, thereby substantially influencing the course of vascular remodelling and its related vascular diseases. Currently, there has not been a review that thoroughly describes the regulation of autophagy in vascular remodelling and its impact on related diseases. Therefore, this review aimed to bridge this gap by focusing on the regulatory roles of autophagy in diseases related to vascular remodelling. This review also summarizes recent advancements in therapeutic agents targeting autophagy to regulate vascular remodelling. Additionally, this review offers an overview of recent breakthroughs in therapeutic agents targeting autophagy to regulate vascular remodelling. A deeper understanding of how autophagy orchestrates vascular remodelling can drive the development of targeted therapies for vascular diseases.
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Aneurisma da Aorta Abdominal , Hipertensão Pulmonar , Hipertensão , Humanos , Remodelação Vascular , Hipertensão/patologia , AutofagiaRESUMO
In arteries and arterioles, a chronic increase in blood pressure raises wall tension. This continuous biomechanical strain causes a change in gene expression in vascular smooth muscle cells (VSMCs) that may lead to pathological changes. Here we have characterised the functional properties of lipoma-preferred partner (LPP), a Lin11-Isl1-Mec3 (LIM)-domain protein, which is most closely related to the mechanotransducer zyxin but selectively expressed by smooth muscle cells, including VSMCs in adult mice. VSMCs isolated from the aorta of LPP knockout (LPP-KO) mice displayed a higher rate of proliferation than their wildtype (WT) counterparts, and when cultured as three-dimensional spheroids, they revealed a higher expression of the proliferation marker Ki 67 and showed greater invasion into a collagen gel. Accordingly, the gelatinase activity was increased in LPP-KO but not WT spheroids. The LPP-KO spheroids adhering to the collagen gel responded with decreased contraction to potassium chloride. The relaxation response to caffeine and norepinephrine was also smaller in the LPP-KO spheroids than in their WT counterparts. The overexpression of zyxin in LPP-KO VSMCs resulted in a reversal to a more quiescent differentiated phenotype. In native VSMCs, i.e., in isolated perfused segments of the mesenteric artery (MA), the contractile responses of LPP-KO segments to potassium chloride, phenylephrine or endothelin-1 did not vary from those in isolated perfused WT segments. In contrast, the myogenic response of LPP-KO MA segments was significantly attenuated while zyxin-deficient MA segments displayed a normal myogenic response. We propose that LPP, which we found to be expressed solely in the medial layer of different arteries from adult mice, may play an important role in controlling the quiescent contractile phenotype of VSMCs.
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Lipoma , Músculo Liso Vascular , Camundongos , Animais , Zixina/metabolismo , Músculo Liso Vascular/metabolismo , Cloreto de Potássio/metabolismo , Colágeno/metabolismo , Fatores de Transcrição/metabolismo , Miócitos de Músculo Liso/metabolismo , Lipoma/metabolismo , Lipoma/patologiaRESUMO
PURPOSE: To investigate ocular and systemic factors associated with the retinal arterial wall-to-lumen ratio (WLR) and to determine the relative contribution of genetic and environmental variation to WLR in healthy adults. METHODS: This cross-sectional twin study included 78 monozygotic and 67 dizygotic same-sex twin pairs aged 58.4 ± 9.8 (mean ± SD) years. Lumen diameter (LD) and outer diameter (OD) of a superotemporal retinal artery were measured using adaptive optics fundus photography, and the WLR was calculated. Linear mixed model regression analysis of associations with WLR comprised the descriptive variables ocular axial length (AL), intraocular pressure (IOP), height, weight, body mass index (BMI), smoking, blood pressure, high density (HDL), low density (LDL) and very low density (VLDL) lipoproteins, total cholesterol and triglycerides. The relative influence of genes and environment on WLR was calculated through polygenetic modelling. RESULTS: Increasing age and arterial blood pressure were associated with a higher WLR, while increasing retinal artery OD and ocular AL were associated with a lower WLR. Sex, smoking status, BMI, IOP, cholesterol levels or triglycerides had no detectable impact on the WLR. Broad-sense heritability of WLR was 21% (95% CI: 1-41%), while environmental factors accounted for the remaining 79% of the interindividual variance (95% CI: 59-99%). CONCLUSION: Retinal artery wall thickness was closely linked to increasing age and higher arterial blood pressure, the latter being mediated by the environment over genes.
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Prolonged vasoconstrictor signalling found in hypertension, increases arterial contraction, and alters vessel architecture by stimulating arterial smooth muscle cell (ASMC) growth, underpinning the development of re-stenosis lesions and vascular remodelling. Vasoconstrictors interact with their cognate G protein coupled receptors activating a variety of signalling pathways to promote smooth muscle proliferation. Here, angiotensin II (AngII) and endothelin 1 (ET1), but not UTP stimulates ASMC proliferation. Moreover, siRNA-mediated depletion of endogenous GRK2 expression, or GRK2 inhibitors, compound 101 or paroxetine, prevented AngII and ET1-promoted ASMC growth. Depletion of GRK2 expression or inhibition of GRK2 activity ablated the prolonged phase of AngII and ET-stimulated ERK signalling, while enhancing and prolonging UTP-stimulated ERK signalling. Increased GRK2 expression enhanced and prolonged AngII and ET1-stimulated ERK signalling, but suppressed UTP-stimulated ERK signalling. In ASMC prepared from 6-week-old WKY and SHR, AngII and ET1-stimulated proliferation rates were similar, however, in cultures prepared from 12-week-old rats AngII and ET1-stimulated growth was enhanced in SHR-derived ASMC, which was reversed following depletion of GRK2 expression. Furthermore, in ASMC cultures isolated from 6-week-old WKY and SHR rats, AngII and ET1-stimulated ERK signals were similar, while in cultures from 12-week-old rats ERK signals were both enhanced and prolonged in SHR-derived ASMC, and were reversed to those seen in age-matched WKY-derived ASMC following pre-treatment of SHR-derived ASMC with compound 101. These data indicate that the presence of GRK2 and its catalytic activity are essential to enable pro-proliferative vasoconstrictors to promote growth via recruitment and activation of the ERK signalling pathway in ASMC.