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Adequate maternal dietary levels of one-carbon metabolites, such as folic acid and choline, play an important role in the closure of the neural tube in utero; however, the impact of deficiencies in one-carbon (1C) metabolism on offspring neurological function after birth remain undefined. Stroke is one of the leading causes of death and disability globally. The aim of our study was to determine the impact of maternal 1C nutritional deficiencies on cerebral and peripheral blood flow after ischemic stroke in adult female offspring. In this study, female mice were placed on either control (CD)-, folic acid (FADD)-, or choline (ChDD)-deficient diets before pregnancy. Female offspring were weaned onto a CD for the duration of the study. Ischemic stroke was induced in offspring and after 6 wk cerebral and peripheral blood flow velocity was measured using ultrasound imaging. Our data showed that 11.5-mo-old female offspring from ChDD mothers had reduced blood flow in the posterior cerebral artery compared with controls. In peripheral blood flow velocity measurements, we report an aging effect. These results emphasize the importance of maternal 1C diet in early life neuro-programming on long-term vasculature health.NEW & NOTEWORTHY We demonstrate that a maternal dietary deficiency in one-carbon (1C) metabolites result in reduced cerebral blood flow in adult female offspring after ischemic stroke, but the long-term effects are not present. This result points to the key role of the maternal diet in early life neuroprogramming, while emphasizing its effects on both fetal development and long-term cerebrovascular health.
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AVC Isquêmico , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Camundongos , Feminino , Animais , Humanos , Ácido Fólico/metabolismo , Dieta , Colina , Carbono , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
PURPOSE: Marfan syndrome (MFS) is a connective tissue disorder that affects skeletal, ocular, pulmonary, cardiovascular, and central nervous systems. Symptoms may lead to diminished quality of life (QoL) in individuals with MFS compared with healthy individuals. Currently, there is little evidence regarding the impact of MFS on swallowing and QoL. This study examined perceptions of swallowing difficulties and QoL among persons with MFS. METHOD: A total of 356 participants (1% response rate) with a self-reported diagnosis of MFS provided medication regime and completed a Quality-of-Life Index and a modified version of the SWAL-QOL used to assess 8 QOL concepts related to swallowing: burden, duration, desire, food choice, fear, mental health, social concerns, and fatigue. RESULTS: Dysphagia symptoms were reported by 62% (N = 356) of the participants. Analyses assessing correlations between responses to SWAL-QOL questions, QoL scores, and reported medications were conducted. Further, responses on the SWAL-QOL predicted QoL satisfaction, even after controlling for medications. Findings revealed that greater swallowing difficulty affects QoL satisfaction and overall QoL, but not QoL importance. Further, specific medications were associated with differences in swallowing difficulty as well as QoL satisfaction. CONCLUSIONS: The findings of the current study suggest that individuals with MFS may experience specific swallowing difficulties which impact QoL. Specific classes of drugs may also be associated with reported swallowing QoL and QoL satisfaction in MFS. These findings have implications for clinicians who work with individuals with MFS.
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Transtornos de Deglutição , Síndrome de Marfan , Humanos , Deglutição/fisiologia , Qualidade de Vida/psicologia , Estudos Transversais , Síndrome de Marfan/psicologia , Inquéritos e Questionários , Transtornos de Deglutição/etiologiaRESUMO
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients also experience pulmonary complications, which are poorly understood. Loss of basal nitric oxide (NO) production and vascular integrity has been implicated in MFS aortic root disease, yet their contribution to lung complications remains unknown. Because of its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 inhibitor, sildenafil (SIL), could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation, and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent microarray analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant down-regulation of connective tissue or transforming growth factor-ß signaling genes. Because phosphodiesterase-5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.
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Síndrome de Marfan , Artéria Pulmonar/fisiopatologia , Enfisema Pulmonar , Citrato de Sildenafila/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Feminino , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/fisiopatologia , Camundongos , Camundongos Mutantes , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/fisiopatologia , Enfisema Pulmonar/prevenção & controleRESUMO
Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal-regulated kinase signaling. In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo. Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.
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Dissecção Aórtica/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/metabolismo , Losartan/farmacologia , Síndrome de Marfan/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Dissecção Aórtica/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Losartan/uso terapêutico , Síndrome de Marfan/tratamento farmacológico , Camundongos , Camundongos Knockout , Receptor Tipo 1 de Angiotensina/genéticaRESUMO
PURPOSE: Marfan syndrome (MFS) is a connective tissue disorder that affects skeletal, ocular, pulmonary, cardiovascular, and central nervous systems. Psychological and physiologic symptoms may lead to diminished quality of life (QoL) in individuals with MFS compared with healthy individuals. Currently, there is little evidence regarding the impact of MFS on executive function and QoL. This study examined perceptions of executive function and QoL among persons with MFS. METHOD: A total of 318 participants with MFS completed surveys assessing perceptions of executive function abilities and QoL. Responses to executive function questions were grouped using principle component analysis. Responses to QoL questions were separated into overall QoL, questions dealing with satisfaction of QoL, and importance placed on aspect of QoL. RESULTS: Principle component analysis revealed that executive function difficulties, particularly mental fatigue, associated with MFS symptoms affect QoL satisfaction and total QoL. Interestingly, medication status did not significantly impact QoL, over and above executive function difficulties. CONCLUSIONS: The findings of the current study suggest that individuals with MFS may experience specific executive function difficulties which impact QoL. These findings also have implications for clinicians who work with individuals with MFS.
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Função Executiva/fisiologia , Síndrome de Marfan/patologia , Síndrome de Marfan/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação Pessoal , Autorrelato , Inquéritos e Questionários , Adulto JovemRESUMO
In a mouse model of Marfan syndrome, conventional Verhoeff-Van Gieson staining displays severe fragmentation, disorganization and loss of the aortic elastic fiber integrity. However, this method involves chemical fixatives and staining, which may alter the native morphology of elastin and collagen. Thus far, quantitative analysis of fiber damage in aorta and skin in Marfan syndrome has not yet been explored. In this study, we have used an advanced noninvasive and label-free imaging technique, multiphoton microscopy to quantify fiber fragmentation, disorganization, and total volumetric density of aortic and cutaneous elastin and collagen in a mouse model of Marfan syndrome. Aorta and skin samples were harvested from Marfan and control mice aged 3-, 6- and 9-month. Elastin and collagen were identified based on two-photon excitation fluorescence and second-harmonic-generation signals, respectively, without exogenous label. Measurement of fiber length indicated significant fragmentation in Marfan vs. control. Fast Fourier transform algorithm analysis demonstrated markedly lower fiber organization in Marfan mice. Significantly reduced volumetric density of elastin and collagen and thinner skin dermis were observed in Marfan mice. Cutaneous content of elastic fibers and thickness of dermis in 3-month Marfan resembled those in the oldest control mice. Our findings of early signs of fiber degradation and thinning of skin dermis support the potential development of a novel non-invasive approach for early diagnosis of Marfan syndrome.
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Aorta/metabolismo , Colágeno/metabolismo , Elastina/metabolismo , Síndrome de Marfan/metabolismo , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Pele/metabolismo , Fatores Etários , Animais , Colágeno/química , Elastina/química , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos MolecularesRESUMO
Maternal nutrition during pregnancy and lactation plays an important role in the neurodevelopment of offspring. One-carbon (1C) metabolism, which centers around folic acid and choline, as well as other B vitamins, plays a key role during the closure of the neural tube of the developing fetus. However, the impact of these maternal nutritional deficiencies during pregnancy on offspring health outcomes after birth remains relatively undefined. Furthermore, maternal dietary deficiencies in folic acid or choline may impact other health outcomes in offspring - making this a valuable model. This protocol aims to outline the procedure for inducing a deficiency in 1C metabolism in female mice through dietary modifications. Females are placed on diets at weaning, up to 2 months of age, for 4-6 weeks prior to mating and remain on diet throughout pregnancy and lactation. Offspring from these females can be evaluated for health outcomes. Females can be used multiple times to generate offspring, and tissues from females can be collected to measure for 1C metabolite measurements. This protocol provides an overview of how to induce maternal dietary deficiencies in folic acid or choline to study offspring health outcomes.
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Deficiência de Colina , Dieta , Deficiência de Ácido Fólico , Fenômenos Fisiológicos da Nutrição Materna , Ácido Fólico/metabolismo , Colina/metabolismo , Feminino , Animais , Camundongos , Deficiência de Ácido Fólico/patologia , Deficiência de Colina/patologiaRESUMO
Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It's well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diets prior to and during pregnancy and lactation. When offspring were 3-months of age, ischemic stroke was induced. One and half months later blood and brain tissue were collected. We measured levels of matrix-metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and report reduced levels of MMP-2 in both, with no changes observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.
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INTRODUCTION: Cardiopulmonary bypass is an essential component of cardiothoracic surgeries. However, significant complications such as systemic inflammatory response syndrome (SIRS) resulting from cardiopulmonary bypass (CPB) are a common occurrence due to contact between circulating blood and foreign surfaces that leads to platelet activation. It is suggested that different available CPB circuit coatings can potentially reduce platelet activation. However, there have been no published evidence-based reports confirming these claims. In addition, there is no well-established protocol for studying platelet activation biomarkers during CPB in vitro in a laboratory setting. METHODS: CPB was simulated in the laboratory using bovine blood in two different types of coated CPB circuits: Trillium® Biosurface by Medtronic, and XcoatingTM Surface by Terumo. Fresh bovine blood samples were collected and circulated through the CPB circuit following the standard protocol used in the operation rooms. Blood samples were then collected at 5 min, 30 min, and 55 min during the circulation. Blood plasmas were separated and subjected to enzyme-linked immunosorbent assay to measure most established platelet activation markers P-selectin, Platelet Factor 4 (PF4), Glycoprotein IIb/IIIa (GPIIb/IIIa), and ß-thromboglobulin (ß-TG) at different time points. RESULTS: The biomarker values at 30 min and 55 min were compared to the base values at 5 min for each type of CPB circuit. The results of the means from all measured biomarkers showed data measurements that indicated no significant variability within each coating. All collected data points fell within ±2 SD of the means, which was considered acceptable variations across technical replicates.⯠Conclusion: In this study, we were able to establish an in vitro protocol in the laboratory setting that is precise and reliable with minimum intra-variability. This established protocol will allow for future studies in which different coated CPB circuits can be compared for their effectiveness in blocking platelet activation during the CPB.
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Biomarcadores , Ponte Cardiopulmonar , Materiais Revestidos Biocompatíveis , Ativação Plaquetária , Ponte Cardiopulmonar/instrumentação , Ponte Cardiopulmonar/efeitos adversos , Ativação Plaquetária/fisiologia , Animais , Biomarcadores/sangue , Bovinos , Teste de Materiais/métodosRESUMO
PURPOSE: Marfan Syndrome (MFS) is a connective tissue disorder that affects skeletal, ocular, pulmonary, cardiovascular, and central nervous systems. Symptoms may lead to diminished quality of life (QoL) in individuals with MFS compared with healthy individuals. Currently, there is little evidence regarding the impact of MFS on voicing and QoL. This study examined perceptions of voicing difficulties and QoL among persons with MFS. METHOD: A total of 356 participants with a self-reported diagnosis of MFS completed the Quality-of-Life Index (QLI) and voice handicap index-10 (VHI-10) and provided medication regime. RESULTS: Some degree of voice handicap was reported by a majority of participants. Analyses assessing correlations between responses to the VHI-10, QLI scores, and reported medications were conducted. Specific medications and responses on the VHI-10 were significantly associated with QLI scores. Multiple regression analyses revealed that a summed VHI-10 score was the strongest predictor of QLI satisfaction, QLI importance, and overall QLI. CONCLUSIONS: The findings of the current study suggest that individuals with MFS may experience self-perceived phonatory dysfunction which impact QoL. Specific classes of drugs may also be associated with reported voice handicap and QoL satisfaction in MFS. These findings have implications for physicians and clinicians who work with individuals with MFS.
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Small volume chamber tensometric myography is a commonly used technique to evaluate the vascular contractility of small and large blood vessels in laboratory animals and small arteries isolated from human tissue. The technique allows researchers to maintain isolated blood vessels in a tightly controlled and standardized (near-physiological) setting, with the option of adjusting to various environmental factors, while challenging the isolated vessels with different pharmacological agents that can induce vasoconstriction or vasodilation. The myograph chamber also provides a platform to measure vascular reactivity in response to various hormones, inhibitors, and agonists that may impact the function of smooth muscle and endothelial layers separately or simultaneously. The blood vessel wall is a complex structure consisting of three different layers: the intima (endothelial layer), media (smooth muscle and elastin fibers), and adventitia (collagen and other connective tissue). To gain a clear understanding of the functional properties of each layer, it is critical to have access to an experimental platform and system that would allow for a combinational approach to study all three layers simultaneously. Such an approach demands access to a semi-physiological condition that would mimic the in vivo environment in an ex vivo setting. Small volume chamber tensometric myography has provided an ideal environment to evaluate the impact of environmental cues, experimental variables, or pharmacological agonists and antagonists on vascular properties. For many years, scientists have used the tensometric myograph technique to measure endothelial function and smooth muscle contractility in response to different agents. In this report, a small volume chamber tensometric myograph system is used to measure endothelial function in the isolated mouse aorta. This report focuses on how small volume chamber tensometric myography can be used to evaluate the functional integrity of the endothelium in small segments of a large artery such as the thoracic aorta.
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Aorta Torácica , Vasodilatação , Animais , Endotélio Vascular/fisiologia , Humanos , Camundongos , Miografia/métodos , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
Background: Connective tissue disorders such as Ehlers-Danlos Syndrome (EDS) can affect collagen and elastin content and structure, including weakening of tissues and vasculature, thus contributing to multiple systemic manifestations. Prior research has successfully focused on peripheral life-threatening manifestations resulting in increased life expectancy, yet clinical observations have warranted investigation of neurological vulnerability, where little is known. Compromised brain tissues and cerebrovasculature could leave these patients vulnerable to mild traumatic brain injury (TBI), with increased severity and duration of post-concussive symptoms and delayed recovery. Clinical reports in adults indicate that higher severity of symptoms after a mild TBI, such as a concussion, can unmask connective tissues disorders leading toward diagnosis. This clinical case report is an example of a pediatric patient with presumed Ehlers-Danlos syndrome who demonstrates increased vulnerability to mild TBI/concussion. Patient: A pediatric female patient presents with unexplained lingering post-concussive symptoms, including trouble sleeping, nausea, frontal headaches, dizziness, visual changes, fatigue, and left-sided weakness more than 6 months post-mild concussion. Patient history of hypermobility, joint derangement, soft tissue mobility, and bruising suggests a potential diagnosis of Ehlers-Danlos syndrome, which may explain symptom severity and length of recovery. Discussion: This case is the first documented instance of increased vulnerability to TBI in a pediatric patient with presumed Ehlers-Danlos syndrome. It highlights the need for awareness and prevention of injury in this vulnerable patient population, suggests more targeted therapeutic intervention for recovery, and demonstrates the need for preclinical research evaluating the influence of genetic mutations associated with connective tissue disorders on the central nervous system.
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Background Stiffer aortas are associated with a faster rate of aortic root (AoR) dilation and higher risk of aortic dissection in patients with Marfan syndrome. We have previously shown that mild aerobic exercise reduces aortic stiffness and rate of AoR dilation in a Marfan mouse model. In this study, we investigated if these results could be translated to pediatric patients with Marfan syndrome. Methods and Results We enrolled 24 patients with Marfan syndrome aged 8 to 19 years to participate in a 6-month physical activity intervention, excluding those with ventricular dysfunction or prior history of aortic surgery. We instructed patients to take 10 000 steps per day, tracked by an activity tracker. At baseline and 6 months, we measured AoR dimension, arterial stiffness, endothelial function, physical activity indices, inflammatory biomarkers, and coping scores. Controls consisted of 15 age-matched patients with Marfan syndrome. Twenty-four patients with Marfan syndrome (median age, 14.4 years [interquartile range {IQR}, 12.2-16.8], 14 male patients) were enrolled. Baseline assessment demonstrated that the majority of these patients were sedentary and had abnormal arterial health. Twenty-two patients completed the intervention and took an average of 7709±2177 steps per day (median, 7627 [IQR, 6344-9671]). Patients wore their Garmin trackers at a median of 92.8% (IQR, 84%-97%) of their intervention days. AoR Z score in the intervention group had a significantly lower rate of change per year compared with the controls (rate of change, -0.24 versus +0.008; P=0.01). Conclusions In this clinical intervention in pediatric patients with Marfan syndrome, we demonstrated that a simple physical activity intervention was feasible in this population and has the potential to decrease the AoR dilation rate. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT03567460.
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Síndrome de Marfan , Masculino , Animais , Camundongos , Síndrome de Marfan/complicações , Aorta Torácica , Nível de Saúde , Exercício FísicoRESUMO
There are no therapeutics that directly enhance chronic endothelial nitric oxide (NO) release, which is typically associated with vascular homeostasis. In contrast, angiotensin II (AngII) receptor type 1 (AT1R) blockers (ARBs) can attenuate AngII-mediated oxidative stress, which often leads to increased endothelial NO bioavailability. Herein, we investigate the potential presence of direct, AngII/AT1R-independent ARB class effects on endothelial NO release and how this may result in enhanced aortic wall homeostasis and endothelial NO-specific transcriptome changes. Treatment of mice with four different ARBs induced sustained, long-term inhibition of vascular contractility by up to 82% at 16 weeks and 63% at 2 weeks, an effect reversed by L-NAME and absent in endothelial NO synthase (eNOS) KO mice or angiotensin converting enzyme inhibitor captopril-treated animals. In absence of AngII or in tissues with blunted AT1R expression or incubated with an AT2R blocker, telmisartan reduced vascular tone, supporting AngII/AT1R-independent pleiotropism. Finally, telmisartan was able to inhibit aging- and Marfan syndrome (MFS)-associated aortic root widening in NO-sensitive, BP-independent fashions, and correct aberrant TGF-ß signaling. RNAseq analyses of aortic tissues identified early eNOS-specific transcriptome reprogramming of the aortic wall in response to telmisartan. This study suggests that ARBs are capable of major class effects on vasodilatory NO release in fashions that may not involve blockade of the AngII/AT1R pathway. Broader prophylactic use of ARBs along with identification of non-AngII/AT1R pathways activated by telmisartan should be investigated.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II , Antagonistas de Receptores de Angiotensina , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Camundongos , Óxido Nítrico/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Telmisartan/farmacologia , Remodelação VascularRESUMO
In this study, we compared the potencies of diosgenin, a plant-derived sapogenin structurally similar to estrogen and progesterone, on vascular smooth muscle functions ranging from contraction and migration to apoptosis. The effects of diosgenin on vascular smooth muscle cell viability and migration were measured using a primary mouse aortic smooth muscle cell culture. The effects of diosgenin on smooth muscle cell contraction and calcium signaling were investigated in the isolated mouse aorta using wire myography and confocal microscopy, respectively. Here, we report that in cultured cells diosgenin (≥ 25 µM) induces apoptosis as measured by the number of annexin V-positive cells and caspase-3 cleavage, while decreasing cell viability as indicated by protein kinase B/Akt phosphorylation. In addition, diosgenin blocks smooth muscle cell migration in a transwell Boyden chamber in response to serum treatment and response to injury in a cell culture system. Diosgenin (≥ 25 µM) also significantly blocks receptor-mediated calcium signals and smooth muscle contraction in the isolated aorta. There is no difference in the inhibitory effects of diosgenin on vascular smooth muscle contraction between the endothelium-intact and endothelium-denuded aortic segments, indicating that they are caused by altered smooth muscle activity. Our findings suggest that over the concentration range of 10 to 15 µM diosgenin may provide overall beneficial effects on diseased vascular smooth muscle cells by blocking migration and contraction without any significant cytopathic effects, implying a potential therapeutic value for diosgenin in vascular disorders.
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Cálcio/fisiologia , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Diosgenina/farmacologia , Homeostase/fisiologia , Miócitos de Músculo Liso/fisiologia , Animais , Cálcio/metabolismo , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacosRESUMO
Marfan syndrome (MFS) is a genetic disorder that results in accelerated aortic root widening and aneurysm. However, management of MFS patients with blood pressure (BP)-lowering medications, such as angiotensin II (AngII) receptor blocker (ARB) losartan, continues to pose challenges due to their questionable efficacy at attenuating the rate of aortic root widening in patients. Herein we investigate the anti-aortic root widening effects of a sub-BP-lowering dose valsartan, an ARB previously linked to non-BP lowering anti-remodeling effects. Despite absence of BP-lowering effects, valsartan attenuated MFS aortic root widening by 75.9%, which was similar to a hypotensive dose of losartan (79.4%) when assessed by ultrasound echocardiography. Medial thickening, elastic fiber fragmentation, and phospho-ERK signaling were also inhibited to a similar degree with both treatments. Valsartan and losartan decreased vascular contractility ex vivo between 60% and 80%, in a nitric oxide (NO)-sensitive fashion. Valsartan increased acetylcholine (Ach)-induced vessel relaxation and phospho-eNOS levels in the aortic vessel supporting BP-independent activation of protective endothelial function, which is critical to ARB-mediated aortic root stability. This study supports the concept of achieving aortic root stability with valsartan in absence of BP-lowering effects, which may help address efficacy and compliance issues with losartan-based MFS patient management.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Losartan/farmacologia , Síndrome de Marfan/fisiopatologia , Valsartana/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Aorta/fisiologia , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Losartan/uso terapêutico , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Valsartana/uso terapêuticoRESUMO
BACKGROUND: Aortic dilation, stiffening, and dissection are common and potentially lethal complications of Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), which involve abnormal transforming growth factor beta (TGF-ß) signalling. The relation of aortic dimensions, stiffness, and biomarker levels is unknown. The objective of this study was to measure aortic dimensions, stiffness, TGF-ß and matrix metalloproteinase (MMP) levels, and endothelial function in patients with MFS, and to compare TGF-ß levels in patients with MFS receiving different therapeutic regimens. METHODS: This was a cohort study of 40 MFS and 4 LDS patients and 87 control participants. Aortic dimension and stiffness indexes, including pulse wave velocity (PWV), were measured using echocardiography and Doppler. Total and free TGF-ß and MMP blood levels were measured using Quantikine (R&D Systems, Inc, Minneapolis, MN) and Quanterix (Billerica, MA) kits. Endothelial function was measured using brachial artery flow-mediated dilation. RESULTS: PWV was increased in patients with MFS. There were increased MMP-2 levels in those with MFS but no increase in free or total TGF-ß or MMP-9 levels compared with control participants. There was no difference in TGF-ß levels between MFS patients receiving no medications, angiotensin receptor blockers, and ß-blockers. PWV correlated most strongly with age. Endothelial function showed premature gradual decline in patients with MFS. CONCLUSIONS: Despite the increased PWV, monitoring aortic stiffness or TGF-ß levels would not be helpful in patients with MFS. TGF-ß levels were not increased and the increased MMP-2 levels suggest consideration of a different therapeutic target.
CONTEXTE: La dilatation, la rigidification et la dissection de l'aorte sont des complications fréquentes et parfois mortelles du syndrome de Marfan (SM) et du syndrome de Loeys-Dietz (SLD), qui sont tous deux dûs à une anomalie de la voie de signalisation du facteur de croissance transformant bêta (TGF-ß). On ne connaît pas la relation entre les dimensions et la rigidité de l'aorte et la présence de biomarqueurs. Notre étude visait à mesurer les dimensions et la rigidité de l'aorte, les taux de TGF-ß et de métalloprotéases matricielles (MMP) et la fonction endothéliale chez des patients atteints du SM, et à les comparer aux taux de TGF-ß observés chez des patients également atteints de SM, mais recevant un autre traitement. MÉTHODOLOGIE: Il s'agissait d'une étude de cohorte menée auprès de 40 patients atteints du SM et de quatre patients atteints du SLD, ainsi que de 87 témoins. Les indices des dimensions et de la rigidité aortiques, y compris la vitesse d'onde de pouls (VOP), ont été mesurés par échocardiographie et par échographie Doppler. Les taux sanguins de TGF-ß et de MMP totaux et libres ont été mesurés à l'aide de trousses Quantikine (R&D Systems, Inc, Minneapolis, MN) et Quanterix (Billerica, MA). La fonction endothéliale a été mesurée par dilatation liée au flux dans l'artère brachiale. RÉSULTATS: La VOP était plus élevée chez les patients atteints du SM. On a aussi observé une hausse des taux de MMP-2 chez les patients atteints de SM, mais aucune augmentation des taux de TGF-ß ou de MMP-9 libres ou totaux comparativement aux témoins. Il n'y avait pas de différence entre les taux de TGF-ß chez les patients atteints de SM ne recevant aucun traitement, ceux qui prenaient un antagoniste des récepteurs de l'angiotensine et ceux qui prenaient un bêtabloquant. La VOP été plus fortement corrélée avec l'âge. La fonction endothéliale a affiché un déclin progressif prématuré chez les patients atteints du SM. CONCLUSIONS: Malgré l'augmentation de la VOP, il ne semble pas utile de surveiller la rigidité aortique ni les taux de TGF-ß en cas de SM. Les taux de TGF-ß n'étaient pas plus élevés chez les patients atteints du SM, et la hausse des taux de MMP-2 indique qu'il conviendrait de choisir une autre cible thérapeutique.
RESUMO
BACKGROUND: Vascular smooth muscle cell migration and accumulation in response to growth factors extensively contribute to the development of intimal thickening within the vessel wall. Cumulative evidence has shown that actin cytoskeleton polymerization and rearrangement are critical steps during cellular spreading and migration. Integrin-linked kinase, an intracellular serine/threonine kinase, is a cytoplasmic interactor of integrin beta-1 and beta-3 receptors regulating cell-cell and/or cell-extracellular matrix interaction, cell contraction, extracellular matrix modification, and cell spreading and migration in response to various stimuli. However, the regulatory role of ILK during vascular smooth muscle cell migration and the importance of integrin signaling in occlusive vascular diseases are not yet fully elucidated. RESULTS: In the present study, we report that integrin-linked kinase controls mouse aortic smooth muscle cell migration in response to platelet-derived growth factor. We have also identified p38 mitogen activated protein kinase as a downstream signaling pathway of the integrin-linked kinase that regulates platelet-derived growth factor-induced actin polymerization and smooth muscle cell migration. CONCLUSION: This study will provide new insights into the potential therapeutic value of modulating integrin signaling in an attempt to block or delay smooth muscle cell migration and the progression of vascular diseases.
Assuntos
Actinas/metabolismo , Músculo Liso Vascular/citologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Movimento Celular , Células Cultivadas , Citoesqueleto , Camundongos , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root widening and aneurysm if unmanaged. We have previously reported doxycycline, a nonselective matrix metalloproteinases (MMPs) inhibitor, to attenuate aortic root widening and improve aortic contractility and elasticity in MFS mice. We were also first to use multiphoton microscopy, a non-invasive and label-free imaging technique, to quantify and link the aortic ultrastructure to possible changes in the skin dermis. Here, we aimed to assess the effects of long-term doxycycline treatment on the aortic ultrastructure and skin dermis of MFS mice through immunohistochemical evaluation and quantification of elastic and collagen content and morphology using multiphoton microscopy. Our results demonstrate a rescue of aortic elastic fiber fragmentation and disorganization accompanied by a decrease in MMP-2 and MMP-9 expression within the aortic wall in doxycycline-treated MFS mice. At 12 months of age, reduced skin dermal thickness was observed in both MFS and control mice, but only dermal thinning in MFS mice was rescued by doxycycline treatment. MMP-2 and MMP-9 expression was reduced in the skin of doxycycline-treated MFS mice. A decrease in dermal thickness was found to be positively associated with increased aortic root elastin disorganization and wall thickness. Our findings confirm the beneficial effects of doxycycline on ultrastructural properties of aortic root as well as on skin elasticity and structural integrity in MFS mice.
Assuntos
Aorta/efeitos dos fármacos , Aneurisma Aórtico/patologia , Doxiciclina/farmacologia , Síndrome de Marfan/patologia , Microscopia/métodos , Animais , Aorta/anatomia & histologia , Aorta/fisiologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , FótonsRESUMO
The purpose of this article was to review the current literature on psychosocial implications of Marfan syndrome (MFS) and its impact on adolescents, adults, their families and to provide important considerations for providers. Since the previous reviews in 2015, numerous studies have been published that are included in the current review. This literature review was conducted using PubMed, Medline, PsychINFO, ERIC, Web of Science, and Academic Search Premier databases and only articles that studied psychosocial factors that influence MFS patients as adolescents, adults, family members, or their interactions with providers were included in this review. Of the 522 articles reviewed, 41 were selected based on the inclusion and exclusion criteria. All articles were peer-reviewed. MFS has various implications that can impact one's life; studies have shown that MFS causes a negative impact on an individual's formative years, quality of life, reproductive decision-making, work participation, and satisfaction with life. Clinicians and multidisciplinary teams should be aware of these factors to provide support focusing on coping strategies for the patient and their family.