Biology subjects

Esfandiarei, M.

Publications and source records attributed to Esfandiarei, M..

6 recordsLinked to original sources

bioRxiv2024

Apoptosis is increased in cortical neurons of female Marfan Syndrome mice

Marfan Syndrome (MFS) is an autosomal dominant genetic disorder that affects connective tissue throughout the body due to mutations in the FBN1 gene. Individuals with MFS display symptoms in different organs, particularly in the vasculature, but the mechanisms of this multi-system dysfunction are still under investigation. There is still a gap in our understanding of the impact of monogenic connective tissue aberrations on the brain. This study aims to determine the impact of MFS on neurodegeneration, in cortical brain tissue of male and female MFS mice. Brain tissue of 6-month-old female and male mice with the FBN1C1041G/+ mutation and wildtype litter mates was collected and stained for active caspase-3 (ac3), brain derived neurotrophic factor (BDNF), and neuronal nuclei (NeuN) or with TUNEL and DAPI. Data revealed increased levels of ac3 in neurons within the sensory and motor cortical areas of female MFS mice compared to sex- and age-matched controls. We confirm increased levels of apoptosis in MFS mice using TUNEL staining within the same brain areas. We also report increased levels of neuronal BDNF levels in cortical brain tissue of male and female MFS mice. These results indicate a heightened susceptibility for neurodegeneration in the mouse model of MFS. Significance StatementThe study revealed that female mice with a FBN1C1041G/+ mutation have more apoptotic neurons in sensory and motor cortical brain tissue compared to wildtype litter mates.

neuroscience↗

bioRxiv2024

Genetic Manipulation of Caveolin-1 in the Mouse Model of Marfan Syndrome Associated Aortic Root Aneurysm: Effects on Endothelial and Smooth Muscle Function

Marfan Syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the gene encoding for the large glycoprotein Fibrillin-1 (Fbn1), leading to wide-spectrum clinical manifestations, with the most life-threatening being aortic root aneurysm. MFS aortic aneurysm is known to be associated with reduced endothelial nitric oxide synthase (eNOS)-mediated nitric oxide (NO) production. Previous studies have shown that caveolin-1 (Cav1), a coat protein of caveolae structure on the plasma membrane, acts as a negative regulator of eNOS activity. This suggests that Cav1 may play a role in the development of aortic root aneurysm in MFS by modulating eNOS activity. In this study, we investigated the role of Cav1 in regulating aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength by generating MFS mice (FBN1+/Cys1041Gly) lacking Cav1 gene expression (MFS/Cav1KO). Our data show that ablation of the Cav1 gene results in a significant decrease in aortic smooth muscle contraction in response to the vasoconstricting agent phenylephrine seemingly due to a marked increase in NO production within the aortic wall. We also showed that acetylcholine-induced vasorelaxation was increased in MFS/Cav1KO mice potentially through the endothelial nitric oxide-dependent mechanism, further confirming inhibitory role of Cav1 on endothelial NO production. In addition, aortic wall elastin fiber structure and strength were markedly improved in male MFS/Cav1KO mice. This study demonstrates the regulatory role of Cav1 during the development of aortic root aneurysm in MFS mice through its effects on smooth muscle and endothelial functions in an NO-dependent manner.

physiology↗

bioRxiv2024

Maternal dietary deficiency in choline reduced levels of MMP-2 levels in blood and brain tissue of male offspring mice

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. Its 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.

neuroscience↗

bioRxiv2024

Cerebral Microvascular Density, Permeability of the Blood-Brain Barrier, and Neuroinflammatory Responses Indicate Early Aging Characteristics in a Marfan Syndrome Mouse Model

Marfan Syndrome (MFS) is a connective tissue disorder due to mutations in fibrillin-1 (Fbn1), where a Fbn1 missense mutation (Fbn1C1039G/+) can result in systemic increases in the bioavailability and signaling of transforming growth factor-{beta} (TGF-{beta}). In a well-established mouse model of MFS (Fbn1C1041G/+), pre-mature aging of the aortic wall and the progression of aortic root aneurysm are observed by 6-months-of-age. TGF-{beta} signaling has been implicated in cerebrovascular dysfunction, loss of blood-brain barrier (BBB) integrity, and age-related neuroinflammation. We have reported that pre-mature vascular aging in MFS mice could extend to cerebrovasculature, where peak blood flow velocity in the posterior cerebral artery (PCA) of 6-month-old (6M) MFS mice was reduced, similarly to 12-month-old (12M) control mice. Case studies of MFS patients have documented neurovascular manifestations, including intracranial aneurysms, stroke, arterial tortuosity, as well as headaches and migraines, with reported incidence of pain and chronic fatigue. Despite these significant clinical observations, investigation into cerebrovascular dysfunction and neuropathology in MFS remains limited. Using 6M-control (C57BL/6) and 6M-MFS (Fbn1C1041G/+) and healthy 12M-control male and female mice, we test the hypothesis that abnormal Fbn1 protein expression is associated with altered cerebral microvascular density, BBB permeability, and neuroinflammation in the PCA-perfused hippocampus, all indicative of a pre-mature aging brain phenotype. Using Glut1 staining, 6M-MFS mice and 12M-CTRL similarly present decreased microvascular density in the dentate gyrus (DG), cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) regions of the hippocampus. 6M-MFS mice exhibit increased BBB permeability in the DG, CA1, and CA3 as evident by Immunoglobulin G (IgG) staining, which was more comparable to 12M-CTRL mice. 6M-MFS mice show a higher number of microglia in the hippocampus compared to age-matched control mice, a pattern resembling that of 12M-CTRL mice. This study represents the first known investigation into neuropathology in a mouse model of MFS and indicates that the pathophysiology underlying MFS leads to a systemic pre-mature aging phenotype. This study is crucial for identifying and understanding MFS-associated neurovascular and neurological abnormalities, underscoring the need for research aimed at improving the quality of life and managing pre-mature aging symptoms in MFS and related connective tissue disorders.

neuroscience↗

bioRxiv2023

In Vivo Phenotypic Vascular Dysfunction Extends Beyond the Aorta in a Mouse Model for Fibrillin-1 (FBN1) Mutation

In individuals with Marfan Syndrome (MFS), fibrillin-1 gene (FBN1) mutations can lead to vascular wall weakening and dysfunction. The experimental mouse model of MFS (FBN1C1041G/+) has been advantageous in investigating MFS-associated life-threatening aortic aneurysms. Although the MFS mouse model presents an accelerated-aging phenotype in elastic organs (e.g., lung, skin), the impact of FBN1 mutations on other central and peripheral arteries function and structure with the consideration of the impact of sex remains underexplored. In this study, we investigate if FBN1 mutation contributes to sex-dependent alterations in central and cerebral vascular function similar to phenotypic changes associated with normal aging in healthy control mice. In vivo ultrasound imaging of central and cerebral vasculature was performed in 6-month-old male and female MFS and C57BL/6 mice and sex-matched 12-month-old (middle-aged) healthy control mice. Our findings confirm aortic enlargement (aneurysm) and wall stiffness in MFS mice, but with exacerbation in male diameters. Coronary artery blood flow velocity (BFV) in diastole was not different but left pulmonary artery BFV was decreased in MFS and 12-month-old control mice regardless of sex. At 6 months of age, MFS male mice show decreased posterior cerebral artery BFV as compared to age-matched control males, with no difference observed between female cohorts. Reduced mitral valve early-filling velocities were indicated in MFS mice regardless of sex. Male MFS mice also demonstrated left ventricular hypertrophy. Overall, these results underscore the significance of biological sex in vascular function and structure in MFS mice, while highlighting a trend of pre-mature vascular aging phenotype in MFS mice that is comparable to phenotypes observed in older healthy controls.

physiology↗

bioRxiv2022

Maternal dietary choline deficiencies during pregnancy and lactation reduce cerebral blood flow in 3-month-old female mice offspring following ischemic stroke to the sensorimotor cortex

Background and PurposeAdequate maternal dietary levels of one-carbon (1C) 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 1C 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. MethodIn this study, female mice were placed on either control (CD), folic acid (FADD), or choline (ChDD) deficient diets prior to pregnancy. Female offspring were weaned onto a CD for the duration of the study. Ischemic stroke was induced in offspring and after six weeks cerebral and peripheral blood flow velocity was measured using ultrasound imaging. ResultsOur data showed that 11.5-month-old female offspring from ChDD mothers had reduced blood flow in the posterior cerebral artery compared to controls. In peripheral blood flow velocity measurements, we report an aging effect. ConclusionsThese results emphasize the importance of maternal 1C diet in early life neuro-programming on long-term vasculature health.

neuroscience↗