Endothelial dysfunction in Marfan syndrome mice is restored by resveratrol

Mieremet, Arnout; Stoel, Miesje M. van der; Li, Siyu; Çelik, Evrim Coşkun; Krimpen, Tsveta van; Huveneers, Stephan; Waard, Vivian de

doi:10.1038/s41598-022-26662-5

Cited by 11 publications

(6 citation statements)

References 94 publications

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“…These morphological changes may have a compound effect in vessels where the ratio of endothelial cells to smooth muscle cells is increased, such as in smaller vessels like cerebral arteries. In addition, aging also plays a role in decline of endothelial cell junctional linearity and reduction in endothelial cell surface area, which may contribute to vascular permeability such as increased blood–brain barrier permeability displayed in normal aging 57 . Thus, this change in endothelial cell morphology could contribute to the changes seen in the posterior cerebral artery blood flow velocity in MFS and 12M CTRL mice.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in endothelial function have be measured in MFS patients through flow-mediated dilation, which is negatively correlated with the diameter of the thoracic aorta 75 . In MFS mice, using en face analysis of the aorta, it was also shown that endothelial cell alignment with blood flow was reduced, endothelial cell roundness was increased, individual endothelial surface area was increased, and endothelial cell junctional linearity was decreased 57 .…”

Section: Discussionmentioning

confidence: 99%

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In vivo phenotypic vascular dysfunction extends beyond the aorta in a mouse model for fibrillin-1 (Fbn1) mutation

Curry,

Barrameda,

Thomas

et al. 2024

Sci Rep

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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. It is well established that the MFS mouse model exhibits an accelerated-aging phenotype in elastic organs like the aorta, lung, and skin. However, the impact of Fbn1 mutations on the in vivo function and structure of various artery types with the consideration of sex and age, has not been adequately explored in real-time and a clinically relevant context. 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. Furthermore, this research is a vital step in understanding MFS's broader implications and sets the stage for more in-depth future analyses, while providing data-driven preclinical justification for re-evaluating diagnostic approaches and therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In vivo phenotypic vascular dysfunction extends beyond the aorta in a mouse model for fibrillin-1 (Fbn1) mutation

Curry,

Barrameda,

Thomas

et al. 2024

Sci Rep

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“…It was previously reported that flow-mediated responses were impaired in Marfan patients 42 and a negative correlation was observed between flow-mediated dilation and the diameter of ascending thoracic aorta 43 . In addition, it has previously been shown that Marfan model mice (Fbn1 C1041G/+ ) show alteration of EC morphology with a rounder shape and reduced alignment to blood flow 44 and reduction of basal NO production in older animals 45 . The abnormal EC phenotypes with upregulation of ICAM-1 and VCAM-1 are observed as early as 1 week of age before manifestation of the gross phenotype in AD mouse aortas, supporting the notion that the activation of ECs with abnormal mechanosensing contributes to the upregulation of adhesion molecules and triggers the recruitment of bone marrow-derived monocytes/macrophages into the intima.…”

Section: Discussionmentioning

confidence: 99%

A novel genetic mouse model of fatal aortic dissection reveals massive inflammatory cell infiltration in the thoracic aorta

Kimura,

Motoyama,

Kanki

et al. 2024

Preprint

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Background: Aortic dissection (AD) is the separation of medial layers of the aorta and is a major cause of death in patients with connective tissue disorders such as Marfan syndrome. However, molecular triggers instigating AD, its temporospatial progression, and how vascular cells in each vessel layer interact and participate in the pathological process remain incompletely understood. To unravel the underlying molecular mechanism of AD, we generated a spontaneous AD mouse model. Methods: We incorporated a novel missense variant (p.G234D) in FBN1, the gene for fibrillin-1, identified in a non-syndromic familial AD patient into mice using CRISPR/Cas9 system. We performed histopathological analyses of the aortic lesions by histology, immunofluorescence staining, electron microscopy, synchrotron-based imaging and single-cell (sc)RNA-sequencing. Biochemical analysis was performed to examine the binding capacity of mutant human FBN1G234D protein to latent Tgfbeta binding proteins (LTBPs), and signaling pathways in the mutant aortic wall were examined by western blot analysis. Results: 50% of the Fbn1G234D/G234D mutant mice died within 5 weeks of age from multiple intimomedial tears that expanded longitudinally and progressed to aortic rupture accompanied by massive immune cell infiltration. scRNA-sequencing, validated by immunostaining, revealed a significant increase in MHC class II-positive pro-inflammatory macrophages and monocytes at the site of intima tears with upregulation of MMP2/9 and marked disruption of elastic lamina. Subendothelial matrices, such as type IV collagen and laminin, expanded into the medial layer, where fibronectin expression was highly upregulated. Fbn1G234D/G234D endothelial cells exhibited altered mechanosensing with loss of parallel alignment to blood flow and upregulation of VCAM-1 and ICAM-1, all of which likely contributed to the infiltration of immune cells. Biochemically, FBN1G234D lost the ability to bind to latent TGFbeta binding protein (LTBP)-1, -2, and -4, resulting in the downregulation of TGFbeta signaling in the aortic wall. Conclusions: We show that dynamic interactions involving endothelial cells (ECs) and macrophages/monocytes in the intima, where the ECM microenvironment is altered with the reduced TGFbeta signaling, contributes to the initiation of AD. Our novel AD mouse model provides a unique opportunity to identify target molecules involved in the intimomedial tears that can be utilized for development of therapeutic strategies.

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“…Further emphasising the importance of the ECM, Marfan syndrome, defined by mutations in the ECM component fibrillin-1 (FBN1), presents with an increased risk of aortic aneurysm ( Pereira et al, 1997 ; Dietz and Pyeritz, 1995 ). Introducing the Marfan-specific mutation Fbn1 C1041G specifically into murine ECs impaired their alignment within both the ascending and descending aorta, and perturbed junctional stability under LF ( Mieremet et al, 2022 ). The same study showed that treatment with resveratrol restored EC alignment, phospho-eNOS expression and vascular structure, effectively rescuing the phenotype.…”

Section: Consequences Of Impaired Endothelial Mechanosensingmentioning

confidence: 99%

Nuclear mechanosensing of the aortic endothelium in health and disease

Mannion,

Holmgren

2023

Disease Models &Amp; Mechanisms

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The endothelium, the monolayer of endothelial cells that line blood vessels, is exposed to a number of mechanical forces, including frictional shear flow, pulsatile stretching and changes in stiffness influenced by extracellular matrix composition. These forces are sensed by mechanosensors that facilitate their transduction to drive appropriate adaptation of the endothelium to maintain vascular homeostasis. In the aorta, the unique architecture of the vessel gives rise to changes in the fluid dynamics, which, in turn, shape cellular morphology, nuclear architecture, chromatin dynamics and gene regulation. In this Review, we discuss recent work focusing on how differential mechanical forces exerted on endothelial cells are sensed and transduced to influence their form and function in giving rise to spatial variation to the endothelium of the aorta. We will also discuss recent developments in understanding how nuclear mechanosensing is implicated in diseases of the aorta.

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Endothelial dysfunction in Marfan syndrome mice is restored by resveratrol

Cited by 11 publications

References 94 publications

In vivo phenotypic vascular dysfunction extends beyond the aorta in a mouse model for fibrillin-1 (Fbn1) mutation

In vivo phenotypic vascular dysfunction extends beyond the aorta in a mouse model for fibrillin-1 (Fbn1) mutation

A novel genetic mouse model of fatal aortic dissection reveals massive inflammatory cell infiltration in the thoracic aorta

Nuclear mechanosensing of the aortic endothelium in health and disease

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