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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 9835

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Dr. Daniel Henrion

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MITOVASC Department, INSERM U1083, CNRS UMR6214, University of Angers, 49055 Angers, France
Interests: blood flow; resistance arteries; endothelium; vascular remodeling; cardiovascular diseases
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Special Issue Information

Dear Colleagues,

Cardiovascular diseases (CVD) and cerebrovascular diseases comprise many disorders that affect the brain, heart and peripheral vasculature structure and blood flow regulation. Despite numerous existing therapeutic tools, they remain the leading cause of death worldwide.

Atherosclerosis is the main driver of CVD. It involves chronic inflammation and endothelial dysfunction associated with the accumulation of oxidized low-density lipoproteins in the vessel wall. Ultimately, endothelial lesions destabilize the atherosclerotic plaque, leading to plaque rupture.

On the other hand, stroke is the most common pathological event related to cerebrovascular diseases. Endothelial cell dysfunction associated with blood vessel wall remodeling is a major pathological substrate in cerebrovascular diseases.

The molecular and cellular mechanisms underlying CVD and cerebrovascular diseases remain incompletely understood, despite numerous existing publications. Signaling pathways involved in endothelial dysfunction and vascular remodeling in both coronary heart disease, stroke and other vascular disorders share common mechanisms and some specificity that require further investigations.

In this Special Issue, we aim to present new data obtained on the molecular mechanisms of CVD and cerebrovascular diseases. We also expect the discovery of new biomarkers and novel therapeutical targets.

Work on endothelial and, more broadly, vascular dysfunctions at the cerebral, cardiac and peripheral levels will be considered.

Dr. Daniel Henrion
Guest Editor

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Published Papers (6 papers)

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Research

15 pages, 6148 KiB

Open AccessArticle

17 β-Estradiol Impedes Aortic Root Dilation and Rupture in Male Marfan Mice

by Louis Saddic, Sean Escopete, Lior Zilberberg, Shannon Kalsow, Divya Gupta, Mansoureh Eghbali and Sarah Parker

Int. J. Mol. Sci. 2023, 24(17), 13571; https://doi.org/10.3390/ijms241713571 - 1 Sep 2023

Viewed by 979

Abstract

Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with worse outcomes in male compared to female patients. In this study, we examine the effects of 17 β-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 β-estradiol, and the growth in the aortic root, along with the risk of aortic rupture, was measured. Transcriptomic profiling was used to identify enriched pathways from 17 β-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 β-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture. The Marfan transcriptome was enriched in inflammatory genes, and the addition of 17 β-estradiol modulated a set of genes that function through TNFα mediated NF-κB signaling. In addition, 17 β-estradiol suppressed the induction of these TNFα induced genes in aortic smooth muscle cells in vitro in an NF-κB dependent manner, and 17 β-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 β-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFα-NF-κB signaling. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular and Cerebrovascular Diseases)

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18 pages, 3029 KiB

Open AccessArticle

Downregulation of Circulating Hsa-miR-200c-3p Correlates with Dyslipidemia in Patients with Stable Coronary Artery Disease

by Chiara Vancheri, Elena Morini, Francesca Romana Prandi, Francesco Barillà, Francesco Romeo, Giuseppe Novelli and Francesca Amati

Int. J. Mol. Sci. 2023, 24(2), 1112; https://doi.org/10.3390/ijms24021112 - 6 Jan 2023

Cited by 1 | Viewed by 1638

Abstract

Coronary heart disease (CHD), one of the leading causes of disability and death worldwide, is a multifactorial disease whose early diagnosis is demanding. Thus, biomarkers predicting the occurrence of this pathology are of great importance from a clinical and therapeutic standpoint. By means of a pilot study on peripheral blood cells (PBMCs) of subjects with no coronary lesions (CTR; n = 2) and patients with stable CAD (CAD; n = 2), we revealed 61 differentially methylated regions (DMRs) (18 promoter regions, 24 genes and 19 CpG islands) and 14.997 differentially methylated single CpG sites (DMCs) in CAD patients. MiRNA-seq results displayed a peculiar miRNAs profile in CAD patients with 18 upregulated and 32 downregulated miRNAs (FC ≥ ±1.5, p ≤ 0.05). An integrated analysis of genome-wide DNA methylation and miRNA-seq results indicated a significant downregulation of hsa-miR-200c-3p (FC_CAD = −2.97, p ≤ 0.05) associated to the hypermethylation of two sites (genomic coordinates: chr12:7073122-7073122 and chr12:7072599-7072599) located intragenic to the miR-200c/141 genomic locus (encoding hsa-miR-200c-3p) (p-value = 0.009) in CAD patients. We extended the hsa-miR-200c-3p expression study in a larger cohort (CAD = 72, CTR = 24), confirming its reduced expression level in CAD patients (FC_CAD = −2; p = 0.02). However, when we analyzed the methylation status of the two CpG sites in the same cohort, we failed to identify significant differences. A ROC curve analysis showed good performance of hsa-miR-200c-3p expression level (AUC = 0.65; p = 0.02) in distinguishing CAD from CTR. Moreover, we found a significant positive correlation between hsa-miR-200c-3p expression and creatinine clearance (R² = 0.212, p < 0.005, Pearson r = 0.461) in CAD patients. Finally, a phenotypic correlation performed in the CAD group revealed lower hsa-miR-200c-3p expression levels in CAD patients affected by dyslipidemia (+DLP, n = 58) (p < 0.01). These results indicate hsa-miR-200c-3p as potential epi-biomarker for the diagnosis and clinical progression of CAD and highlight the importance of deeper studies on the expression of this miRNA to understand its functional role in coronary artery disease development. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular and Cerebrovascular Diseases)

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12 pages, 562 KiB

Open AccessArticle

Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial

by Cristina Razquin, Miguel Ruiz-Canela, Estefania Toledo, Clary B. Clish, Marta Guasch-Ferré, Jesús F. García-Gavilán, Clemens Wittenbecher, Angel Alonso-Gómez, Montse Fitó, Liming Liang, Dolores Corella, Enrique Gómez-Gracia, Ramon Estruch, Miquel Fiol, Jose M. Santos-Lozano, Luis Serra-Majem, Emilio Ros, Fernando Aros, Jordi Salas-Salvadó, Frank B. Hu and Miguel A. Martínez-González Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(1), 270; https://doi.org/10.3390/ijms24010270 - 23 Dec 2022

Cited by 4 | Viewed by 2247

Abstract

Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (OR_{for 1 SD increase} = 0.78 (0.61–0.99); 0.67 (0.51–0.86) and 0.75 (0.59–0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (OR_{for 1 SD increase} = 1.50 (1.14–1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular and Cerebrovascular Diseases)

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16 pages, 17558 KiB

Open AccessArticle

De Novo Asp219Val Mutation in Cardiac Tropomyosin Associated with Hypertrophic Cardiomyopathy

by Andrey K. Tsaturyan, Elena V. Zaklyazminskaya, Margarita E. Polyak, Galina V. Kopylova, Daniil V. Shchepkin, Anastasia M. Kochurova, Anastasiia D. Gonchar, Sergey Y. Kleymenov, Natalia A. Koubasova, Sergey Y. Bershitsky, Alexander M. Matyushenko and Dmitrii I. Levitsky

Int. J. Mol. Sci. 2023, 24(1), 18; https://doi.org/10.3390/ijms24010018 - 20 Dec 2022

Cited by 5 | Viewed by 1399

Abstract

Hypertrophic cardiomyopathy (HCM), caused by mutations in thin filament proteins, manifests as moderate cardiac hypertrophy and is associated with sudden cardiac death (SCD). We identified a new de novo variant, c.656A>T (p.D219V), in the TPM1 gene encoding cardiac tropomyosin 1.1 (Tpm) in a young SCD victim with post-mortem-diagnosed HCM. We produced recombinant D219V Tpm1.1 and studied its structural and functional properties using various biochemical and biophysical methods. The D219V mutation did not affect the Tpm affinity for F-actin but increased the thermal stability of the Tpm molecule and Tpm-F-actin complex. The D219V mutation significantly increased the Ca²⁺ sensitivity of the sliding velocity of thin filaments over cardiac myosin in an in vitro motility assay and impaired the inhibition of the filament sliding at low Ca²⁺ concentration. The molecular dynamics (MD) simulation provided insight into a possible molecular mechanism of the effect of the mutation that is most likely a cause of the weakening of the Tpm interaction with actin in the "closed" state and so makes it an easier transition to the “open” state. The changes in the Ca²⁺ regulation of the actin-myosin interaction characteristic of genetic HCM suggest that the mutation is likely pathogenic. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular and Cerebrovascular Diseases)

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15 pages, 2846 KiB

Open AccessArticle

Microglia-Derived Olfactomedin-like 3 Is a Potent Angiogenic Factor in Primary Mouse Brain Endothelial Cells: A Novel Target for Glioblastoma

by Laila M. Joseph, Ryan G. Toedebusch, Eshetu Debebe, Aurelie H. Bastian, Christopher A. Lucchesi, Shafee Syed-Quadri, Luke A. Wittenburg, Xinbin Chen, Frederick J. Meyers and Christine M. Toedebusch

Int. J. Mol. Sci. 2022, 23(23), 14613; https://doi.org/10.3390/ijms232314613 - 23 Nov 2022

Cited by 2 | Viewed by 1380

Abstract

Neoangiogenesis, a hallmark feature of all malignancies, is robust in glioblastoma (GBM). Vascular endothelial growth factor (VEGF) has long been regarded as the primary pro-angiogenic molecule in GBM. However, anti-VEGF therapies have had little clinical efficacy, highlighting the need to explore VEGF-independent mechanisms of neoangiogenesis. Olfactomedin-like 3 (OLFML3), a secreted glycoprotein, is an established proangiogenic factor in many cancers, but its role in GBM neoangiogenesis is unknown. To gain insight into the role of OLFML3 in microglia-mediated angiogenesis, we assessed endothelial cell (EC) viability, migration and differentiation following (1) siRNA knockdown targeting endogenous EC Olfml3 and (2) EC exposure to human recombinant OLFML3 (rhOLFML3; 10 ng/mL, 48 h), and conditioned medium (CM) from isogenic control and Olfml3^−/− microglia (48 h). Despite a 70% reduction in Olfml3 mRNA levels, EC angiogenic parameters were not affected. However, exposure to both rhOLFML3 and isogenic control microglial CM increased EC viability (p < 0.01), migration (p < 0.05) and differentiation (p < 0.05). Strikingly, these increases were abolished, or markedly attenuated, following exposure to Olfml3^−/− microglial CM despite corresponding increased microglial secretion of VEGF-A (p < 0.0001). Consistent with reports in non-CNS malignancies, we have demonstrated that OLFML3, specifically microglia-derived OLFML3, promotes VEGF-independent angiogenesis in primary brain microvascular ECs and may provide a complementary target to mitigate neovascularization in GBM. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular and Cerebrovascular Diseases)

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32 pages, 7990 KiB

Open AccessArticle

High Glycemia and Soluble Epoxide Hydrolase in Females: Differential Multiomics in Murine Brain Microvasculature

by Saivageethi Nuthikattu, Dragan Milenkovic, Jennifer E. Norman, John Rutledge and Amparo Villablanca

Int. J. Mol. Sci. 2022, 23(21), 13044; https://doi.org/10.3390/ijms232113044 - 27 Oct 2022

Cited by 4 | Viewed by 1663

Abstract

The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular and Cerebrovascular Diseases)

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