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Molecular Mechanisms of Vascular Disease
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Molecular Mechanisms of Vascular Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 22229

Special Issue Editors

Dr. Elena M. Gallo

E-Mail Website
Guest Editor
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA
Interests: aortic disease; Loeys–Dietz syndrome; cell signaling
Dr. Mary B. Sheppard

E-Mail Website
Guest Editor
College of Medicine, University of Kentucky, Lexington, KY 40506, USA
Interests: aortic disease; Marfan syndrome; molecular genetics

Special Issue Information

Dear Colleagues,

Pathologies of the vascular system comprise a vast number of conditions that include coronary heart disease, retinopathies, atherosclerosis, calcification disorders, and aneurysm. Fundamental discoveries in the mechanisms of vascular development and homeostasis, as well as the identification of pathogenic mutations in components of specific signaling pathways regulating these processes, have improved our understanding of many of these conditions. The development of novel in vivo and in vitro disease models, together with the application of proteomics, metabolomics, single-cell sequencing, and new imaging technologies, has provided novel insights on how the cellular and extracellular components of the vasculature are affected in vascular disease. The aim of this Special Issue entitled “Molecular Mechanisms of Vascular Disease” is to present state-of-the art review articles summarizing trends within the scientific community and to publish original articles. We especially invite studies that focus on the identification of molecular mechanisms of disease that may inform the development of new therapies that target disease-specific vulnerabilities.

Dr. Elena M. Gallo
Dr. Mary B. Sheppard
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • atherosclerosis
  • aneurysm
  • vascular calcification
  • coronary artery disease
  • molecular pathogenesis

Published Papers (8 papers)

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Research

Jump to: Review

13 pages, 1864 KiB  
Article
HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease
by Wenli Zhao, Hitoe Mori, Yuki Tomiga, Kenichi Tanaka, Rasheda Perveen, Keiichiro Mine, Chika Inadomi, Wataru Yoshioka, Yoshihito Kubotsu, Hiroshi Isoda, Takuya Kuwashiro, Satoshi Oeda, Takumi Akiyama, Ye Zhao, Iwata Ozaki, Seiho Nagafuchi, Atsushi Kawaguchi, Shinichi Aishima, Keizo Anzai and Hirokazu Takahashi
Genes 2022, 13(7), 1265; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13071265 - 16 Jul 2022
Viewed by 2206
Abstract
There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 [...] Read more.
There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima–media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
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15 pages, 402 KiB  
Article
Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome
by Yanireth Jimenez, Cesar Paulsen, Eduardo Turner, Sebastian Iturra, Oscar Cuevas, Guillermo Lay-son, Gabriela M. Repetto, Marcelo Rojas and Juan F. Calderon
Genes 2022, 13(6), 1027; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13061027 - 08 Jun 2022
Cited by 1 | Viewed by 2327
Abstract
Marfan Syndrome (MFS) is an autosomal dominant condition caused by variants in the fibrillin-1 (FBN1) gene. Cardinal features of MFS include ectopia lentis (EL), musculoskeletal features and aortic root aneurysm and dissection. Although dissection of the ascending aorta is the main [...] Read more.
Marfan Syndrome (MFS) is an autosomal dominant condition caused by variants in the fibrillin-1 (FBN1) gene. Cardinal features of MFS include ectopia lentis (EL), musculoskeletal features and aortic root aneurysm and dissection. Although dissection of the ascending aorta is the main cause of mortality in MFS, the clinical course differs considerably in age of onset and severity, even among individuals who share the same causative variant, suggesting the existence of additional genetic variants that modify the severity of the cardiovascular phenotype in MFS. We recruited MFS patients and classified them into severe (n = 8) or mild aortic phenotype (n = 14) according to age of presentation of the first aorta-related incident. We used Exome Sequencing to identify the genetic variants associated with the severity of aortic manifestations and we performed linkage analysis where suitable. We found five genes associated with severe aortic phenotype and three genes that could be protective for this phenotype in MFS. These genes regulate components of the extracellular matrix, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management and, potentially, therapies for these patients. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
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21 pages, 3712 KiB  
Article
Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
by Ashley Dawson, Yanming Li, Yang Li, Pingping Ren, Hernan G. Vasquez, Chen Zhang, Kimberly R. Rebello, Waleed Ageedi, Alon R. Azares, Aladdein Burchett Mattar, Mary Burchett Sheppard, Hong S. Lu, Joseph S. Coselli, Lisa A. Cassis, Alan Daugherty, Ying H. Shen and Scott A. LeMaire
Genes 2022, 13(1), 95; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010095 - 30 Dec 2021
Cited by 20 | Viewed by 4329
Abstract
The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic [...] Read more.
The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (n = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (n = 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of MYOCD and MYH11 in SMCs, and an upregulation of COL1A1/2 in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that TGFB1 was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly TGFBR2) and SMAD genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of TGFB1, the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
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11 pages, 752 KiB  
Article
An Emergent Nexus between Striae and Thoracic Aortic Dissection
by Benjamin J. Landis, Courtney E. Vujakovich, Lindsey R. Elmore, Saila T. Pillai, Lawrence S. Lee, Jeffrey E. Everett, Larry W. Markham, John W. Brown, Phillip J. Hess and Joel S. Corvera
Genes 2022, 13(1), 23; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010023 - 23 Dec 2021
Viewed by 2327
Abstract
Current approaches to stratify the risk for disease progression in thoracic aortic aneurysm (TAA) lack precision, which hinders clinical decision making. Connective tissue phenotyping of children with TAA previously identified the association between skin striae and increased rate of aortic dilation. The objective [...] Read more.
Current approaches to stratify the risk for disease progression in thoracic aortic aneurysm (TAA) lack precision, which hinders clinical decision making. Connective tissue phenotyping of children with TAA previously identified the association between skin striae and increased rate of aortic dilation. The objective of this study was to analyze associations between connective tissue abnormalities and clinical endpoints in adults with aortopathy. Participants with TAA or aortic dissection (TAD) and trileaflet aortic valve were enrolled from 2016 to 2019 in the setting of cardiothoracic surgical care. Data were ascertained by structured interviews with participants. The mean age among 241 cases was 61 ± 13 years. Eighty (33%) had history of TAD. While most participants lacked a formal syndromic diagnosis clinically, connective tissue abnormalities were identified in 113 (47%). This included 20% with abdominal hernia and 13% with skin striae in atypical location. In multivariate analysis, striae and hypertension were significantly associated with TAD. Striae were associated with younger age of TAD or prophylactic aortic surgery. Striae were more frequent in TAD cases than age- and sex-matched controls. Thus, systemic features of connective tissue dysfunction were prevalent in adults with aortopathy. The emerging nexus between striae and aortopathy severity creates opportunities for clinical stratification and basic research. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
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8 pages, 235 KiB  
Article
RNF213 c.14576G>A Is Associated with Intracranial Internal Carotid Artery Saccular Aneurysms
by Yasuo Murai, Eitaro Ishisaka, Atsushi Watanabe, Tetsuro Sekine, Kazutaka Shirokane, Fumihiro Matano, Ryuta Nakae, Tomonori Tamaki, Kenta Koketsu and Akio Morita
Genes 2021, 12(10), 1468; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101468 - 23 Sep 2021
Cited by 1 | Viewed by 2028
Abstract
A mutation in RNF213 (c.14576G>A), a gene associated with moyamoya disease (>80%), plays a role in terminal internal carotid artery (ICA) stenosis (>15%) (ICS). Studies on RNF213 and cerebral aneurysms (AN), which did not focus on the site of origin or morphology, could [...] Read more.
A mutation in RNF213 (c.14576G>A), a gene associated with moyamoya disease (>80%), plays a role in terminal internal carotid artery (ICA) stenosis (>15%) (ICS). Studies on RNF213 and cerebral aneurysms (AN), which did not focus on the site of origin or morphology, could not elucidate the relationship between the two. However, a report suggested a relationship between RNF213 and AN in French-Canadians. Here, we investigated the relationship between ICA saccular aneurysm (ICA-AN) and RNF213. We analyzed RNF213 expression in subjects with ICA-AN and atherosclerotic ICS. Cases with a family history of moyamoya disease were excluded. AN smaller than 4 mm were confirmed as AN only by surgical or angiographic findings. RNF213 was detected in 12.2% of patients with ICA-AN and 13.6% of patients with ICS; patients with ICA-AN and ICS had a similar risk of RNF213 mutation expression (odds ratio, 0.884; 95% confidence interval, 0.199–3.91; p = 0.871). The relationship between ICA-AN and RNF213 (c.14576G>A) was not correlated with the location of the ICA and bifurcation, presence of rupture, or multiplicity. When the etiology and location of AN were more restricted, the incidence of RNF213 mutations in ICA-AN was higher than that reported in previous studies. Our results suggest that strict maternal vessel selection and pathological selection of AN morphology may reveal an association between genetic mutations and ICA-AN development. The results of this study may form a basis for further research on systemic vascular diseases, in which the RNF213 (c.14576G>A) mutation has been implicated. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
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Review

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25 pages, 454 KiB  
Review
Risk Factors for Thoracic Aortic Dissection
by Zhen Zhou, Alana C. Cecchi, Siddharth K. Prakash and Dianna M. Milewicz
Genes 2022, 13(10), 1814; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101814 - 07 Oct 2022
Cited by 22 | Viewed by 3979
Abstract
Thoracic aortic aneurysms involving the root and/or the ascending aorta enlarge over time until an acute tear in the intimal layer leads to a highly fatal condition, an acute aortic dissection (AAD). These Stanford type A AADs, in which the tear occurs above [...] Read more.
Thoracic aortic aneurysms involving the root and/or the ascending aorta enlarge over time until an acute tear in the intimal layer leads to a highly fatal condition, an acute aortic dissection (AAD). These Stanford type A AADs, in which the tear occurs above the sinotubular junction, leading to the formation of a false lumen in the aortic wall that may extend to the arch and thoracoabdominal aorta. Type B AADs originate in the descending thoracic aorta just distal to the left subclavian artery. Genetic variants and various environmental conditions that disrupt the aortic wall integrity have been identified that increase the risk for thoracic aortic aneurysms and dissections (TAD). In this review, we discuss the predominant TAD-associated risk factors, focusing primarily on the non-genetic factors, and discuss the underlying mechanisms leading to TAD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
10 pages, 664 KiB  
Review
Embryonic Heterogeneity of Smooth Muscle Cells in the Complex Mechanisms of Thoracic Aortic Aneurysms
by Sohei Ito, Hong S. Lu, Alan Daugherty and Hisashi Sawada
Genes 2022, 13(9), 1618; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13091618 - 09 Sep 2022
Cited by 2 | Viewed by 1696
Abstract
Smooth muscle cells (SMCs) are the major cell type of the aortic wall and play a pivotal role in the pathophysiology of thoracic aortic aneurysms (TAAs). TAAs occur in a region-specific manner with the proximal region being a common location. In this region, [...] Read more.
Smooth muscle cells (SMCs) are the major cell type of the aortic wall and play a pivotal role in the pathophysiology of thoracic aortic aneurysms (TAAs). TAAs occur in a region-specific manner with the proximal region being a common location. In this region, SMCs are derived embryonically from either the cardiac neural crest or the second heart field. These cells of distinct origins reside in specific locations and exhibit different biological behaviors in the complex mechanism of TAAs. The purpose of this review is to enhance understanding of the embryonic heterogeneity of SMCs in the proximal thoracic aorta and their functions in TAAs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
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20 pages, 1276 KiB  
Review
Genetic and Epigenetic Regulation of Lipoxygenase Pathways and Reverse Cholesterol Transport in Atherogenesis
by Stanislav Kotlyarov
Genes 2022, 13(8), 1474; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13081474 - 18 Aug 2022
Cited by 3 | Viewed by 2268
Abstract
Atherosclerosis is one of the most important medical and social problems of modern society. Atherosclerosis causes a large number of hospitalizations, disability, and mortality. A considerable amount of evidence suggests that inflammation is one of the key links in the pathogenesis of atherosclerosis. [...] Read more.
Atherosclerosis is one of the most important medical and social problems of modern society. Atherosclerosis causes a large number of hospitalizations, disability, and mortality. A considerable amount of evidence suggests that inflammation is one of the key links in the pathogenesis of atherosclerosis. Inflammation in the vascular wall has extensive cross-linkages with lipid metabolism, and lipid mediators act as a central link in the regulation of inflammation in the vascular wall. Data on the role of genetics and epigenetic factors in the development of atherosclerosis are of great interest. A growing body of evidence is strengthening the understanding of the significance of gene polymorphism, as well as gene expression dysregulation involved in cross-links between lipid metabolism and the innate immune system. A better understanding of the genetic basis and molecular mechanisms of disease pathogenesis is an important step towards solving the problems of its early diagnosis and treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Vascular Disease)
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