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Molecular Basis of Vascular Remodeling 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 29775

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Prof. Dr. Ana Belen Garcia-Redondo

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Department of Physiology, Medicine Faculty, University Autónoma of Madrid, 28029 Madrid, Spain
Interests: cardiovascular diseases; remodeling; inflammation; oxidative stress
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Dear Colleagues,

Cardiovascular diseases are the major cause of morbidity and mortality worldwide. A key pathological hallmark of cardiovascular disease is vascular remodeling, i.e., the ability of the arteries to modify their structure in response to pathological situations. The processes underlying vascular remodeling mainly affect the biology of vascular smooth muscle cells (changes in their contractile, migratory, proliferative, and apoptotic capacity), as well as the content of the extracellular matrix and the maintenance of their elastic properties.

Although the processes that accompany the development of vascular remodeling are known, the underlying molecular basis is less understood. For that, knowing new mechanisms that participate in this pathological process is fundamental to understand its development from early stages and would allow having new targets for pharmacological action or new diagnostic biomarkers.

In this Special Issue of IJMS, we want to offer a platform for high-quality publications on new mechanisms underlying vascular remodeling.

Prof. Dr. Ana Belen Garcia-Redondo
Guest Editor

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Keywords

aneurysm
atherosclerosis
cell signaling
extracellular matrix
hypertension
immune system
mechanotransduction
smooth muscle cells
vascular remodeling
vascular stiffness

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Published Papers (11 papers)

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Research

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15 pages, 2016 KiB

Open AccessArticle

The Effects of Silencing PTX3 on the Proteome of Human Endothelial Cells

by Cristina Banfi, Maura Brioschi, Lucia M. Vicentini and Maria Grazia Cattaneo

Int. J. Mol. Sci. 2022, 23(21), 13487; https://doi.org/10.3390/ijms232113487 - 3 Nov 2022

Cited by 3 | Viewed by 1728

Abstract

The human long pentraxin PTX3 has complex regulatory roles at the crossroad of innate immunity, inflammation, and tissue repair. PTX3 can be produced by various cell types, including vascular endothelial cells (ECs), in response to pro-inflammatory cytokines or bacterial molecules. PTX3 has also been involved in the regulation of cardiovascular biology, even if ambiguous results have been so far provided in both preclinical and clinical research. In this study, we compared the proteomic profiles of human ECs (human umbilical vein ECs, HUVECs), focusing on differentially expressed proteins between the control and PTX3-silenced ECs. We identified 19 proteins that were more abundant in the proteome of control ECs and 23 proteins that were more expressed in PTX3-silenced cells. Among the latter, proteins with multifunctional roles in angiogenesis, oxidative stress, and inflammation were found, and were further validated by assessing their mRNAs with RT-qPCR. Nevertheless, the knock down of PTX3 did not affect in vitro angiogenesis. On the contrary, the lack of the protein induced an increase in pro-inflammatory markers and a shift to the more oxidative profile of PTX3-deficient ECs. Altogether, our results support the idea of a protective function for PTX3 in the control of endothelial homeostasis, and more generally, in cardiovascular biology. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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12 pages, 2866 KiB

Open AccessArticle

Connecting Aortic Stiffness to Vascular Contraction: Does Sex Matter?

by Amanda A. de Oliveira, Fernanda Priviero, Ana Delgado, Pengfei Dong, Valentina O. Mendoza, Linxia Gu, R. Clinton Webb and Kenia P. Nunes

Int. J. Mol. Sci. 2022, 23(19), 11314; https://doi.org/10.3390/ijms231911314 - 25 Sep 2022

Cited by 1 | Viewed by 2172

Abstract

This study was designed to connect aortic stiffness to vascular contraction in young male and female Wistar rats. We hypothesized that female animals display reduced intrinsic media-layer stiffness, which associates with improved vascular function. Atomic force microscopy (AFM)-based nanoindentation analysis was used to derive stiffness (Young’s modulus) in biaxially (i.e., longitudinal and circumferential) unloaded aortic rings. Reactivity studies compatible with uniaxial loading (i.e., circumferential) were used to assess vascular responses to a selective

α_{1}

adrenergic receptor agonist in the presence or absence of extracellular calcium. Elastin and collagen levels were indirectly evaluated with fluorescence microscopy and a picrosirius red staining kit, respectively. We report that male and female Wistar rats display similar AFM-derived aortic media-layer stiffness, even though female animals withstand higher aortic intima-media thickness-to-diameter ratio than males. Female animals also present reduced phenylephrine-induced aortic force development in concentration-response and time-force curves. Specifically, we observed impaired force displacement in both parts of the contraction curve (

A_{p h a s i c}

and

A_{t o n i c}

) in experiments conducted with and without extracellular calcium. Additionally, collagen levels were lower in female animals without significant elastin content and fragmentation changes. In summary, sex-related functional differences in isolated aortas appear to be related to dissimilarities in the dynamics of vascular reactivity and extracellular matrix composition rather than a direct response to a shift in intrinsic media-layer stiffness. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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16 pages, 3055 KiB

Open AccessArticle

Sildenafil-Induced Revascularization of Rat Hindlimb Involves Arteriogenesis through PI3K/AKT and eNOS Activation

by Celine Baron-Menguy, Arnaud Bocquet, Alexis Richard, Anne-Laure Guihot, Bertrand Toutain, Pierre Pacaud, Celine Fassot, Gervaise Loirand, Daniel Henrion and Laurent Loufrani

Int. J. Mol. Sci. 2022, 23(10), 5542; https://doi.org/10.3390/ijms23105542 - 16 May 2022

Cited by 2 | Viewed by 1879

Abstract

Hypoxia and inflammation play a major role in revascularization following ischemia. Sildenafil inhibits phosphodiesterase-5, increases intracellular cGMP and induces revascularization through a pathway which remains incompletely understood. Thus, we investigated the effect of sildenafil on post-ischemic revascularization. The left femoral artery was ligated in control and sildenafil-treated (25 mg/kg per day) rats. Vascular density was evaluated and expressed as the left/right leg (L/R) ratio. In control rats, L/R ratio was 33 ± 2% and 54 ± 9%, at 7- and 21-days post-ligation, respectively, and was significantly increased in sildenafil-treated rats to 47 ± 4% and 128 ± 11%, respectively. A neutralizing anti-VEGF antibody significantly decreased vascular density (by 0.48-fold) in control without effect in sildenafil-treated animals. Blood flow and arteriolar density followed the same pattern. In the ischemic leg, HIF-1α and VEGF expression levels increased in control, but not in sildenafil–treated rats, suggesting that sildenafil did not induce angiogenesis. PI3-kinase, Akt and eNOS increased after 7 days, with down-regulation after 21 days. Sildenafil induced outward remodeling or arteriogenesis in mesenteric resistance arteries in association with eNOS protein activation. We conclude that sildenafil treatment increased tissue blood flow and arteriogenesis independently of VEGF, but in association with PI3-kinase, Akt and eNOS activation. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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12 pages, 2523 KiB

Open AccessArticle

Somatostatin Primes Endothelial Cells for Agonist-Induced Hyperpermeability and Angiogenesis In Vitro

by Muhammad Aslam, Hafiza Idrees, Peter Ferdinandy, Zsuzsanna Helyes, Christian Hamm and Rainer Schulz

Int. J. Mol. Sci. 2022, 23(6), 3098; https://doi.org/10.3390/ijms23063098 - 13 Mar 2022

Cited by 4 | Viewed by 2074

Abstract

Somatostatin is an inhibitory peptide, which regulates the release of several hormones, and affects neurotransmission and cell proliferation via its five G_i protein-coupled receptors (SST_1-5). Although its endocrine regulatory and anti-tumour effects have been thoroughly studied, little is known about its effect on the vascular system. The aim of the present study was to analyse the effects and potential mechanisms of somatostatin on endothelial barrier function. Cultured human umbilical vein endothelial cells (HUVECs) express mainly SST₁ and SST₅ receptors. Somatostatin did not affect the basal HUVEC permeability, but primed HUVEC monolayers for thrombin-induced hyperpermeability. Western blot data demonstrated that somatostatin activated the phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and p42/44 mitogen-activated protein kinase (MAPK) pathways by phosphorylation. The HUVEC barrier destabilizing effects were abrogated by pre-treating HUVECs with mitogen-activated protein kinase kinase/extracellular signal regulated kinase (MEK/ERK), but not the Akt inhibitor. Moreover, somatostatin pre-treatment amplified vascular endothelial growth factor (VEGF)-induced angiogenesis (3D spheroid formation) in HUVECs. In conclusion, the data demonstrate that HUVECs under quiescence conditions express SST₁ and SST₅ receptors. Moreover, somatostatin primes HUVECs for thrombin-induced hyperpermeability mainly via the activation of MEK/ERK signalling and promotes HUVEC proliferation and angiogenesis in vitro. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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24 pages, 6365 KiB

Open AccessArticle

Fluid Shear Stress Regulates the Landscape of microRNAs in Endothelial Cell-Derived Small Extracellular Vesicles and Modulates the Function of Endothelial Cells

by Jihwa Chung, Kyoung Hwa Kim, Namhee Yu, Shung Hyun An, Sanghyuk Lee and Kihwan Kwon

Int. J. Mol. Sci. 2022, 23(3), 1314; https://doi.org/10.3390/ijms23031314 - 24 Jan 2022

Cited by 10 | Viewed by 3229

Abstract

Blood fluid shear stress (FSS) modulates endothelial function and vascular pathophysiology. The small extracellular vesicles (sEVs) such as exosomes are potent mediators of intercellular communication, and their contents reflect cellular stress. Here, we explored the miRNA profiles in endothelial cells (EC)-derived sEVs (EC-sEVs) under atheroprotective laminar shear stress (LSS) and atheroprone low-oscillatory shear stress (OSS) and conducted a network analysis to identify the main biological processes modulated by sEVs’ miRNAs. The EC-sEVs were collected from culture media of human umbilical vein endothelial cells exposed to atheroprotective LSS (20 dyne/cm²) and atheroprone OSS (±5 dyne/cm²). We explored the miRNA profiles in FSS-induced EC-sEVs (LSS-sEVs and OSS-sEVs) and conducted a network analysis to identify the main biological processes modulated by sEVs’ miRNAs. In vivo studies were performed in a mouse model of partial carotid ligation. The sEVs’ miRNAs-targeted genes were enriched for endothelial activation such as angiogenesis, cell migration, and vascular inflammation. OSS-sEVs promoted tube formation, cell migration, monocyte adhesion, and apoptosis, and upregulated the expression of proteins that stimulate these biological processes. FSS-induced EC-sEVs had the same effects on endothelial mechanotransduction signaling as direct stimulation by FSS. In vivo studies showed that LSS-sEVs reduced the expression of pro-inflammatory genes, whereas OSS-sEVs had the opposite effect. Understanding the landscape of EC-exosomal miRNAs regulated by differential FSS patterns, this research establishes their biological functions on a system level and provides a platform for modulating the overall phenotypic effects of sEVs. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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24 pages, 16161 KiB

Open AccessArticle

Paracrine Shear-Stress-Dependent Signaling from Endothelial Cells Affects Downstream Endothelial Function and Inflammation

by Fabio Bertani, Dalila Di Francesco, Maria Dolores Corrado, Maria Talmon, Luigia Grazia Fresu and Francesca Boccafoschi

Int. J. Mol. Sci. 2021, 22(24), 13300; https://doi.org/10.3390/ijms222413300 - 10 Dec 2021

Cited by 14 | Viewed by 3185

Abstract

Cardiovascular diseases (CVDs), mainly ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and major contributors to disability worldwide. Despite their heterogeneity, almost all CVDs share a common feature: the endothelial dysfunction. This is defined as a loss of functionality in terms of anti-inflammatory, anti-thrombotic and vasodilatory abilities of endothelial cells (ECs). Endothelial function is greatly ensured by the mechanotransduction of shear forces, namely, endothelial wall shear stress (WSS). Low WSS is associated with endothelial dysfunction, representing the primary cause of atherosclerotic plaque formation and an important factor in plaque progression and remodeling. In this work, the role of factors released by ECs subjected to different magnitudes of shear stress driving the functionality of downstream endothelium has been evaluated. By means of a microfluidic system, HUVEC monolayers have been subjected to shear stress and the conditioned media collected to be used for the subsequent static culture. The results demonstrate that conditioned media retrieved from low shear stress experimental conditions (LSS-CM) induce the downregulation of endothelial nitric oxide synthase (eNOS) expression while upregulating peripheral blood mononuclear cell (PBMC) adhesion by means of higher levels of adhesion molecules such as E-selectin and ICAM-1. Moreover, LSS-CM demonstrated a significant angiogenic ability comparable to the inflammatory control media (TNFα-CM); thus, it is likely related to tissue suffering. We can therefore suggest that ECs stimulated at low shear stress (LSS) magnitudes are possibly involved in the paracrine induction of peripheral endothelial dysfunction, opening interesting insights into the pathogenetic mechanisms of coronary microvascular dysfunction. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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16 pages, 16542 KiB

Open AccessArticle

Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats

by Ekaterina K. Selivanova, Anastasia A. Shvetsova, Anna A. Borzykh, Dina K. Gaynullina, Oxana O. Kiryukhina, Elena V. Lukoshkova, Viktoria M. Potekhina, Vladislav S. Kuzmin and Olga S. Tarasova

Int. J. Mol. Sci. 2021, 22(22), 12327; https://doi.org/10.3390/ijms222212327 - 15 Nov 2021

Cited by 2 | Viewed by 1628

Abstract

Nitric oxide (NO) has been shown to stimulate differentiation and increase the survival of ganglionic sympathetic neurons. The proportion of neuronal NOS-immunoreactive sympathetic preganglionic neurons is particularly high in newborn rats and decreases with maturation. However, the role of NO in the development of vascular sympathetic innervation has never been studied before. We tested the hypothesis that intrauterine NO deficiency weakened the development of vascular sympathetic innervation and thereby changed the contractility of peripheral arteries and blood pressure level in two-week-old offspring. Pregnant rats consumed NOS inhibitor L-NAME (250 mg/L in drinking water) from gestational day 10 until delivery. Pups in the L-NAME group had a reduced body weight and blood level of NO metabolites at 1–2 postnatal days. Saphenous arteries from two-week-old L-NAME offspring demonstrated a lower density of sympathetic innervation, a smaller inner diameter, reduced maximal active force and decreased α-actin/β-actin mRNA expression ratio compared to the controls. Importantly, pups in the L-NAME group exhibited decreased blood pressure levels before, but not after, ganglionic blockade with chlorisondamine. In conclusion, intrauterine L-NAME exposure is followed by the impaired development of the sympathetic nervous system in early postnatal life, which is accompanied by the structural and functional remodeling of arterial blood vessels. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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15 pages, 1515 KiB

Open AccessReview

Mitochondrial Homeostasis in VSMCs as a Central Hub in Vascular Remodeling

by Yi Xia, Xu Zhang, Peng An, Junjie Luo and Yongting Luo

Int. J. Mol. Sci. 2023, 24(4), 3483; https://doi.org/10.3390/ijms24043483 - 9 Feb 2023

Cited by 10 | Viewed by 2559

Abstract

Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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19 pages, 2809 KiB

Open AccessReview

Specialized Pro-Resolving Lipid Mediators: New Therapeutic Approaches for Vascular Remodeling

by Lucía Serrano Díaz del Campo, Raquel Rodrigues-Díez, Mercedes Salaices, Ana M. Briones and Ana B. García-Redondo

Int. J. Mol. Sci. 2022, 23(7), 3592; https://doi.org/10.3390/ijms23073592 - 25 Mar 2022

Cited by 11 | Viewed by 3401

Abstract

Vascular remodeling is a typical feature of vascular diseases, such as atherosclerosis, aneurysms or restenosis. Excessive inflammation is a key mechanism underlying vascular remodeling via the modulation of vascular fibrosis, phenotype and function. Recent evidence suggests that not only augmented inflammation but unresolved inflammation might also contribute to different aspects of vascular diseases. Resolution of inflammation is mediated by a family of specialized pro-resolving mediators (SPMs) that limit immune cell infiltration and initiate tissue repair mechanisms. SPMs (lipoxins, resolvins, protectins, maresins) are generated from essential polyunsaturated fatty acids. Synthases and receptors for SPMs were initially described in immune cells, but they are also present in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), where they regulate processes important for vascular physiology, such as EC activation and VSMC phenotype. Evidence from genetic models targeting SPM pathways and pharmacological supplementation with SPMs have demonstrated that these mediators may play a protective role against the development of vascular remodeling in atherosclerosis, aneurysms and restenosis. This review focuses on the latest advances in understanding the role of SPMs in vascular cells and their therapeutic effects in the vascular remodeling associated with different cardiovascular diseases. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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22 pages, 1203 KiB

Open AccessReview

Key Role of Astrocytes in Postnatal Brain and Retinal Angiogenesis

by Mariela Puebla, Pablo J. Tapia and Hilda Espinoza

Int. J. Mol. Sci. 2022, 23(5), 2646; https://doi.org/10.3390/ijms23052646 - 28 Feb 2022

Cited by 17 | Viewed by 3424

Abstract

Angiogenesis is a key process in various physiological and pathological conditions in the nervous system and in the retina during postnatal life. Although an increasing number of studies have addressed the role of endothelial cells in this event, the astrocytes contribution in angiogenesis has received less attention. This review is focused on the role of astrocytes as a scaffold and in the stabilization of the new blood vessels, through different molecules release, which can modulate the angiogenesis process in the brain and in the retina. Further, differences in the astrocytes phenotype are addressed in glioblastoma, one of the most devastating types of brain cancer, in order to provide potential targets involved in the cross signaling between endothelial cells, astrocytes and glioma cells, that mediate tumor progression and pathological angiogenesis. Given the relevance of astrocytes in angiogenesis in physiological and pathological conditions, future studies are required to better understand the interrelation between endothelial and astrocyte signaling pathways during this process. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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24 pages, 1100 KiB

Open AccessReview

Signal Transduction during Metabolic and Inflammatory Reprogramming in Pulmonary Vascular Remodeling

by Marta T. Gomes, Yang Bai, Simone R. Potje, Lu Zhang, Angelia D. Lockett and Roberto F. Machado

Int. J. Mol. Sci. 2022, 23(5), 2410; https://doi.org/10.3390/ijms23052410 - 22 Feb 2022

Cited by 8 | Viewed by 3377

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombosis, and neovascularization. Vascular remodeling in PAH is associated with cellular metabolic and inflammatory reprogramming that induce profound endothelial and smooth muscle cell phenotypic changes. Multiple signaling pathways and regulatory loops act on metabolic and inflammatory mediators which influence cellular behavior and trigger pulmonary vascular remodeling in vivo. This review discusses the role of bioenergetic and inflammatory impairments in PAH development. Full article

(This article belongs to the Special Issue Molecular Basis of Vascular Remodeling 2.0)

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