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Special Issue "Molecular Research on Chronic Venous Disease"

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 March 2018).

Special Issue Editors

Prof. Dr. Ferdinando Mannello
E-Mail Website
Guest Editor
Full Professor of Clinical Biochemistry and Clinical Molecular Biology, Department of Biomolecular Sciences, Section of Biochemistry and Biotechnology, Unit of Clinical Biochemistry, University Carlo Bo of Urbino, 61029 Urbino, Italy
Interests: vascular medicine; vascular biology; inflammatory biomarkers; proteolytic biomarkers; endothelium; translational research; matrix metalloproteinases; chronic venous disorders; athero-thrombotic diseases; vascular pharmacology; vascular funcxtion; metabolomics; clinical biochemistry; nutraceuticals; platelets; neutrophils; macrophages; vascular aging; laboratory medicine; diagnostic and laboratory errors; biomarkers in cardiovascular diseases; laboratory testing for inflammatory chronic diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Daniela Ligi
E-Mail Website
Co-Guest Editor
Department of Biomolecular Sciences, Section of Biochemistry and Biotechnology, Unit of Clinical Biochemistry, University Carlo Bo of Urbino, 61029 Urbino, Italy
Interests: chronic venous disease; bio-molecular approaches of wounds; inflammation; proteolysis; cytokines and growth factors; therapeutic options for improving wound healing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic venous diseases (CVeD) of the lower limbs include different pathological events characterized by distinctive features sharing common hallmarks of hemodynamic alteration, inflammation, and proteolysis. The first step is represented by varicose veins (C-2) and the final disease is named non-healing leg ulcers (C-6), according to the international CEAP classification. CVeD affects a significant part of the populations worldwide with a prevalence up-to 15% in subjects aged over 70 years. Non-healing skin wounds represent a cause of significant disability and huge financial burden to the healthcare budget worldwide. Although great efforts have been made in characterizing early biochemical and molecular pathways during CVeD initiation and progression, discerning the biomolecular basis of healing/nonhealing processes, the exact biomolecular pathogenetic basis from C-2 to C-6 stages is not fully understood. Several previously published histochemical, biochemical and molecular analyses, and pharmacological treatments, have indicated that the hemodynamic shear stress, pro-apoptotic and pro-inflammatory processes, coagulative events, and enhanced degradative proteolysis, may cooperate in harmful pathways leading to nonhealing ulcers. In this respect, there is an urgent need to focus more attention on the importance of adequate biomolecular screening for hemodynamic stress, endothelial damage/repair, wound microenvironment, therapeutic treatments for improving ulcer healing. This Special Issue aims to collect insights about this complex and intricate cross talk, increasing the knowledge on the pathophysiological processes of CVeD for improving the knowledge in this field, enhancing diagnosis and therapy, and translating the usefulness of investigations in vascular medicine and health sciences.

Prof. Dr. Ferdinando Mannello
Dr. Daniela Ligi
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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Apoptosis
  • Chronic venous disease
  • Chronic venous insufficiency
  • Cytokines
  • Endothelial cells
  • Gene expression
  • Growth factors
  • Hemodynamic shear stress
  • Inflammation
  • Microcirculation
  • MMP and TIMP
  • Molecular markers
  • Monocyte/macrophage and neutrophil cells
  • Proteinases
  • Predisposing genetic factors
  • Signal transduction
  • Soluble mediators
  • Therapeutic treatments
  • Varicose vein
  • Venous leg ulcer
  • Wound microenvironment

Published Papers (6 papers)

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Editorial

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Editorial
Chronic Venous Disorders: The Dangerous, the Good, and the Diverse
Int. J. Mol. Sci. 2018, 19(9), 2544; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092544 - 28 Aug 2018
Cited by 19 | Viewed by 2223
Abstract
Chronic venous disorders are common vascular pathology of great medical and socioeconomic impact, characterized by a wide spectrum of clinical manifestations occurring with symptoms and/or signs that vary in type and severity. The predominant pathophysiological mechanisms of chronic venous disease start from the [...] Read more.
Chronic venous disorders are common vascular pathology of great medical and socioeconomic impact, characterized by a wide spectrum of clinical manifestations occurring with symptoms and/or signs that vary in type and severity. The predominant pathophysiological mechanisms of chronic venous disease start from the development of venous hypertension from shear stress and reflux, leading to endothelial dysfunction and venous wall dilatation. The altered hemodynamic transduces physical signals into harmful bio-molecular pathways, creating a vicious cycle among shear stress, proteolytic remodeling, and inflammatory processes. This intricate network is further exacerbated by the degradation of protective endothelial glycocalyx. In this special issue, at least three main aspects of these interactions are highlighted: the dangerous, the good, and the diverse, which may help to focus attention on the biomolecular mechanisms and the possible targeted therapy of chronic venous disorders (CVeD). Full article
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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Research

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Article
Variability of MMP/TIMP and TGF-β1 Receptors throughout the Clinical Progression of Chronic Venous Disease
Int. J. Mol. Sci. 2018, 19(1), 6; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010006 - 21 Dec 2017
Cited by 13 | Viewed by 2155
Abstract
Chronic venous disease (CVeD) is a prevalent condition with a significant socioeconomic burden, yet the pathophysiology is only just beginning to be understood. Previous studies concerning the dysregulation of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases (TIMPs)) within the varicose [...] Read more.
Chronic venous disease (CVeD) is a prevalent condition with a significant socioeconomic burden, yet the pathophysiology is only just beginning to be understood. Previous studies concerning the dysregulation of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases (TIMPs)) within the varicose vein wall are inconsistent and disregard clinical progression. Moreover, it is highly plausible that MMP and TIMP expression/activity is affected by transforming growth factor (TGF)-β1 and its signaling receptors (TGFβRs) expression/activity in the vein wall. A case–control study was undertaken to analyze genetic and immunohistochemical differences between healthy (n = 13) and CVeD (early stages: n = 19; advanced stages: n = 12) great saphenous vein samples. Samples were grouped based on anatomic harvest site and subjected to quantitative polymerase chain reaction for MMP1, MMP2, MMP8, MMP9, MMP12, MMP13, TIMP1, TIMP2, TIMP3, TIMP4, TGFβR1, TGFβR2, and TGFβR3 gene expression analysis, and then to immunohistochemistry for immunolocalization of MMP2, TIMP2, and TGFβR2. Decreased gene expression of MMP12, TIMP2, TIMP3, TIMP4, and TGFβR2 was found in varicose veins when compared to controls. Regarding CVeD clinical progression, two facts arose: results across anatomical regions were uneven; decreased gene expression of MMP9 and TGFβR3 and increased gene expression of MMP2 and TIMP3 were found in advanced clinical stages. Most immunohistochemistry results for tunica intima were coherent with qPCR results. In conclusion, decreased expression of TGFβRs might suggest a reduction in TGF-β1 participation in the MMP/TIMP imbalance throughout CVeD progression. Further studies about molecular events in the varicose vein wall are required and should take into consideration the venous anatomical region and CVeD clinical progression. Full article
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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Communication
Chronic Venous Insufficiency: Transforming Growth Factor-β Isoforms and Soluble Endoglin Concentration in Different States of Wound Healing
Int. J. Mol. Sci. 2017, 18(10), 2206; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102206 - 21 Oct 2017
Cited by 15 | Viewed by 2787
Abstract
Venous leg ulcer (VLU) is a huge healthcare problem with poorly understood pathophysiology. Transforming growth factor-β (TGF-β) and endoglin (Eng), are inflammatory and wound healing mediators. Eng, co-receptor for TGF-β type-II receptors, may be cleaved forming soluble Eng (sEng), antagonizing TGF-β signaling, a [...] Read more.
Venous leg ulcer (VLU) is a huge healthcare problem with poorly understood pathophysiology. Transforming growth factor-β (TGF-β) and endoglin (Eng), are inflammatory and wound healing mediators. Eng, co-receptor for TGF-β type-II receptors, may be cleaved forming soluble Eng (sEng), antagonizing TGF-β signaling, a crucial process in vascular pathologies. We evaluated the accumulation in wound fluid (WF) of TGF-β isoforms and sEng in healing stages, showing the effects of sulodexide treatments, a glycosaminoglycan with clinical efficacy in VLU healing. Patients with inflammatory (Infl) and granulating (Gran) VLU were recruited. WFs and THP-1 monocytes exposed to Infl and Gran WF (treated/untreated with sulodexide) were analyzed for TGF-β isoforms and sEng by multiplex immunoassay. In both Infl and Gran WF, TGF-β1 and β2 were similar; TGF-β3 was significantly increased in Infl compared to Gran WFs (p = 0.033). sEng was significantly elevated in Gran compared to Infl WFs (p = 0.002). In THP-1 monocytes there was a significant increase in sEng after co-treatment of WF and sulodexide. The increase in TGF-β3 found in Infl WF highlights its negative effect on wound healing, while the increased levels of sEng in Gran WF affects the leukocyte adhesion/transmigration through the endothelium, reducing the inflammatory response and favoring the wound healing. Glycosaminoglycan sulodexide potentiates the effects of sEng release from monocyte, representing an important therapeutic option for wound healing. Full article
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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Review

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Review
Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy
Int. J. Mol. Sci. 2018, 19(6), 1669; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061669 - 05 Jun 2018
Cited by 69 | Viewed by 3926
Abstract
Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles [...] Read more.
Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles of inflammation and endothelial dysfunction been properly assessed. Although still incompletely understood, current knowledge of the pathophysiological mechanisms of CVD reveals several potential targets and strategies for therapeutic intervention, some of which are addressable by currently available venoactive drugs. The roles of these drugs in the clinical improvement of venous tone and contractility, reduction of edema and inflammation, as well as in improved microcirculation and venous ulcer healing have been studied extensively, with favorable results reported in the literature. Here, we aim to review these pathophysiological mechanisms and their implications regarding currently available venoactive drug therapies. Full article
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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Review
Molecular and Clinical Issues about the Risk of Venous Thromboembolism in Older Patients: A Focus on Parkinson’s Disease and Parkinsonism
Int. J. Mol. Sci. 2018, 19(5), 1299; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051299 - 26 Apr 2018
Cited by 7 | Viewed by 2306
Abstract
Venous thromboembolism (VTE) is a common and potentially life-threatening condition which includes both deep-vein thrombosis (DVT) and pulmonary embolism (PE). VTE has a significant clinical and epidemiological impact in the elderly, and its incidence increases to more than 1% per year in older [...] Read more.
Venous thromboembolism (VTE) is a common and potentially life-threatening condition which includes both deep-vein thrombosis (DVT) and pulmonary embolism (PE). VTE has a significant clinical and epidemiological impact in the elderly, and its incidence increases to more than 1% per year in older patients, suggesting the presence of specific age-related risk factors in this population. Immobilization seems to predominate as the main cause in patients admitted for medical acute illness in medicine wards, and there is evidence of a high risk in older patients with immobilization resulting from advanced forms of Parkinson’s disease (PD), regardless of the presence of an acute medical condition. In this review, we would to discuss the recent evidence on clinical, molecular and epidemiological features of VTE in older frail subjects focusing on patients with PD and parkinsonism. We also discuss some therapeutic issues about the risk prevention and we suggest a thorough comprehensive geriatric assessment that can represent an optimal strategy to identify and prevent the VTE risk in these patients. Full article
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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Review
TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology
Int. J. Mol. Sci. 2017, 18(12), 2534; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122534 - 26 Nov 2017
Cited by 22 | Viewed by 3946
Abstract
Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth [...] Read more.
Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-β1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-β1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency. Full article
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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