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Angiogenesis in wound healing
... endothelial tyrosine kinase -TEK), mięśnie gładkie oraz perycyty. Przyłączenie Ang-1 do TEK na powierzchni aktywowanych komórek śródbłonka prowadzi do produkcji PDGF i rekrutacji komórek mięśni gładkich oraz pericytów do nowo powstałej sieci naczyniowej [17,34]. ...
... insulin-like growth factor-1 -IGF-1) w keratynocytach [39,40]. Z kolei owrzodzenia związane z niewydolnością żylną wynikają z nadmiernego wzrostu stężenia VEGF, prowadzącego do znacznego zwiększenia przepuszczalności naczyń i utworzenia się mikrośrodowiska sprzyjającego tworzeniu gęstej sieci fibrynowej zakłócającej wymianę gazową w ranie [17,41]. Ponadto u pacjentów z niewydolnością żylną obserwuje się zwiększoną aktywność proteaz, które niszczą białkowe czynniki wzrostu, zakłócając tworzenie tkanki ziarninowej. ...
... One day after wounding, PDGF expression is detected on the vascular endothelium of injured skin. At day 5, basic FGF is expressed at its peak levels, which, by day 7 returns to baseline levels [6]. TGF-β stimulates the formation of granulation tissue by acting as a chemoattractant for neutrophils, macrophages and fibroblasts. ...
-Abstract is not required - Keywords: Wound healing, Angiogenesis, Regulating Factors, Nurses, Perspectives Received: 08 January 2019; Reviewed: 19 January 2019; Received: in revised from 25 February 2019; Accepted: 28 February 2019 DOI: 10.35898/ghmj-31548
... After an injury, the process of angiogenesis and the subsequent expansion of blood vessels are regulated by the actions of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). 52 Angiogenesis is accelerated during the inflammatory phase. The number of newly formed vessels surpasses the standard amount seen during the proliferation stage. ...
Background: The purpose of the current work was to manufacture vitamin A (Vit A) niosome and solid lipid nanoparticle (SLN) using an ultrasonic approach and to evaluate its effect on wound healing. Methods: The nanoparticles were prepared through an ultrasonication technique and characterized by dynamic light scattering (DLS), and transmission electron microscopy (TEM). Further, the nanoparticles were evaluated for their various parameters such as pH, viscosity, spreadability, stability, in-vitro drug release study, in-vitro cytotoxicity, and in-vivo wound healing. Results: TEM confirmed the spherical nature of the Vit A-niosome and SLN. The Vit A formulations (niosome and SLN) were stable in the accelerated stability test (freeze-thaw cycle). Vit A release from the SLN gel and niosome gel was significantly higher (almost 70 and 80%, respectively) than simple Vit A gel. According to the animal study, the wound healing closure in the Vit A niosomal gel and Vit A SLN gel was greater than the other groups during the 21 days after surgery (P < 0.05) and was close to each other over time and on day 21. Based on histological data, wounds treated with Vit A niosome gel and Vit A-SLN gel had more collagen than the other groups. MDA malondialdehyde (MDA, an end-product of lipid peroxidation) significantly decreased in the Vit A-niosome and Vit A-SLN gel group after 21 days, while glutathione peroxidase (GPx), superoxide dismutase (SOD, an endogenous antioxidant), and hydroxyproline levels demonstrated an increase. Conclusion: The findings of this study revealed that the prepared Vit A nano-formulations could be used as a possible and safe nano-vesicle for Vit A cutaneous delivery thus potentially opening up new prospects for the treatment of wound disorders.
... Anyway, no studies have been conducted that have investigated the single nucleotide polymorphisms (SNPs) of the VEGF gene and their relationship to the susceptibility of CRC. Accordingly, the present study investigated the relation of two VEGF gene polymorphisms (405C > G and − 460C > T) with the CRC susceptibility and clinicopathological characteristics in the Iranian population [12,13]. ...
Vascular endothelial growth factor (VEGF) is one of the most important regulators of angiogenesis. Several single nucleotide polymorphisms (SNPs) are associated with the VEGF overexpression and tumor progression in several cancers. This study aimed to determine the association of VEGF rs833061 and rs2010963 polymorphism and their haplotypes with susceptibility to colorectal cancer (CRC) in the Iranian population. A total of 284 colorectal cancer patients (37.3% women, 62.7% men) were enrolled in this study. Healthy controls without evidence of cancer history or family cancer predispositions were frequency-matched to the cases by sex and age (± 5 years). Genotyping was performed by the Sequenom mass ARRAY method and the genotype distribution and risk estimate were analyzed by SPSS software. The correlation between the genotypes and clinicopathological parameters (Dukes stage, phenotype, location, differentiation, and tumor size) among colorectal cancer patients were investigated. We found a significant relationship, between rs833061T/C genotype and their TG haplotype with the age of diagnosis < 60; (p = 0.012, p = 0.014) and rs2010963G/C genotype with female gender and TG haplotype with third and fourth tumor stage and tumor location (p = 0.04and p = 0.047). This study showed that rs833061T/C genotype and TG haplotype increase the susceptibility to colon cancer in the Iranian population. This susceptibility has a significant relationship with the age of diagnosis and different stages of the tumor.
... 7 days is seemingly caused by the PRF's natural fibrin architecture. 6 PRF differs from PRP in a way that platelet activation does not simultaneously occur because platelet cells are trapped in the fibrin mesh. 7 PRF is regarded as a new generation of platelet concentrates that can speed up wound healing. ...
Autologous growth factor (AGF) is a cytokine that has gained medical research interest because it helps improve and accelerate the wound healing process. Platelet-rich fibrin (PRF) is the latest generation of platelet concentrate that can be obtained through a simple procedure known as AGF referencing. One of the most common complications of total laryngectomy (TL) is pharyngocutaneous fistula. To prevent this complication, health care providers must closely monitor the postoperative wound healing process.This study aimed to investigate the effectiveness of PRF application in enhancing wound healing after TL. A randomized controlled trial was conducted in the Department of Otorhinolaryngology - Head and Neck Surgery, Faculty of Medicine, Dr. Cipto Mangunkusumo Hospital Universitas Indonesia, Jakarta, Indonesia, from June 2019 to December 2019. We included 20 patients who underwent TL for laryngeal squamous cell carcinoma. They were divided into two groups (10 patients who received applied autologous PRF around the esophageal stoma during TL and another 10 patients as the control). These patients were observed for 2 weeks postoperatively. In the bivariate analysis performed using the chi-square test, the pain threshold and edema of postoperative wounds in the PRF-treated group demonstrated significant differences compared with those in the control group. PRF application in TL enhanced the postoperative wound healing process, especially with regard to edema and pain.
... The repair of skin architecture has been studied by H&E and MT staining of the tissue specimens. After an injury, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), initiate angiogenesis and mediate blood vessel growth [43]. Angiogenesis is amplified during the inflammatory stage. ...
Following skin injury, the overproduction of reactive oxygen species (ROS) during the inflammatory phase can cause tissue damage and delay in wound healing. Methylene blue (MB) decreases mitochondrial ROS production and has antioxidant effects. The authors aimed to prepare MB-loaded niosomes using the ultra-sonication technique as a green formulation method. A Box–Behnken design was selected to optimize formulation variables. The emulsifier to cholesterol ratio, HLB of mixed surfactants (Span 60 and Tween 60), and sonication time were selected as independent variables. Vesicle size, zeta potential (ZP), and drug entrapment capacity percentage were studied as dependent variables. The optimized formulation of niosomes showed spherical shape with optimum vesicle size of 147.8 nm, ZP of − 18.0 and entrapment efficiency of 63.27%. FTIR study showed no observable interaction between MB and other ingredients. In vivo efficacy of optimized formulation was evaluated using an excision wound model in male Wistar rat. Superoxide dismutase (SOD, an endogenous antioxidant) and malondialdehyde (MDA, an end product of lipid peroxidation) levels in skin tissue samples were evaluated. After 3 days, MDA was significantly decreased in niosomal gel-treated group, whereas SOD level was increased. Histological results indicate rats that received niosomal MB were treated effectively faster than other ones.
Graphical abstract
... One day after wounding, PDGF expression is detected on the vascular endothelium of injured skin. At day 5, basic FGF is expressed at its peak levels, which, by day 7 returns to baseline levels [6]. TGF-β stimulates the formation of granulation tissue by acting as a chemoattractant for neutrophils, macrophages and fibroblasts. ...
... Capillary tubes extend branches to transfer oxygen and nutrients to the granulation tissue, which is required for successful tissue regeneration and wound closure [15,16]. One of the characteristics of delayed healing and chronic wounds is the failure of vascularization and blood circulation [17][18][19]. ...
The physiology of wound healing is dependent on the crosstalk between inflammatory mediators and cellular components of skin regeneration including fibroblasts and endothelial cells. Therefore, strategies to promote healing must regulate this crosstalk to achieve maximum efficacy. In light of the remarkable potential of natural compounds to target multiple signaling mechanisms, this study aims to demonstrate the potential of hypermongone C, a polycyclic polyprenylated acylphloroglucinol (PPAP), to accelerate wound closure by concurrently enhancing fibroblast proliferation and migration, promoting angiogenesis, and suppressing pro-inflammatory cytokines. This compound belongs to a family of plants (Hypericum) that traditionally have been used to treat injuries. Nevertheless, the exact biological evidence to support the claims is still missing. The results were obtained using a traditional model of cell scratch assay and endothelial cell tube formation, combined with the analysis of protein and gene expression by macrophages. In summary, the data suggest that hypermongone C is a multi-targeting therapeutic natural compound for the promotion of tissue repair and the regulation of inflammation.
... Nové kapiláry proliferujú kaskádou biologických procesov za účelom vytvorenia granulačného tkaniva. Proces trvá až do zhojenia rany, keď je angiogenéza zastavená zníženou hladinou rastových faktorov, ústupom zápalu, stabilizáciou bunkovej matrix a endogénnymi inhibítormi angiogenézy (2). Kmeňové bunky z dospelej kostnej drene významnou mierou prispievajú k angiogenéze. ...
... During proliferation stage, angiogenesis plays a crucial role in wound healing; it restores blood flow to tissues after injury and further leads to wound closure. It is believed that any disturbance in angiogenesis mechanism may lead to delayed period of wound healing [4]. An ideal wound dressing material should provide a favourable microclimate for effective healing, whilst preventing dehydration, providing a moist environment, being permeable to oxygen, supplying mechanical protection to the wound, acting as a barrier to microorganisms, and absorbing blood and exudates [5]. ...
The present study investigates the development of methyl cellulose (MC)-sodium alginate (SA)-montmorillonite (MMT) clay based bionanocomposite films with interesting wound healing properties. The differential scanning calorimetry analysis of the composite films revealed presence of single glass transition temperature (Tg) confirming the miscible nature of the ternary blended films. The increase in MMT ratio in the composite films reduced the mobility of biopolymer chains (MC/SA) which increased the Tg of the film. Thermogravimetric analysis showed that dispersion of clay (MMT) at nano level significantly delayed the weight loss that correlated with higher thermal stability of the composite films. It was observed that the developed films were able to exhibit antimicrobial activity against four typical pathogenic bacteria found in the presence of wound. The developed films were able to significantly inhibit (10 mg/ml) the growth of Enterococcus faecium and Pseudomonas aeruginosa. In vitro scratch assay indicated potential wound closure activities of MC-2-4 bionanocomposite films at their respective highest subtoxic doses. In conclusion, these ternary bionanocomposite films were found to be promising systems for wound healing applications.
... PDGF mediates tissue repair via:12 i) mitosis of mesenchymal cells including dermal fibroblasts, smooth muscle cells and wound capillary endothelial cells (angiogenesis); ii) chemoattraction of fibroblasts, smooth muscle cells, monocytes and neutrophils; iii) induction of extracellular matrix components in fibroblasts, including fibronectin and hyaluronic acid; iv) induction of metalloproteinases involved in wound remodeling. ...
THIS STUDY AIMS TO COMPARE THE EFFICACY OF ANTISEPTIC DRESSINGS, HYPERBARIC OXYGEN THERAPY, AND RECOMBINANT HUMAN PLATELET DERIVED GROWTH FACTOR (RHPDGF) FOR TWO REASONS: i) to reduce the incidence of lower limb amputations in diabetic foot ulcer; ii) to limit the duration of stay in the hospital. A prospective randomized trial was conducted on 60 patients with stage III and IV diabetic foot ulcers (International Association of Enterostomal Therapy classification) and patients were divided randomly in three different therapy groups - antiseptics, hyperbaric oxygen therapy, recombinant platelet derived growth factor, with 20 patients in each group. Patients were managed initially on inpatient and then on outpatient basis till the ulcer healed completely. Results among three groups were compared using unpaired T test and the level of significance was set at P<0.05 using ANOVA. This study compares the efficacy of hyperbaric oxygen therapy, antiseptic dressings, and rhPDGF in grade III and IV diabetic foot ulcers. P value (0.0348) was significant for complete wound contraction while p value healing time (0.6534) and ulcer size (0.0593) in the groups was not significant. PDGF is safe, effective and easy to apply. Results are comparable with hyperbaric oxygen (HBO) therapy and cost of treatment is lower than other therapies. Diabetic foot ulcer management requires multidisciplinary and aggressive approach. PDGF should be recommended for all grade III and IV diabetic foot ulcer at least 8 weeks old. HBO is equally good an option but has limitations and side effects.
... Chronic wounds differ from the acute form due to the failure of the epithelial cells to migrate over the wound bed but instead, proliferate at the wound margins and are unresponsive to growth factor signals [7]. While wound repair depends on a multitude of factors such as age, sex of patient, type of wound, depth and its location [13], aberrant angiogenesis is associated with almost all chronic wounds [14] (Fig. 2). ...
Chronic diseases such as vascular disease and diabetes are witnessing a global increase in prevalence. Such diseases often predispose patients to the development of severe, debilitating, chronic wounds. Angiogenesis, the formation of new capillaries from the pre-existing vascular network, is an essential component of wound healing and aberrant angiogenesis is evident in almost all chronic wounds. Natural products, derived from both plants and animals, provide a significant haven of compounds which have proved to be of great benefit to man and his ailments. Whilst significant advances have been made in the understanding of impaired angiogenesis in a non-healing wound, in the clinical setting, few effective agents exist that can expedite wound healing and closure. The lack of effective healing agents has led to a renewed interest in investigations into natural wound healing resources. In this review, we collate new evidence that details the potential for several natural compounds to promote angiogenesis and wound healing, most predominately via the up regulation of VEGF expression, that warrant urgent further investigation for development into new pro-angiogenic/wound healing therapies.
... In the proliferative phase, angiogenesis is an essential mechanism for healing wounds, restoring blood flow to tissues after injury, and achieving wound closure. In fact, the impairment of wound angiogenesis may lead to a prolonged period of wound healing [2,3]. Together with the inflammatory process, poor blood perfusion may hinder the dynamic process of wound healing and result in scar formation, especially in full-thickness wounds [4]. ...
Acanthus ebracteatus Vahl. is a Thai herb that is effective in wound healing. We sought to quantitatively determine whether or not the combined application of Acanthus ebracteatus Vahl. and a collagen scaffold will increase wound closure and angiogenesis. Balb/c mice (body weight: 22-25 g) were anesthetized with sodium thiopental. The dorsal skin incision measuring 1.5 × 1.5 cm was made and then deepened using scissors to produce a full-thickness incision down to the level of the panniculus carnosus. The size of the wound was approximately 10% of the total body surface area. The collagen sheet was implanted onto the wound. Animals were divided into 4 major groups as follows: wound with normal saline (W-NSS), wound treated with 0.3 g/kg BW of Acanthus ebracteatus Vahl. extract (W-AE (0.3 g/kg.bw)), wound implanted with collagen scaffold (W-Coll), and wound implanted with collagen scaffold and treated with 0.3 g/kg BW of Acanthus ebracteatus Vahl. (W-Coll-AE combination). On day 14, the W-Coll-AE group showed decreased wound areas and increased capillary vascularity (CV) when compared to the other 3 groups, W-NSS, W-AE0.3, and W-Coll. In the present study, the combination of AE0.3 with collagen showed the best effect on skin angiogenesis and promoted wound closure with less neutrophil infiltration.
... They seem to stimulate persistent glomeruloid vessels formation characterized by poor perfusion in venous leg insufficiency. [24][25][26] Because pro-inflammatory factors are also secreted in the wound bed, 10 the addition of minced micrograft releasing a lower concentration of these factors seems to be more favorable than fullthickness skin autograft, which releases higher levels of pro-inflammatory factors. ...
A new effective surgical procedure to repair chronic ulcers called minced micrografts technique has been recently reported. The technique consists in spreading a finely minced skin sample upon the wound bed. In this study, we investigate the in vitro release of cytokines (interleukin-6, tumor necrosis factor-α, interleukin-1α, and granulocyte-colony stimulating factor), chemokines (monocyte chemoattractant protein-1 and growth-related oncogene-α), and growth factors (platelet-derived growth factor, basic fibroblast growth factor, vascular endothelial growth factor, hepatocyte growth factor, and nerve growth factor) by minced (referred to as the minced sample) vs. not minced (referred to as the whole sample) human skin biopsy samples from the same donor. Factor release in the culture medium at different time points was detected using a multiplexed protein assay. The minced sample, which could behave like the skin fragments used in vivo in the autologous minced micrografts technique, expressed higher levels of tumor necrosis factor-α, interleukin-1α, platelet-derived growth factor, and basic fibroblast growth factor, and lower levels of interleukin-6, monocyte chemoattractant protein-1, growth related oncogene-α, and vascular endothelial growth factor compared with the whole sample. In conclusion, mincing of healthy skin may allow appropriate regulation of the inflammatory phase of wound healing and could induce overexpression of some growth factors, which facilitates the proliferative phase of healing.
... Chronic wounds differ from the acute form due to the failure of the epithelial cells to migrate over the wound bed but instead, proliferate at the wound margins and are unresponsive to growth factor signals [7]. While wound repair depends on a multitude of factors such as age, sex of patient, type of wound, depth and its location [13], aberrant angiogenesis is associated with almost all chronic wounds [14] (Fig. 2). ...
Maggot therapy, utilizing the larvae of Lucilia sericata, has been reported to reduce the bacterial load within wounds and also to enhance wound healing. Maggot excretions/secretions (ES) have been shown to have a role in the success of maggot therapy. While the protein content of ES has been investigated, to date little research has focused on the small metabolites present in ES and their potential contribution to the therapy. Study of the molecular composition of the secretions and the potential bioactivities present will allow for a more detailed evaluation of the efficacy of maggot therapy.
We studied the amino acid-like compounds present in ES of L. sericata larvae in order to determine the compounds present and their potential role in the wound healing process.
These included thin-layer chromatography/mass spectrometric analysis of ES to identify amino acid-like components, a turbidometric assay to investigate their potential antibacterial activity and cell proliferation studies to investigate their potential mitogenic ability.
Three prominent compounds were detected and identified as histidine, valinol and 3-guanidinopropionic acid. While these amino acids were not shown to exhibit antibacterial activity, a proliferative effect on the growth of human endothelial cells, but not fibroblasts, was noted.
The demonstrated proliferative effect, selectively on endothelial cells, suggests that the amino acid-like compounds present in maggot ES may have a role in wound healing, by stimulating angiogenesis.
در دو دهه اخیر استرس اکسیداتیو ناشی از فعالیت و آنتی اکسیدان ها به یکی از حیطه هاي پژوهشی مهم و پرطرفدار در بین محققین
علوم ورزشی تبدیل شده است. استرس اکسیداتیو به مفهوم به هم خوردن توازن بین گونه هاي فعال و سیستم آنتی اکسیدانی بدن به
نفع گونه هاي فعال و رادیکال هاي آزاد است. فعالیت بدنی شدید و طولانی مدت می تواند باعث افزایش تولید گونه هاي فعال و
رادیکال هاي آزاد شده و منجر به بروز استرس اکسیداتیو شود. ضمنا استرس اکسیداتیو می تواند باعث تسریع پدیده پیري و بروز
بسیاري از بیماري هاي مختلف از قبیل سرطان و سندرم متابولیک شود. به همین دلیل، بسیاري از قهرمانان ورزشی و حتی مردم عادي
جهت جلوگیري از اثرات منفی فعالیت بدنی و پیشگیري از استرس اکسیداتیو ناشی از فعالیت و آسیب هاي عضلانی به مصرف مکمل
هاي آنتی اکسیدانی روي آوردهاند. بهرحال، تحقیقات اخیر نشان می دهند که مصرف آنتی اکسیدان ها گاها نه تنها باعث کاهش
استرس اکسیداتیو نمی شود بلکه باعث افزایش آن نیز می گردد. ضمنا محققین دریافته اند که مصرف مداوم مکمل هاي آنتی اکسیدانی
می تواند از اثرات سازگارکننده فعالیت بدنی از قبیل آنژیوژنزیس، بیوژنزیس میتوکندریایی و هایپرتروفی عضلانی جلوگیري نماید. مقاله
حاضر مروري است بر تحقیقات اخیر و پاسخی به این سوال مهم که آیا واقعا مصرف مکمل هاي آنتی اکسیدانی براي افرادي که به
فعالیت بدنی می پردارند، ضرورت دارد؟
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Angiogenesis, de novo capillary outgrowth from preexisting vascular network, is crucial for wound healing and involves endothelial loosening, endothelial cell migration, stalk elongation, anastomosis, and stabilization. This process is initiated and sustained until the terminal stage of healing orchestrated by a variety of growth factors or cytokines with vascular endothelial growth factor (VEGF) being the predominant regulator of physiological and pathophysiological angiogenesis. Insufficient angiogenesis and nonfunctional vasculature are common features of non-healing diabetic wounds. This phenomenon may stem from an imbalance between pro-angiogenic (e.g., VEGF) and anti-angiogenic (e.g., thrombospondins) mediators with a shift in balance occurring in favor of suppressed angiogenesis. Current therapeutic strategies to enhance wound-based angiogenesis, including topical applications of growth factors, are inadequate, and new treatment is needed especially when viewed in the context of increasing rates of obesity and diabetes during the recent years. To this end, we will describe the “angiogenesis model of wound healing.” Moreover, the cellular and molecular cascades that coordinate angiogenesis in healthy and diabetic wounds will be addressed. Finally, rather than providing an encyclopedia survey, we will focus on a recent discovery by our laboratory confirming a new molecular target (e.g., CREM/ICER-HIF-1-VEGF axis) that may have translational potential in providing therapeutic avenues, aimed at advancing the treatment of angiogenesis-dependent disorders including delayed wound healing.
Introduction:
The growing demand for skin rejuvenation procedures with minimal down time and low risk has led to the development of fractional radiofrequency (RF) systems. The new VoluDerm™ RF microneedle technology creates minute columns of tissue thermal microablation. Treatment triggers natural fractional healing, resulting in dermal volumizing and skin renewal. This preclinical research assessed the safety and efficacy of the VoluDerm through histological evaluation of morphological changes in the target tissue.
Methods:
Following approval of protocol by ethical committee, treatments were conducted on two domestic pigs using VoluDerm disposable tips. Histological samples of 14, 7, 4 days and immediately after treatment with various energy settings were analyzed.
Results:
Immediate VoluDerm epidermal and dermal effects, and progress of healing process, as function of time following treatment (days 4 and 7), were demonstrated. Histology analysis of samples of 14 days demonstrated complete healing for all energy levels.
Summary:
This in vivo histology confirmed the safe and effective performance of the VoluDerm treatment. A fractional pattern of affected areas, surrounded by healthy tissue, was demonstrated. Healing process proved natural dermal renewal and epidermal complete regeneration. Histology supports clinical advantages of the VoluDerm natural-looking skin enhancement, with none to minimal pain and no downtime.
Traumatic wounds can be labor intensive and expensive to manage. Furthermore, full-thickness wounds often must heal by second intention, which ultimately leads to scarring. The optimal objective of repair is re-establishment of the epithelial cover and recovery of tissue integrity, strength and function. Veterinarians can positively influence wound repair by understanding its mechanisms, which will ensure selection of appropriate wound management techniques. Repair begins the moment a cellular barrier is broken and follows a predictable pattern. The events can be divided into synchronized and interrelated phases including: acute inflammation, cellular proliferation, and finally, matrix synthesis and remodeling. The exact manner in which dermal repair is regulated is not fully understood, but it is increasingly apparent that the process involves complex interactions between many cell types, their mediators (in particular cytokines and growth factors) and the extracellular matrix. This article will review the cellular, physiologic, biochemical and molecular mechanisms involved in the repair process.
The fibroplasia noted during wound repair is resolved by fibroblast cell death. How fibroblasts undergo death and how this is prevented by trophic growth factors present during the regenerative phase are unknown at the molecular level. We examined a model of staurosporine-induced apoptosis in fibroblasts. We demonstrated that epidermal growth factor (EGF) stimulation of fibroblast NR6WT expressing human EGF receptors blocks staurosporine-induced apoptosis by inhibiting the activation of caspase-3. The survival effect of EGF on rescuing apoptotic NR6WT involves signaling pathways that derive from PI3K and Rac; the blockade of apoptosis is abolished when PI3K and Rac signals are inhibited simultaneously. Furthermore, by using KP372-1, a specific Akt inhibitor, we found that downstream of Akt signaling pathways is absolutely required for the EGF rescue from staurosporine-induced apoptosis in NR6WT. Interestingly, EGF prevention of apoptosis induced by tumor necrosis factor-alpha in the face of cycloheximide blockade of protein translation occurs via a different set of pathways as the simultaneous inhibition of extracellular signal-regulated kinase, Rac, and PI3K signaling did not eliminate EGF from rescuing fibroblasts in the face of this cytokine. These findings indicate that EGF receptor activation provides survival response against staurosporine-induced apoptosis through signal pathways of PI3K and Rac, which then may prevent the activation of caspase-3.
Studies in our laboratory indicate that collagenase from Clostridium histolyticum promotes endothelial cell and keratinocyte responses to injury in vitro and wound healing in vivo. We postulate that matrix degradation by Clostridial collagenase creates bioactive fragments that can stimulate cellular responses to injury and angiogenesis. To test this hypothesis, we performed limited digestion of defined capillary-endothelial-derived extracellular matrices using purified human or bacterial collagenases. Immunoprecipitation with antibodies recognizing collagens I, II, III, IV, and V, followed by mass spectrometry reveals the presence of unique fragments in bacterial, but not human-enzyme-digested matrix. Results show that there are several bioactive peptides liberated from Clostridial collagenase-treated matrices, which facilitate endothelial responses to injury, and accelerate microvascular remodeling in vitro. Fragments of collagen IV, fibrillin-1, tenascin X, and a novel peptide created by combining specific amino acids contained within fibrillin 1 and tenascin X each have profound proangiogenic properties. The peptides used at 10-100 nM increase rates of microvascular endothelial cell proliferation by up to 47% and in vitro angiogenesis by 200% when compared with serum-stimulated controls. Current studies are aimed at revealing the molecular mechanisms regulating peptide-induced wound healing while extending these in vitro observations using animal modeling.
Resolution of inflammation is critical for normal wound healing. Inflammation is prolonged and fails to resolve properly in chronic wounds. We used in vivo and in vitro approaches to show that vascular endothelial growth factor (VEGF) induces macrophage apoptosis and to delineate mechanisms involved in this process. VEGF inhibition during wound healing leads to an increased number of macrophages remaining in wounds, suggesting the involvement of VEGF in removal of these cells from the wound. If this effect has physiological relevance, it likely occurs via apoptosis. We show that VEGF increases apoptosis of macrophages in vitro using Annexin V-FITC staining and caspase activation. Microarray analysis, reverse transcription-polymerase chain reaction, and immunoblotting showed that VEGF increases the expression of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) in macrophages. We also show that in macrophages LIGHT promotes apoptosis through the lymphotoxin beta receptor. Moreover, inhibition of LIGHT prevents VEGF-induced death, suggesting that LIGHT mediates VEGF-induced macrophage apoptosis. Taken together, our results identify a novel role for VEGF and for LIGHT in macrophage apoptosis during wound healing, an event critical in the resolution of inflammation. This finding may lead to the development of new strategies to improve resolution of inflammation in problematic wounds.
Tunicates are useful models for comparing differing developmental processes such as embryogenesis, asexual reproduction, and regeneration, because they are the closest relatives to vertebrates and are the only chordates to reproduce both sexually and asexually. Among them, the ascidian Botryllus schlosseri displays high regenerative potential of the colonial circulatory system (CCS). The CCS runs in the common tunic, forming an anastomized network of vessels defined by simple epithelia and connected to the open circulatory system of the zooids. During asexual propagation, new vessels form by means of a tubular-sprouting mechanism, resembling that occurring in other metazoans, particularly during vertebrate angiogenesis. We studied the regeneration of experimentally ablated CCS by analyzing the general dynamics of reorganization of vessels and tunic, their ultrastructure, cell proliferation, and the immunohistology of regenerating structures using antibodies against vertebrate angiogenic factors-vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), and receptors: VEGFR-1, VEGFR-2, and EGFR. Results show that the regenerative process of CCS occurs by a sprouting mechanism, with participation of angiogenic factors. They also show correspondence between the CCS sprouting of B. schlosseri and angiogenic sprouting in vertebrates, during both normal development and regeneration, and support the idea that this morphogenetic mechanism was co-opted during the evolution of various developmental processes in different taxa.
We deleted the hypoxia-responsive transcription factor HIF-1alpha in endothelial cells (EC) to determine its role during neovascularization. We found that loss of HIF-1alpha inhibits a number of important parameters of EC behavior during angiogenesis: these include proliferation, chemotaxis, extracellular matrix penetration, and wound healing. Most strikingly, loss of HIF-1alpha in EC results in a profound inhibition of blood vessel growth in solid tumors. These phenomena are all linked to a decreased level of VEGF expression and loss of autocrine response of VEGFR-2 in HIF-1alpha null EC. We thus show that a HIF-1alpha-driven, VEGF-mediated autocrine loop in EC is an essential component of solid tumor angiogenesis.
For most of the last century, chronic wound care was a practice of passive techniques, designed to prevent the progression of the wound. In the last decade, however, advanced techniques have focused on improving the wound at the molecular level to accelerate wound healing. Successful modalities include tissue-engineered products, hyperbaric oxygen, negative pressure therapy, electrical stimulation, and recombinant growth factors. This shift in the treatment of wound care saw the development of a recombinant human platelet-derived growth factor, becaplermin, which stimulates granulation and increases the incidence of complete wound closure. Another product is oxidized regenerated cellulose/collagen, which protects growth factors and granulation tissue by inhibiting wound proteases. Used together, an optimal environment for wound healing can be created.
Microvascular permeability is a pharmacologic indicator of tumor response to therapy, and it is expected that this biomarker will evolve into a clinical surrogate endpoint and be integrated into protocols for determining patient response to antiangiogenic or antivascular therapies. This review discusses the physiological context of vessel permeability in an imaging setting, how it is affected by active and passive transport mechanisms, and how it is described mathematically for both theoretical and complex dynamic microvessel membranes. Many research groups have established dynamic-enhanced imaging protocols for estimating this important parameter. This review discusses those imaging modalities, the advantages and disadvantages of each, and how they compare in terms of their ability to deliver information about therapy-associated changes in microvessel permeability in humans. Finally, this review discusses future directions and improvements needed in these areas.
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