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1.
Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under "pathological" conditions ex vivo.
Post, H, Hundt, JE, Zhang, G, Depping, R, Rose, C, Langan, EA, Paus, R
Archives of dermatological research. 2021;(3):181-192
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Abstract
Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic "pathological" wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams' E medium or in unsupplemented medium under "pathological" conditions (i.e. hypoxia [5% O2], oxidative damage [10 mM H2O2], absence of insulin, excess glucose). Under these "pathological" conditions, dermal-epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (p < 0.001), associated with reduced keratinocyte proliferation (p < 0.001), cytokeratin 6 expression (p < 0.001) and increased apoptosis (p < 0.001). Moreover, markers of intracutaneous angiogenesis (CD31 immunoreactivity and the number of of CD31 positive cells and CD31 positive vessel lumina) were significantly reduced. Since we had previously shown that thyroxine promotes wound healing in healthy human skin ex vivo, we tested whether this in principle also occurs under "pathological" wound healing conditions. Indeed, thyroxine administration sufficed to rescue re-epithelialisation (p < 0.001) and promoted both epidermal keratinocyte proliferation (p < 0.01) and angiogenesis in terms of CD31 immunoreactivity and CD31 positive cells under "pathological" conditions (p < 0.001) ex vivo. This demonstrates the utility of this pragmatic short-term ex vivo model, which recapitulates some key parameters of impaired human skin wound healing, for the preclinical identification of promising wound healing promoters.
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Regulation of Obesity by Antiangiogenic Herbal Medicines.
Shin, SS, Yoon, M
Molecules (Basel, Switzerland). 2020;(19)
Abstract
Obesity is the result of an energy imbalance caused by an increased ratio of caloric intake to energy expenditure. In conjunction with obesity, related metabolic disorders, such as dyslipidemia, atherosclerosis, and type 2 diabetes, have become global health problems. Obesity progression is thought to be associated with angiogenesis and extracellular matrix (ECM) remodeling. Angiogenesis occurs in growing adult adipose tissues, which are similar to neoplastic tissues. Adipose tissue is highly vascularized, and each adipocyte is nourished by an extensive capillary network. Adipocytes produce proangiogenic factors, such as vascular endothelial growth factor A and fibroblast growth factor 2, which promote neovascularization within the adipose tissue. Furthermore, matrix metalloproteinases (MMPs), including MMP-2 and MMP-9, play important roles in adipose tissue development and microvessel maturation by modifying the ECM. Thus, modulation of angiogenesis and MMP activity provides a promising therapeutic approach for controlling human obesity and its related disorders. Over the past decade, there has been a great increase in the use of alternative treatments, such as herbal remedies, for these diseases. This review will focus on the role of angiogenesis in adipose tissue growth and the regulation of obesity by antiangiogenic herbal medicines.
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Therapeutic Approaches of Resveratrol on Endometriosis via Anti-Inflammatory and Anti-Angiogenic Pathways.
Dull, AM, Moga, MA, Dimienescu, OG, Sechel, G, Burtea, V, Anastasiu, CV
Molecules (Basel, Switzerland). 2019;(4)
Abstract
Endometriosis represents a severe gynecological pathology, defined by implantation of endometrial glands and stroma outside the uterine cavity. This pathology affects almost 15% of women during reproductive age and has a wide range of consequences. In affected women, infertility has a 30% rate of prevalence and endometriosis implants increase the risk of ovarian cancer. Despite long periods of studies and investigations, the etiology and pathogenesis of this disease still remain not fully understood. Initially, endometriosis was related to retrograde menstruation, but new theories have been launched, suggesting that chronic inflammation can influence the development of endometriosis because inflammatory mediators have been identified elevated in patients with endometriosis, specifically in the peritoneal fluid. The importance of dietary phytochemicals and their effect on different inflammatory diseases have been highlighted, and nowadays more and more studies are focused on the analysis of nutraceuticals. Resveratrol is a phytoestrogen, a natural polyphenolic compound with antiproliferative and anti-inflammatory actions, found in many dietary sources such as grapes, wine, peanuts, soy, berries, and stilbenes. Resveratrol possesses a significant anti-inflammatory effect via inhibition of prostaglandin synthesis and it has been proved that resveratrol can exhibit apoptosis-inducing activities. From the studies reviewed in this paper, it is clear that the anti-inflammatory effect of this natural compound can contribute to the prevention of endometriosis, this phenolic compound now being considered a new innovative drug in the prevention and treatment of this disease.
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Potential molecular mechanisms underlying the effect of arsenic on angiogenesis.
Zhang, J, Zhang, Y, Wang, W, Zhang, Z
Archives of pharmacal research. 2019;(11):962-976
Abstract
Arsenic is a potent chemotherapeutic drug that is applied as a treatment for cancer; it exerts its functions through multiple pathways, including angiogenesis inhibition. As angiogenesis is a critical component of the progression of many diseases, arsenic is a feasible treatment option for patients with other angiogenic diseases, including rheumatoid arthritis and psoriasis, among others. However, arsenic is also a well-known carcinogen, demonstrating a pro-angiogenesis effect. This review will focus on the dual effects of arsenic on neovascularization and the relevant mechanisms underlying these effects, aiming to provide a rational understanding of arsenic treatment. In particular, we expect to provide a comprehensive overview of the current knowledge of the mechanisms by which arsenic influences angiogenesis.
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Enantioselective Synthesis of Homoisoflavanones by Asymmetric Transfer Hydrogenation and Their Biological Evaluation for Antiangiogenic Activity.
Heo, M, Lee, B, Sishtla, K, Fei, X, Lee, S, Park, S, Yuan, Y, Lee, S, Kwon, S, Lee, J, et al
The Journal of organic chemistry. 2019;(16):9995-10011
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Abstract
Neovascular eye diseases are a major cause of blindness. Excessive angiogenesis is a feature of several conditions, including wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity. Development of novel antiangiogenic small molecules for the treatment of neovascular eye disease is essential to provide new therapeutic leads for these diseases. We have previously reported the therapeutic potential of anti-angiogenic homoisoflavanone derivatives with efficacy in retinal and choroidal neovascularization models, although these are racemic compounds due to the C3-stereogenic center in the molecules. This work presents asymmetric synthesis and structural determination of anti-angiogenic homoisoflavanones and pharmacological characterization of the stereoisomers. We describe an enantioselective synthesis of homoisoflavanones by virtue of ruthenium-catalyzed asymmetric transfer hydrogenation accompanying dynamic kinetic resolution, providing a basis for the further development of these compounds into novel experimental therapeutics for neovascular eye diseases.
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Chronic Resveratrol Treatment Reduces the Pro-angiogenic Effect of Human Fibroblast "Senescent-Associated Secretory Phenotype" on Endothelial Colony-Forming Cells: The Role of IL8.
Menicacci, B, Margheri, F, Laurenzana, A, Chillà, A, Del Rosso, M, Giovannelli, L, Fibbi, G, Mocali, A
The journals of gerontology. Series A, Biological sciences and medical sciences. 2019;(5):625-633
Abstract
Senescent cells are characterized by an increased secretion of inflammatory and growth factors, known as the "senescence-associated secretory phenotype" (SASP), producing a pro-tumoral and pro-angiogenic microenvironment. This work proposes chronic resveratrol treatment (5 µM for 5 weeks, termed R5) of senescent MRC5 fibroblasts as a mean to mimic and target the angiogenic trait of stromal fibroblast SASP. Senescent fibroblast conditioned medium (CM sen) was effective in enhancing the angiogenic properties of endothelial colony-forming cells (ECFCs), that is, invasive activity and capillary morphogenesis capability in vitro, that were significantly reduced when conditioned media were collected after resveratrol pretreatment (CM senR5). The attenuation of ECFC angiogenic phenotype induced by CM senR5 was accompanied by reduced protein levels of epidermal growth factor and urokinase plasminogen activator receptors (EGFR, uPAR), and by a related decreased activation of receptor-tyrosine-kinase signaling pathways. IL8 levels were found reduced in CM senR5 compared to CM sen, with the associated reduction of IL8-CXCR2 binding in ECFCs. IL8-subtraction mitigated the pro-angiogenic features of CM sen and the associated intracellular signaling in ECFCs, indicating a prominent role of IL8 in the pro-angiogenic effects of CM sen. IL8 modulation is an important mechanism underlying the antiangiogenic activity of resveratrol on MRC5 SASP.
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Manipulating Intracellular Ca2+ Signals to Stimulate Therapeutic Angiogenesis in Cardiovascular Disorders.
Moccia, F, Berra-Romani, R, Rosti, V
Current pharmaceutical biotechnology. 2018;(9):686-699
Abstract
Endothelial progenitor cells (EPCs) are mobilized in peripheral blood to rescue blood perfusion in ischemic tissues. Several approaches were, therefore, designed to inject autologous EPCs and induce therapeutic angiogenesis in patients affected by cardiovascular disorders. Endothelial colony forming cells (ECFCs) represent the only truly endothelial precursors and are regarded as the most suitable substrate for cell based therapy of ischemic diseases. Intracellular Ca2+ signalling drives ECFC proliferation, migration, homing and neovessel formation. Vascular endothelial growth factor (VEGF) triggers repetitive oscillations in intracellular Ca2+ concentration ([Ca2+]i) in peripheral blood- and umbilical cord blood-derived ECFCs by initiating a dynamic interplay between inositol-1,4,5-trisphosphate (InsP3)-dependent Ca2+ release and store-operated Ca2+ entry (SOCE). SOCE, in turn, is mediated by Stim1, Orai1 and Transient Receptor Potential (TRP) Canonical 1 (TRPC1). Intriguingly, intracellular Ca2+ oscillations are triggered by TRPC3 in umbilical cord blood-derived ECFCs, which display higher proliferative potential. Additionally, stromal cell-derived factor-1α (SDF-1α) triggers a biphasic increase in [Ca2+]i in ECFCs which is mediated by InsP3 receptors (InsP3Rs) and SOCE. Finally, arachidonic acid (AA) and nicotinic acid adenine dinucleotide phosphate (NAADP) stimulate ECFC proliferation by stimulating two-pore channel 1 (TPC1), thereby promoting Ca2+ release from the endolysosomal Ca2+ compartment. AA-evoked Ca2+ signals are further supported by InsP3Rs and TRP Vanilloid 4 (TRPV4). In this article, we describe how genetic manipulation of the Ca2+ toolkit (i.e. TRPC3, SOCE, TPC1) endowed to circulating ECFCs could rejuvenate or restore their reparative phenotype for therapeutic angiogenesis purposes.
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Panta Rhei: Neovascularization, Angiogenesis and Nutritive Perfusion in Wound Healing.
Sorg, H, Tilkorn, DJ, Mirastschijski, U, Hauser, J, Kraemer, R
European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes. 2018;(3-4):232-241
Abstract
BACKGROUND In response to tissue damage, angiogenesis is an extremely dynamic process that is finely regulated by signals from cells, the surrounding extracellular matrix (ECM), and derived mediators. As the only process, angiogenesis remains of decisive importance in the context of the entire wound healing process and is subject to constant change. The dissolution of the endothelial basement membrane, the migration of endothelial cells, and the development of new capillary vessels during wound healing depend not only on the cells and cytokines present, but also on the production and organization of ECM components in the immediate wound. SUMMARY Angiogenesis in wound healing can be divided into two main phases. During the pro-angiogenic phase at the beginning of wound healing, excessive neo-formation of blood vessels, some of which are poorly differentiated, occurs, which restore blood flow and thus nutritive perfusion as quickly as possible. This is followed by an anti-angiogenic phase in which the initially established vascular network undergoes a maturing process, which, however, is accompanied by a significant reduction in the number of vessels. Key Messages: Although many mechanisms and specific cell functions in wound healing have already been described, many underlying pathophysiological processes remain unknown. Because angiogenesis and its maturation is a very fast but also very long-lasting process, the understanding of the underlying mechanisms is of crucial importance. This article will give an overview of the current understanding and controversy in this sub-step of wound healing.
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The role of fibrinolysis inhibition in engineered vascular networks derived from endothelial cells and adipose-derived stem cells.
Mühleder, S, Pill, K, Schaupper, M, Labuda, K, Priglinger, E, Hofbauer, P, Charwat, V, Marx, U, Redl, H, Holnthoner, W
Stem cell research & therapy. 2018;(1):35
Abstract
BACKGROUND Co-cultures of endothelial cells with mesenchymal stem cells currently represent one of the most promising approaches in providing oxygen and nutrient supply for microvascular tissue engineering. Still, to translate this model into clinics several in vitro parameters including growth medium and scaffold degradation need to be fine-tuned. METHODS We recently described the co-culture of adipose-derived stem cells with endothelial cells in fibrin, resulting in capillary formation in vitro as well as their perfusion in vivo. Here, we aimed to further characterise microvascular tube formation in fibrin by determining the role of scaffold degradation, thrombin concentration and culture conditions on vascularisation. RESULTS We observed that inhibition of cell-mediated fibrin degradation by the commonly used inhibitor aprotinin resulted in impaired vascular network formation. Aprotinin had no effect on laminin and collagen type IV deposition or formation of tube-like structures in scaffold-free co-culture, indicating that poor vascularisation of fibrin clots is primarily caused by inhibition of plasminogen-driven fibrinolysis. Co-culture in plasminogen- and factor XIII-depleted fibrin did not result in different vascular network density compared to controls. Furthermore, we demonstrate that thrombin negatively affects vascular network density at high concentrations. However, only transient activation of incorporated endothelial cells by thrombin could be observed, thus excluding a long-term inflammatory response in tissue-engineered micro-capillaries. Finally, we show that vascularisation of fibrin scaffolds in basal medium is undermined because of increased fibrinolytic activity leading to scaffold destabilisation without aprotinin. CONCLUSIONS Taken together, our data reveal a critical role of fibrinolysis inhibition in in vitro cell-mediated vascularisation of fibrin scaffolds.
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GPR182 is a novel marker for sinusoidal endothelial differentiation with distinct GPCR signaling activity in vitro.
Schmid, CD, Schledzewski, K, Mogler, C, Waldburger, N, Kalna, V, Marx, A, Randi, AM, Géraud, C, Goerdt, S, Koch, PS
Biochemical and biophysical research communications. 2018;(1):32-38
Abstract
Endothelial cells (EC) along the vascular tree exhibit organ-specific angiodiversity. Compared to most other ECs, liver sinusoidal endothelial cells (LSEC) that constitute the organ-specific microvasculature of the liver are morphologically and functionally unique. Previously, we showed that transcription factor Gata4 acts as a master regulator controlling LSEC differentiation. Upon analysis of the molecular signature of LSEC, we identified GPR182 as a potential LSEC-specific orphan G-protein coupled receptor (GPCR). Here, we demonstrate that GPR182 is expressed by LSEC and by EC with sinusoidal differentiation in spleen, lymph node and bone marrow in healthy human tissues. In a tissue microarray analysis of human hepatocellular carcinoma (HCC) samples, endothelial GPR182 expression was significantly reduced in tumor samples compared to peritumoral liver tissue samples (p = 0.0105). Loss of endothelial GPR182 expression was also seen in fibrotic and cirrhotic liver tissues. In vitro, GPR182 differentially regulated canonical GPCR signaling pathways as shown using reporter luciferase assays in HEK293T cells. Whereas ERK and RhoA signaling were inhibited, CREB and Calcium signaling were activated by ectopic GPR182 overexpression. Our data demonstrate that GPR182 is an endothelial subtype-specific marker for human sinusoidal EC of the liver, spleen, lymph node and bone marrow. In addition, we provide evidence for GPR182-dependent downstream signaling via ERK and SRF pathways that may be involved in regulating endothelial subtype-specific sinusoidal differentiation and sinusoidal functions such as permeability.