21 results on '"Mikelis, Constantinos M."'
Search Results
2. Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions
- Author
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Sajib, Sanaullah, Zahra, Fatema Tuz, Lionakis, Michail S., German, Nadezhda A., and Mikelis, Constantinos M.
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- 2018
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3. Protein tyrosine phosphatase receptor-ξ1 deletion triggers defective heart morphogenesis in mice and zebrafish.
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Katraki-Pavlou, Stamatiki, Kastana, Pinelopi, Bousis, Dimitris, Ntenekou, Despoina, Varela, Aimilia, Davos, Constantinos H., Nikou, Sophia, Papadaki, Eleni, Tsigkas, Grigorios, Athanasiadis, Emmanouil, Herradon, Gonzalo, Mikelis, Constantinos M., Beis, Dimitris, and Papadimitriou, Evangelia
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PROTEIN-tyrosine phosphatase ,PHOSPHOPROTEIN phosphatases ,FETAL heart ,BRACHYDANIO ,EMBRYONIC stem cells ,DOBUTAMINE ,CONTRACTILE proteins - Abstract
Protein tyrosine phosphatase receptor-ξ1 (PTPRZ1) is a transmembrane tyrosine phosphatase receptor highly expressed in embryonic stem cells. In the present work, gene expression analyses of Ptprz1-/- and Ptprz1þ/þ mice endothelial cells and hearts pointed to an unidentified role of PTPRZ1 in heart development through the regulation of heart-specific transcription factor genes. Echocardiography analysis in mice identified that both systolic and diastolic functions are affected in Ptprz1-/-compared with Ptprz1þ/þ hearts, based on a dilated left ventricular (LV) cavity, decreased ejection fraction and fraction shortening, and increased angiogenesis in Ptprz1-/- hearts, with no signs of cardiac hypertrophy. A zebrafish ptprz1-/- knockout was also generated and exhibited misregulated expression of developmental cardiac markers, bradycardia, and defective heart morphogenesis characterized by enlarged ventricles and defected contractility. A selective PTPRZ1 tyrosine phosphatase inhibitor affected zebrafish heart development and function in a way like what is observed in the ptprz1-/- zebrafish. The same inhibitor had no effect in the function of the adult zebrafish heart, suggesting that PTPRZ1 is not important for the adult heart function, in line with data from the human cell atlas showing very low to negligible PTPRZ1 expression in the adult human heart. However, in line with the animal models, Ptprz1 was expressed in many different cell types in the human fetal heart, such as valvar, fibroblast-like, cardiomyocytes, and endothelial cells. Collectively, these data suggest that PTPRZ1 regulates cardiac morphogenesis in a way that subsequently affects heart function and warrant further studies for the involvement of PTPRZ1 in idiopathic congenital cardiac pathologies. [ABSTRACT FROM AUTHOR]
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- 2022
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4. MiRNAs as Anti-Angiogenic Adjuvant Therapy in Cancer: Synopsis and Potential.
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Lahooti, Behnaz, Poudel, Sagun, Mikelis, Constantinos M., and Mattheolabakis, George
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NEOVASCULARIZATION inhibitors ,CANCER treatment ,DRUG target ,MICRORNA ,REGULATOR genes - Abstract
Angiogenesis is a key mechanism for tumor growth and metastasis and has been a therapeutic target for anti-cancer treatments. Intensive vascular growth is concomitant with the rapidly proliferating tumor cell population and tumor outgrowth. Current angiogenesis inhibitors targeting either one or a few pro-angiogenic factors or a range of downstream signaling molecules provide clinical benefit, but not without significant side effects. miRNAs are important post-transcriptional regulators of gene expression, and their dysregulation has been associated with tumor progression, metastasis, resistance, and the promotion of tumor-induced angiogenesis. In this mini-review, we provide a brief overview of the current anti-angiogenic approaches, their molecular targets, and side effects, as well as discuss existing literature on the role of miRNAs in angiogenesis. As we highlight specific miRNAs, based on their activity on endothelial or cancer cells, we discuss their potential for anti-angiogenic targeting in cancer as adjuvant therapy and the importance of angiogenesis being evaluated in such combinatorial approaches. [ABSTRACT FROM AUTHOR]
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- 2021
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5. Pleiotrophin selectively binds to vascular endothelial growth factor receptor 2 and inhibits or stimulates cell migration depending on ανβ3 integrin expression.
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Lamprou, Margarita, Kastana, Pinelopi, Kofina, Fani, Tzoupis, Ηaralampos, Barmpoutsi, Spyridoula, Sajib, Md Sanaullah, Koutsioumpa, Marina, Poimenidi, Evangelia, Zompra, Aikaterini A., Tassopoulos, Dimitrios, Choleva, Effrosyni, Tselios, Theodore, Mikelis, Constantinos M., and Papadimitriou, Evangelia
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VASCULAR endothelial growth factor receptors ,CELL migration ,CELLULAR control mechanisms ,PROTHROMBIN - Abstract
Pleiotrophin (PTN) has a moderate stimulatory effect on endothelial cell migration through α
ν β3 integrin, while it decreases the stimulatory effect of vascular endothelial growth factor A (VEGFA) and inhibits cell migration in the absence of αν β3 through unknown mechanism(s). In the present work, by using a multitude of experimental approaches, we show that PTN binds to VEGF receptor type 2 (VEGFR2) with a KD of 11.6 nM. Molecular dynamics approach suggests that PTN binds to the same VEGFR2 region with VEGFA through its N-terminal domain. PTN inhibits phosphorylation of VEGFR2 at Tyr1175 and still stimulates endothelial cell migration in the presence of a selective VEGFR2 tyrosine kinase inhibitor. VEGFR2 downregulation by siRNA or an anti-VEGFR2 antibody that binds to the ligand-binding VEGFR2 domain also induce endothelial cell migration, which is abolished by a function-blocking antibody against αν β3 or the peptide PTN112−136 that binds αν β3 and inhibits PTN binding. In cells that do not express αν β3 , PTN decreases both VEGFR2 Tyr1175 phosphorylation and cell migration in a VEGFR2-dependent manner. Collectively, our data identify VEGFR2 as a novel PTN receptor involved in the regulation of cell migration by PTN and contribute to the elucidation of the mechanism of activation of endothelial cell migration through the interplay between VEGFR2 and αν β3 . [ABSTRACT FROM AUTHOR]- Published
- 2020
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6. Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer.
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Zahra, Fatema Tuz, Sajib, Md. Sanaullah, Mikelis, Constantinos M., and Ribatti, Domenico
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VASCULAR endothelial growth factor antagonists ,NEOVASCULARIZATION inhibitors ,FIBROBLASTS ,GROWTH factors ,NEOVASCULARIZATION ,CANCER ,MOLECULAR biology ,TUMORS ,DRUG resistance in cancer cells ,MEDICAL research - Abstract
Simple Summary: Anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) signaling are established in the arsenal of cancer treatments. Despite the expectations, their benefits are temporary in cancer patients, partly due to the compensatory function of other angiogenic growth factors. This review focuses on the role of basic fibroblast growth factor (bFGF), one of the highly implicated players in the emergence of resistance to anti-angiogenic approaches. Here, we summarize data from various tumor types where bFGF is upregulated after anti-angiogenic treatment, the molecular mechanisms involved, and we highlight the current status and future perspectives of multi-target anti-angiogenic drugs for cancer. Anti-angiogenic approaches targeting the vascular endothelial growth factor (VEGF) signaling pathway have been a significant research focus during the past decades and are well established in clinical practice. Despite the expectations, their benefit is ephemeral in several diseases, including specific cancers. One of the most prominent side effects of the current, VEGF-based, anti-angiogenic treatments remains the development of resistance, mostly due to the upregulation and compensatory mechanisms of other growth factors, with the basic fibroblast growth factor (bFGF) being at the top of the list. Over the past decade, several anti-angiogenic approaches targeting simultaneously different growth factors and their signaling pathways have been developed and some have reached the clinical practice. In the present review, we summarize the knowledge regarding resistance mechanisms upon anti-angiogenic treatment, mainly focusing on bFGF. We discuss its role in acquired resistance upon prolonged anti-angiogenic treatment in different tumor settings, outline the reported resistance mechanisms leading to bFGF upregulation, and summarize the efforts and outcome of combined anti-angiogenic approaches to date. [ABSTRACT FROM AUTHOR]
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- 2021
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7. Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis.
- Author
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Srivastava, Suyash, Zahra, Fatema Tuz, Gupta, Nehal, Tullar, Paul E., Srivastava, Sanjay K., and Mikelis, Constantinos M.
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METASTATIC breast cancer ,NEOVASCULARIZATION ,VASCULAR endothelial growth factors ,ENDOTHELIAL cells ,CELL migration ,BLOOD-brain barrier - Abstract
Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood–brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology.
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Akwii, Racheal G., Sajib, Md S., Zahra, Fatema T., and Mikelis, Constantinos M.
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ANGIOPOIETIN-2 ,VASCULAR endothelial growth factors ,GROWTH factors ,ANGIOPOIETINS ,ENDOTHELIAL cells ,MOLECULAR pathology - Abstract
Angiopoietins 1–4 (Ang1–4) represent an important family of growth factors, whose activities are mediated through the tyrosine kinase receptors, Tie1 and Tie2. The best characterized are angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2). Ang1 is a potent angiogenic growth factor signaling through Tie2, whereas Ang2 was initially identified as a vascular disruptive agent with antagonistic activity through the same receptor. Recent data demonstrates that Ang2 has context-dependent agonist activities. Ang2 plays important roles in physiological processes and the deregulation of its expression is characteristic of several diseases. In this review, we summarize the activity of Ang2 on blood and lymphatic endothelial cells, its significance in human physiology and disease, and provide a current view of the molecular signaling pathways regulated by Ang2 in endothelial cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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9. Cell–Extracellular Matrix Adhesions in Vascular Endothelium
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Valaris, Sophia, Kostourou, Vassiliki, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
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10. Leading Roles of Heparan Sulfate in Angiogenesis and Cancer
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Lopes, Carla Cristina, Onyeisi, Jessica Oyie Sousa, Meneghetti, Maria Cecilia Zorél, Melo, Carina Mucciolo, Vicente, Carolina Meloni, de Azevedo, Luis Cesar, da Silva Pinhal, Maria Aparecida, Toma, Leny, Nader, Helena Bonciani, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
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11. Hypoxia: A Potent Regulator of Angiogenesis Through Extracellular Matrix Remodelling
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Karavasili, Katerina, Koolwijk, Pieter, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
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12. Kruppel-Like Factor 2 and Matrix Metalloproteinases in the Context of Vasculature
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Anderson, Sarah, Barthels, Derek, Das, Hiranmoy, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
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13. Fibronectin Fibrillogenesis During Angiogenesis
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Gan, Xiangyi, Ramesh, Lariza, Nair, Nidhi, Sundararaman, Ananthalakshmy, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
- Full Text
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14. Extracellular Matrix Remodeling Enzymes as Targets for Natural Antiangiogenic Compounds
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Carrillo, Paloma, García-Caballero, Melissa, Bernal, Manuel, Manrique-Poyato, María Inmaculada, Martínez-Poveda, Beatriz, Quesada, Ana R., Medina, Miguel Ángel, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
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15. Collagens and Collagen-Degrading Enzymes in the Regulation of Angiogenesis
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Kanellopoulou, Vasiliki Κ., Xanthopoulos, Athanasios, Mikelis, Constantinos Marios, Papadimitriou, Evangelia, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
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16. The Role of Pericytes in Tumor Angiogenesis
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Ribatti, Domenico, Solimando, Antonio Giovanni, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
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17. Endothelial Cell–Matrix Interactions in Angiogenesis and Vessel Homeostasis: A Focus on Laminins and Their Integrin Receptors
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LaFlamme, Susan E., Xu, Hao, Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
- Full Text
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18. Functional Interplay Between Fibronectin and Matricellular Proteins in the Control of Endothelial Tubulogenesis
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Morandi, Verônica, Fernandes, Laila R., Silva de Barros, Aline O., Karamanos, Nikos K., Series Editor, Kletsas, Dimitris, Editorial Board Member, Oh, Eok-Soo, Editorial Board Member, Passi, Alberto, Editorial Board Member, Pihlajaniemi, Taina, Editorial Board Member, Ricard-Blum, Sylvie, Editorial Board Member, Sagi, Irit, Editorial Board Member, Savani, Rashmin, Editorial Board Member, Watanabe, Hideto, Editorial Board Member, Papadimitriou, Evangelia, editor, and Mikelis, Constantinos M., editor
- Published
- 2023
- Full Text
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19. Delayed Exercise-induced Upregulation of Angiogenic Proteins and Recovery of Motor Function after Photothrombotic Stroke in Mice.
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Al Shoyaib, Abdullah, Alamri, Faisal F., Biggers, Abbie, Karamyan, Serob T., Arumugam, Thiruma V., Ahsan, Fakhrul, Mikelis, Constantinos M., Al-Hilal, Taslim A., and Karamyan, Vardan T.
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VASCULAR endothelial growth factors , *MOLECULAR motor proteins , *ISCHEMIC stroke , *CEREBRAL cortex , *MICE - Abstract
• Dose-dependent effect of delayed physiotherapy on post-stroke recovery was studied. • Overnight but not 5 h voluntary wheel running promoted post-stroke motor recovery. • Recovery of motor function was accompanied by induction of angiogenic proteins. • Induction of angiogenic proteins was observed in peri-infract region and infarct core. • Infarct core maybe involved in mechanisms governing post-stroke functional recovery. Treatments promoting post-stroke functional recovery continue to be an unmet therapeutic problem with physical rehabilitation being the most reproduced intervention in preclinical and clinical studies. Unfortunately, physiotherapy is typically effective at high intensity and early after stroke – requirements that are hardly attainable by stroke survivors. The aim of this study was to directly evaluate and compare the dose-dependent effect of delayed physical rehabilitation (daily 5 h or overnight voluntary wheel running; initiated on post-stroke day 7 and continuing through day 21) on recovery of motor function in the mouse photothrombotic model of ischemic stroke and correlate it with angiogenic potential of the brain. Our observations indicate that overnight but not 5 h access to running wheels facilitates recovery of motor function in mice in grid-walking test. Western blotting and immunofluorescence microscopy experiments evaluating the expression of angiogenesis-associated proteins VEGFR2, doppel and PDGFRβ in the peri-infarct and corresponding contralateral motor cortices indicate substantial upregulation of these proteins (≥2-fold) in the infarct core and surrounding cerebral cortex in the overnight running mice on post-stroke day 21. These findings indicate that there is a dose-dependent relationship between the extent of voluntary exercise, motor recovery and expression of angiogenesis-associated proteins in this expert-recommended mouse ischemic stroke model. Notably, our observations also point out to enhanced angiogenesis and presence of pericytes within the infarct core region during the chronic phase of stroke, suggesting a potential contribution of this tissue area in the mechanisms governing post-stroke functional recovery. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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20. Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation.
- Author
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Huwaimel, Bader I., Jonnalagadda, Sravan, Jonnalagadda, Shirisha, Zahra, Fatema T., Nocentini, Alessio, Supuran, Claudiu T., Mikelis, Constantinos M., and Trippier, Paul C.
- Subjects
- *
NEOVASCULARIZATION , *NEOVASCULARIZATION inhibitors , *DRUG therapy , *PHOSPHORYLATION - Abstract
[Display omitted] Angiogenesis inhibitors are a critical pharmacological tool for the treatment of solid tumors. Suppressing vascular permeability leads to inhibition of tumor growth, invasion, and metastatic potential by blocking the supply of oxygen and nutrients. Disruption of the vascular endothelial growth factor (VEGF) signaling pathway is a validated target for the design of antiangiogenic agents. Several VEGFR2 inhibitors have been clinically approved over the past years. Structural analysis of these clinical VEGFR2 inhibitors highlighted key functional group overlap with the benzothiadiazine core contained in a library of in-house compounds. Herein we ascribe anti-angiogenic activity to a series of chlorinated benzothiadiazines. Selected compounds show significant activity to completely ameliorate VEGF-induced endothelial cell proliferation by suppression of VEGFR2 phosphorylation. The scaffold is devoid of activity to inhibit carbonic anhydrases and generally lacks cytotoxicity across a range of cancer and non-malignant cell lines. Assay of activity at 468 kinases shows remarkable selectivity with only four kinases inhibited > 65% at 10 µM concentration, and with significant activity to inhibit TNK2/ACK1 and PKRD2 by > 90%. All four identified kinase targets are known modulators of angiogenesis, thus highlighting compound 17b as a novel angiogenesis inhibitor for further development. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
21. CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis
- Author
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J. Silvio Gutkind, Amber N. Stratman, Brigid D. Lo, Brant M. Weinstein, Constantinos M. Mikelis, Kameha R. Kidd, Makoto Kamei, Weijun Pan, George E. Davis, Kenna M. Shaw, Daniel Castranova, Van N. Pham, Jesús Torres-Vázquez, Pan, Weijun, Pham, Van N, Stratman, Amber N, Castranova, Daniel, Kamei, Makoto, Kidd, Kameha R, Lo, Brigid D, Shaw, Kenna M, Torres-Vázquez, Jesús, Mikelis, Constantinos M, Silvio Gutkind, J, Davis, George E, and Weinstein, Brant M
- Subjects
Vascular Endothelial Growth Factor A ,DNA, Complementary ,Angiogenesis ,Immunology ,Morphogenesis ,Neovascularization, Physiologic ,Phospholipase ,Biology ,Phosphatidylinositols ,Biochemistry ,Animals, Genetically Modified ,Neovascularization ,Vascular Biology ,In vivo ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Zebrafish ,in-vivo ,transgenic zebrafish ,vessel formation ,growth-factor ,angiogenesis ,synthase ,kinase ,vasculogenesis ,Base Sequence ,endothelial lumen formation ,Cell Biology ,Hematology ,Zebrafish Proteins ,biology.organism_classification ,Cell biology ,Vascular endothelial growth factor A ,Diacylglycerol Cholinephosphotransferase ,Mutation ,zebrafish embryos ,Blood Vessels ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,medicine.symptom ,Signal Transduction - Abstract
Understanding the mechanisms that regulate angiogenesis and translating these into effective therapies are of enormous scientific and clinical interests. In this report, we demonstrate the central role of CDP-diacylglycerol synthetase (CDS) in the regulation of VEGFA signaling and angiogenesis. CDS activity maintains phosphoinositide 4,5 bisphosphate (PIP2) availability through resynthesis of phosphoinositides, whereas VEGFA, mainly through phospholipase Cγ1, consumes PIP2 for signal transduction. Loss of CDS2, 1 of 2 vertebrate CDS enzymes, results in vascular-specific defects in zebrafish in vivo and failure of VEGFA-induced angiogenesis in endothelial cells in vitro. Absence of CDS2 also results in reduced arterial differentiation and reduced angiogenic signaling. CDS2 deficit-caused phenotypes can be successfully rescued by artificial elevation of PIP2 levels, and excess PIP2 or increased CDS2 activity can promote excess angiogenesis. These results suggest that availability of CDS-controlled resynthesis of phosphoinositides is essential for angiogenesis.
- Published
- 2012
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