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Showing 1 - 200 of 3562 Journals sorted alphabetically
16 de Abril     Open Access  
AADE in Practice     Hybrid Journal   (Followers: 4)
ABCS Health Sciences     Open Access   (Followers: 1)
Abia State University Medical Students' Association Journal     Full-text available via subscription  
ACIMED     Open Access   (Followers: 1)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
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African Health Sciences     Open Access   (Followers: 2)
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African Journal of Laboratory Medicine     Open Access   (Followers: 2)
African Journal of Medical and Health Sciences     Open Access   (Followers: 1)
African Journal of Trauma     Open Access  
Afrimedic Journal     Open Access   (Followers: 2)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
AIDS Research and Human Retroviruses     Hybrid Journal   (Followers: 8)
AJOB Primary Research     Partially Free   (Followers: 3)
Aktuelle Ernährungsmedizin     Hybrid Journal   (Followers: 4)
Al-Azhar Assiut Medical Journal     Open Access  
Alexandria Journal of Medicine     Open Access  
Allgemeine Homöopathische Zeitung     Hybrid Journal   (Followers: 2)
Alpha Omegan     Full-text available via subscription  
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
American Journal of Biomedical Engineering     Open Access   (Followers: 11)
American Journal of Biomedical Research     Open Access   (Followers: 2)
American Journal of Biomedicine     Full-text available via subscription   (Followers: 6)
American Journal of Chinese Medicine, The     Hybrid Journal   (Followers: 5)
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American Journal of Family Therapy     Hybrid Journal   (Followers: 11)
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American Journal of Medicine     Hybrid Journal   (Followers: 45)
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American Journal of Medicine Studies     Open Access  
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American Journal of the Medical Sciences     Hybrid Journal   (Followers: 12)
American Journal on Addictions     Hybrid Journal   (Followers: 9)
American Medical Journal     Open Access   (Followers: 4)
American medical news     Free   (Followers: 3)
American Medical Writers Association Journal     Full-text available via subscription   (Followers: 2)
Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 4)
Anales de la Facultad de Medicina     Open Access  
Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
Analgesia & Resuscitation : Current Research     Hybrid Journal   (Followers: 2)
Anatomical Science International     Hybrid Journal   (Followers: 2)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1)
Anatomy Research International     Open Access   (Followers: 2)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3)
Annales de Pathologie     Full-text available via subscription  
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annals of African Medicine     Open Access   (Followers: 1)
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Annals of Bioanthropology     Open Access   (Followers: 3)
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Annals of Fundeni Hospital     Open Access   (Followers: 1)
Annals of Ibadan Postgraduate Medicine     Open Access  
Annals of Medical and Health Sciences Research     Open Access   (Followers: 7)
Annals of Medicine     Hybrid Journal   (Followers: 11)
Annals of Medicine and Surgery     Open Access   (Followers: 5)
Annals of Microbiology     Hybrid Journal   (Followers: 10)
Annals of Nigerian Medicine     Open Access   (Followers: 1)
Annals of Saudi Medicine     Open Access  
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5)
Annals of The Royal College of Surgeons of England     Full-text available via subscription   (Followers: 3)
Annual Reports in Medicinal Chemistry     Full-text available via subscription   (Followers: 7)
Annual Reports on NMR Spectroscopy     Full-text available via subscription   (Followers: 4)
Annual Review of Medicine     Full-text available via subscription   (Followers: 18)
Anthropological Review     Open Access   (Followers: 24)
Anthropologie et santé     Open Access   (Followers: 5)
Antibiotics     Open Access   (Followers: 9)
Antibodies     Open Access   (Followers: 2)
Antibody Technology Journal     Open Access   (Followers: 1)
Anuradhapura Medical Journal     Open Access  
Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
Apmis     Hybrid Journal   (Followers: 1)
Apparence(s)     Open Access   (Followers: 1)
Applied Clinical Informatics     Hybrid Journal   (Followers: 2)
Applied Medical Informatics     Open Access   (Followers: 11)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
Arak Medical University Journal     Open Access  
Archive of Clinical Medicine     Open Access   (Followers: 1)
Archive of Community Health     Open Access  
Archives of Biomedical Sciences     Open Access   (Followers: 7)
Archives of Medical and Biomedical Research     Open Access   (Followers: 3)
Archives of Medical Laboratory Sciences     Open Access   (Followers: 1)
Archives of Medicine and Health Sciences     Open Access   (Followers: 3)
Archives of Trauma Research     Open Access   (Followers: 2)
Archivos de Medicina (Manizales)     Open Access  
ArgoSpine News & Journal     Hybrid Journal  
Arquivos Brasileiros de Oftalmologia     Open Access  
Arquivos de Ciências da Saúde     Open Access  
Arquivos de Medicina     Open Access  
ARS Medica Tomitana     Open Access   (Followers: 1)
Art Therapy: Journal of the American Art Therapy Association     Full-text available via subscription   (Followers: 10)
Arterial Hypertension     Open Access  
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 12)
Artificial Organs     Hybrid Journal   (Followers: 1)
Asia Pacific Family Medicine     Open Access  
Asia Pacific Journal of Clinical Nutrition     Full-text available via subscription   (Followers: 10)
Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 1)
Asian Journal of Cell Biology     Open Access   (Followers: 6)
Asian Journal of Health     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 1)
Asian Journal of Medical Sciences     Open Access   (Followers: 1)
Asian Journal of Scientific Research     Open Access   (Followers: 1)
Asian Journal of Transfusion Science     Open Access   (Followers: 2)
Asian Medicine     Hybrid Journal   (Followers: 4)
ASPIRATOR : Journal of Vector-borne Disease Studies     Open Access  
Astrocyte     Open Access  
Atención Familiar     Open Access  
Atención Primaria     Open Access   (Followers: 1)
Audiology - Communication Research     Open Access   (Followers: 8)
Auris Nasus Larynx     Full-text available via subscription  
Australasian Medical Journal     Open Access   (Followers: 3)
Australian Coeliac     Full-text available via subscription   (Followers: 2)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 1)
Autopsy and Case Reports     Open Access  
Aviation, Space, and Environmental Medicine     Full-text available via subscription   (Followers: 9)
Avicenna     Open Access   (Followers: 2)
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 1)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 3)
Bangladesh Journal of Medical Education     Open Access   (Followers: 2)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 2)
Bangladesh Journal of Medical Physics     Open Access  
Bangladesh Journal of Medical Science     Open Access  
Bangladesh Journal of Medicine     Open Access   (Followers: 1)
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Bangladesh Medical Journal     Open Access  
Bangladesh Medical Journal Khulna     Open Access  
Bangladesh Medical Research Council Bulletin     Open Access  
Basal Ganglia     Hybrid Journal  
Basic Sciences of Medicine     Open Access   (Followers: 2)
BBA Clinical     Open Access  
BC Medical Journal     Free  
Benha Medical Journal     Open Access  
Bijblijven     Hybrid Journal  
Bijzijn     Hybrid Journal   (Followers: 2)
Bijzijn XL     Hybrid Journal   (Followers: 1)
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 1)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioengineering & Translational Medicine     Open Access  
Bioethics     Hybrid Journal   (Followers: 14)
Bioethics Research Notes     Full-text available via subscription   (Followers: 14)
Biologics in Therapy     Open Access  
Biology of Sex Differences     Open Access   (Followers: 4)
Biomarker Research     Open Access   (Followers: 2)

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Journal Cover Angiogenesis
  [SJR: 2.212]   [H-I: 69]   [3 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1573-7209 - ISSN (Online) 0969-6970
   Published by Springer-Verlag Homepage  [2352 journals]
  • The role of vasculature in bone development, regeneration and proper
           systemic functioning
    • Authors: Joanna Filipowska; Krzysztof A. Tomaszewski; Łukasz Niedźwiedzki; Jerzy A. Walocha; Tadeusz Niedźwiedzki
      Pages: 291 - 302
      Abstract: Abstract Bone is a richly vascularized connective tissue. As the main source of oxygen, nutrients, hormones, neurotransmitters and growth factors delivered to the bone cells, vasculature is indispensable for appropriate bone development, regeneration and remodeling. Bone vasculature also orchestrates the process of hematopoiesis. Blood supply to the skeletal system is provided by the networks of arteries and arterioles, having distinct molecular characteristics and localizations within the bone structures. Blood vessels of the bone develop through the process of angiogenesis, taking place through different, bone-specific mechanisms. Impaired functioning of the bone blood vessels may be associated with the occurrence of some skeletal and systemic diseases, i.e., osteonecrosis, osteoporosis, atherosclerosis or diabetes mellitus. When a disease or trauma-related large bone defects appear, bone grafting or bone tissue engineering-based strategies are required. However, a successful bone regeneration in both approaches largely depends on a proper blood supply. In this paper, we review the most recent data on the functions, molecular characteristics and significance of the bone blood vessels, with a particular emphasis on the role of angiogenesis and blood vessel functioning in bone development and regeneration, as well as the consequences of its impairment in the course of different skeletal and systemic diseases.
      PubDate: 2017-08-01
      DOI: 10.1007/s10456-017-9541-1
      Issue No: Vol. 20, No. 3 (2017)
  • A somatic GNA11 mutation is associated with extremity capillary
           malformation and overgrowth
    • Authors: Javier A. Couto; Ugur M. Ayturk; Dennis J. Konczyk; Jeremy A. Goss; August Y. Huang; Steve Hann; Jennifer L. Reeve; Marilyn G. Liang; Joyce Bischoff; Matthew L. Warman; Arin K. Greene
      Pages: 303 - 306
      Abstract: Background Capillary malformation is a cutaneous vascular anomaly that is present at birth, darkens over time, and can cause overgrowth of tissues beneath the stain. The lesion is caused by a somatic activating mutation in GNAQ. In a previous study, we were unable to identify a GNAQ mutation in patients with a capillary malformation involving an overgrown lower extremity. We hypothesized that mutations in GNA11 or GNA14, genes closely related to GNAQ, also may cause capillary malformations. Methods Human capillary malformation tissue obtained from 8 patients that had tested negative for GNAQ mutations were studied. Lesions involved an extremity (n = 7) or trunk (n = 1). Droplet digital PCR (ddPCR) was used to detect GNA11 or GNA14 mutant cells (p.Arg183) in the specimens. Single molecule molecular inversion probe sequencing (smMIP-seq) was performed to search for other mutations in GNA11. Mutations were validated by subcloning and sequencing amplimers. Results We found a somatic GNA11 missense mutation (c.547C > T; p.Arg183Cys) in 3 patients with a diffuse capillary malformation of an extremity. Mutant allelic frequencies ranged from 0.3 to 5.0%. GNA11 or GNA14 mutations were not found in 5 affected tissues or in unaffected tissues (white blood cell DNA). Conculsions GNA11 mutations are associated with extremity capillary malformations causing overgrowth. Pharmacotherapy that affects GNA11 signaling may prevent the progression of capillary malformations.
      PubDate: 2017-08-01
      DOI: 10.1007/s10456-016-9538-1
      Issue No: Vol. 20, No. 3 (2017)
  • ETS transcription factors Etv2 and Fli1b are required for tumor
    • Authors: Kristina Baltrunaite; Michael P. Craig; Sharina Palencia Desai; Praneet Chaturvedi; Ram Naresh Pandey; Rashmi S. Hegde; Saulius Sumanas
      Pages: 307 - 323
      Abstract: Abstract ETS transcription factor ETV2/Etsrp functions as a key regulator of embryonic vascular development in multiple vertebrates. However, its role in pathological vascular development has not been previously investigated. To analyze its role in tumor angiogenesis, we utilized a zebrafish xenotransplantation model. Using a photoconvertible kdrl:NLS-KikGR line, we demonstrated that all tumor vessels originate from the existing embryonic vasculature by the mechanism of angiogenesis. Xenotransplantation of mouse B16 melanoma cells resulted in a significant increase in expression of the ETS transcription factors etv2 and fli1b expression throughout the embryonic vasculature. etv2 null mutants which undergo significant recovery of embryonic angiogenesis during later developmental stages displayed a strong inhibition of tumor angiogenesis. We utilized highly specific and fully validated photoactivatable morpholinos to inhibit Etv2 function after embryonic vasculogenesis has completed. Inducible inhibition of Etv2 function resulted in a significant reduction of tumor angiogenesis and inhibition of tumor growth. Furthermore, inducible inhibition of Etv2 function in fli1b mutant embryos resulted in even stronger reduction in tumor angiogenesis and growth, demonstrating that Etv2 and Fli1b have a partially redundant requirement during tumor angiogenesis. These results demonstrate the requirement for Etv2 and Fli1b in tumor angiogenesis and suggest that inhibition of these ETS factors may present a novel strategy to inhibit tumor angiogenesis and reduce tumor growth.
      PubDate: 2017-08-01
      DOI: 10.1007/s10456-017-9539-8
      Issue No: Vol. 20, No. 3 (2017)
  • RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in
           human microvascular endothelial cells
    • Authors: Ahmad F. Alghanem; Emma L. Wilkinson; Maxine S. Emmett; Mohammad A. Aljasir; Katherine Holmes; Beverley A. Rothermel; Victoria A. Simms; Victoria L. Heath; Michael J. Cross
      Pages: 341 - 358
      Abstract: Abstract Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF.
      PubDate: 2017-08-01
      DOI: 10.1007/s10456-017-9542-0
      Issue No: Vol. 20, No. 3 (2017)
  • N - tert -butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the
           angiogenic activity of heparin-binding growth factors
    • Authors: Imtiaz M. Nawaz; Paola Chiodelli; Sara Rezzola; Giuseppe Paganini; Michela Corsini; Alessio Lodola; Alessio Di Ianni; Marco Mor; Marco Presta
      Abstract: Abstract The peptides N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) and BOC-Met-Leu-Phe (BOC1) are widely used antagonists of formyl peptide receptors (FPRs), BOC2 acting as an FPR1/FPR2 antagonist whereas BOC1 inhibits FPR1 only. Extensive investigations have been performed by using these FPR antagonists as a tool to assess the role of FPRs in physiological and pathological conditions. Based on previous observations from our laboratory, we assessed the possibility that BOC2 may exert also a direct inhibitory effect on the angiogenic activity of vascular endothelial growth factor-A (VEGF-A). Our data demonstrate that BOC2, but not BOC1, inhibits the angiogenic activity of heparin-binding VEGF-A165 with no effect on the activity of the non-heparin-binding VEGF-A121 isoform. Endothelial cell-based bioassays, surface plasmon resonance analysis, and computer modeling indicate that BOC2 may interact with the heparin-binding domain of VEGF-A165, thus competing for heparin interaction and preventing the binding of VEGF-A165 to tyrosine kinase receptor VEGFR2, its phosphorylation and downstream signaling. In addition, BOC2 inhibits the interaction of a variety of heparin-binding angiogenic growth factors with heparin, including fibroblast growth factor 2 (FGF2) whose angiogenic activity is blocked by the compound. Accordingly, BOC2 suppresses the angiogenic potential of human tumor cell lines that co-express VEGF-A and FGF2. Thus, BOC2 appears to act as a novel multi-heparin-binding growth factor antagonist. These findings caution about the interpretation of FPR-focusing experimental data obtained with this compound and set the basis for the design of novel BOC2-derived, FPR independent multi-target angiogenesis inhibitors.
      PubDate: 2017-10-13
      DOI: 10.1007/s10456-017-9581-6
  • Notch signaling controls sprouting angiogenesis of endometriotic lesions
    • Authors: Christina Körbel; Miriam D. Gerstner; Michael D. Menger; Matthias W. Laschke
      Abstract: Abstract Angiogenesis is essential for the engraftment and growth of endometriotic lesions. In this study, we analyzed whether this process is regulated by Notch signaling. Endometriotic lesions were induced by endometrial tissue transplantation into dorsal skinfold chambers of C57BL/6 mice, which were treated with the γ-secretase inhibitor DAPT or vehicle. Vascularization, morphology, and proliferation of the newly developing lesions were analyzed using intravital fluorescence microscopy, histology, and immunohistochemistry over 14 days. Inhibition of Notch signaling by DAPT significantly increased the number of angiogenic sprouts within the endometrial grafts during the first days after transplantation when compared to vehicle-treated controls. This was associated with an accelerated vascularization, as indicated by a higher functional microvessel density of DAPT-treated lesions on day 6. However, inhibition of Notch signaling did not affect the morphology and proliferating activity of the lesions, as previously described for tumors. Both DAPT- and vehicle-treated lesions finally consisted of cyst-like dilated glands, which were surrounded by a well-vascularized stroma and contained comparable numbers of proliferating cell nuclear antigen-positive cells. These findings demonstrate that sprouting angiogenesis in endometriotic lesions is controlled by Notch signaling. However, inhibition of Notch signaling does not have beneficial therapeutic effects on lesion development.
      PubDate: 2017-10-09
      DOI: 10.1007/s10456-017-9580-7
  • Antiangiogenesis and medical therapy failure in intracranial
    • Authors: Nestor R. Gonzalez; Raymond Liou; Florian Kurth; Hao Jiang; Jeffrey Saver
      Abstract: Abstract Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months. Thirteen pro- and eight antiangiogenic factors were measured in the participants’ serum using a sandwich multiplex ELISA. Angiogenic profiles were calculated using principal component analysis. We tested the association between angiogenic profiles and recurring cerebrovascular events despite intensive medical therapy, disability at 6 months after enrollment, and angiographic neovascularization in patients who failed medical treatment and underwent indirect revascularization surgery. There is a strong association between a functionally antiangiogenic profile and recurrent stroke or TIA in patients with ICAD (OR = 7.2, CI 2.4–34.4). Multivariable regression analysis showed that this antiangiogenic profile was also associated with poor functional status after 6 months (p = 0.002), independent from other clinical features such as history of previous stroke, diabetes, and age. In patients who failed medical management and underwent indirect revascularization surgery, high endostatin and angiostatin levels were also associated with low angiographic neovascularization (p = 0.02). The results of this study point to the striking importance of antiangiogenesis as a determinant of ICAD patient prognosis and suggest a possible new target for therapy.
      PubDate: 2017-10-09
      DOI: 10.1007/s10456-017-9578-1
  • Pre-culture in endothelial growth medium enhances the angiogenic
           properties of adipose-derived stem/stromal cells
    • Authors: Lucas E. B. Souza; Liziane R. Beckenkamp; Lays M. Sobral; Daianne M. C. Fantacini; Fernanda U. F. Melo; Josiane S. Borges; Andréia M. Leopoldino; Simone Kashima; Dimas Tadeu Covas
      Abstract: Abstract Considerable progress has been made on the development of adipose-derived stem/stromal cells (ASCs) as pro-angiogenic therapeutic tools. However, variable clinical results highlight the need for devising strategies to enhance their therapeutic efficacy. Since ASCs proliferate and stabilize newly formed vessels during the angiogenic phase of adipose tissue formation, we hypothesized that mimicking an angiogenic milieu during culture of ASCs would enhance their capacity to support endothelial cell survival and angiogenesis. To test this, we compared the effect of an endothelial growth medium (EGM-2) and conventional media (αMEM) on the progenitor and angiogenic properties of ASCs. ASCs cultured in EGM-2 (ASC-EGM) displayed the highest clonogenic efficiency, proliferative potential and multilineage potential. After co-culture under growth factor starvation, only ASC-EGM attenuated luciferase-expressing human umbilical vein endothelial cells (HUVECluc) apoptosis and supported the formation of endothelial cords in a dose-dependent manner. These effects were recapitulated by the conditioned medium of ASC-EGM, which displayed a 100-fold higher expression of hepatocyte growth factor in comparison with ASC-αMEM. Next, HUVECluc and ASCs were co-transplanted subcutaneously into immunodeficient mice, and the survival of HUVECluc was monitored by bioluminescent imaging. After 60 days, the survival of HUVECluc transplanted alone was equivalent to that of HUVECluc co-transplanted with ASC-αMEM (15.0 ± 0.7 vs. 13.0 ± 0.5%). Strikingly, co-transplantation with ASC-EGM increased HUVECluc survival to 105.0 ± 3.5%, and the resulting organoids displayed functional vasculature with the highest human-derived vascular area. These findings demonstrate that pre-conditioning of ASCs in endothelial growth medium augment their pro-angiogenic properties and could enhance their therapeutic efficacy against ischemic diseases.
      PubDate: 2017-10-07
      DOI: 10.1007/s10456-017-9579-0
  • Bone marrow sinusoidal endothelium: damage and potential regeneration
           following cancer radiotherapy or chemotherapy
    • Authors: Mohammadhossein Hassanshahi; Alireza Hassanshahi; Samira Khabbazi; Yu-Wen Su; Cory J. Xian
      Abstract: Abstract It is very well known that bone marrow (BM) microvasculature may possess a crucial role in the maintenance of homeostasis of BM due to mutual interactions between BM microvascular system and other physiological functions including haematopoiesis and osteogenesis. Chemotherapy and radiotherapy are known as main approaches for cancer treatment and also are known as the main cause of damage to the BM microvascular system. However, despite the importance of BM microvasculature in orchestrating various biological functions, less attention has been drawn to address the underlying mechanisms for the damage and to explore cellular and molecular mechanisms by which the recovery/regeneration of chemotherapy- and/or radiotherapy-induced BM microvascular system damage can occur. Therefore, in this review we firstly discuss the ultra-/structure and biological characteristics of BM microvascular system (sinusoids). Secondly, potential contribution of BM sinusoids is discussed in pathophysiological circumstances (bone remodelling, haematopoiesis, cancer bone metastasis, and haematological cancers). Thirdly, we address previous preclinical and clinical studies regarding chemotherapy- and irradiation-induced BM microvasculature damage. Finally, potential cellular and molecular mechanisms are discussed for the recovery/regeneration of damaged BM microvascular system, including the potential roles of endothelial progenitor cells, haematopoietic stem/progenitor cells, and stimulation of VEGF/VEGFR and Ang-1/Tie-2 signalling pathways.
      PubDate: 2017-09-27
      DOI: 10.1007/s10456-017-9577-2
  • A genomic screen for angiosuppressor genes in the tumor endothelium
           identifies a multifaceted angiostatic role for bromodomain containing 7
    • Authors: Judy R. van Beijnum; Patrycja Nowak-Sliwinska; Maaike van Berkel; Tse J. Wong; Arjan W. Griffioen
      Abstract: Abstract Tumor angiogenesis is characterized by deregulated gene expression in endothelial cells (EC). While studies until now have mainly focused on overexpressed genes in tumor endothelium, we here describe the identification of transcripts that are repressed in tumor endothelium and thus have potential suppressive effects on angiogenesis. We identified nineteen putative angiosuppressor genes, one of them being bromodomain containing 7 (BRD7), a gene that has been assigned tumor suppressor properties. BRD7 was studied in more detail, and we demonstrate that BRD7 expression is inversely related to EC activation. Ectopic expression of BRD7 resulted in a dramatic reduction of EC proliferation and viability. Furthermore, overexpression of BRD7 resulted in a bromodomain-dependent induction of NFκB-activity and NFκB-dependent gene expression, including ICAM1, enabling leukocyte–endothelial interactions. In silico functional annotation analysis of genome-wide expression data on BRD7 knockdown and overexpression revealed that the transcriptional signature of low BRD7 expressing cells is associated with increased angiogenesis (a.o. upregulation of angiopoietin-2, VEGF receptor-1 and neuropilin-1), cytokine activity (a.o. upregulation of CXCL1 and CXCL6), and a reduction of immune surveillance (TNF-α, NFκB, ICAM1). Thus, combining in silico and in vitro data reveals multiple pathways of angiosuppressor and anti-tumor activities of BRD7.
      PubDate: 2017-09-26
      DOI: 10.1007/s10456-017-9576-3
  • 3D endothelial cell spheroid/human vitreous humor assay for the
           characterization of anti-angiogenic inhibitors for the treatment of
           proliferative diabetic retinopathy
    • Authors: Sara Rezzola; Imtiaz M. Nawaz; Anna Cancarini; Cosetta Ravelli; Stefano Calza; Francesco Semeraro; Marco Presta
      Abstract: Abstract Proliferative diabetic retinopathy (PDR) represents a main cause of acquired blindness. Despite the recognition of the key role exerted by vascular endothelial growth factor (VEGF) in the pathogenesis of PDR, limitations to anti-VEGF therapies do exist. Thus, rapid and cost-effective angiogenesis assays are crucial for the screening of anti-angiogenic drug candidates for PDR therapy. In this context, evaluation of the angiogenic potential of PDR vitreous fluid may represent a valuable tool for preclinical assessment of angiostatic molecules. Here, vitreous fluid obtained from PDR patients after pars plana vitrectomy was used as a pro-angiogenic stimulus in a 3D endothelial cell spheroid/human vitreous assay. The results show that PDR vitreous is able to stimulate the sprouting of fibrin-embedded HUVEC spheroids in a time- and dose-dependent manner. A remarkable variability was observed among 40 individual vitreous fluid samples in terms of sprouting-inducing activity that was related, at least in part, to defined clinical features of the PDR patient. This activity was hampered by various extracellular and intracellular signaling pathway inhibitors, including the VEGF antagonist ranibizumab. When tested on 20 individual vitreous fluid samples, the inhibitory activity of ranibizumab ranged between 0 and 100% of the activity measured in the absence of the drug, reflecting a variable contribution of angiogenic mediators distinct from VEGF. In conclusion, the 3D endothelial cell spheroid/human vitreous assay represents a rapid and cost-effective experimental procedure suitable for the evaluation of the anti-angiogenic activity of novel extracellular and intracellular drug candidates, with possible implications for the therapy of PDR.
      PubDate: 2017-09-13
      DOI: 10.1007/s10456-017-9575-4
  • Tumor vessel disintegration by maximum tolerable PFKFB3 blockade
    • Authors: Lena-Christin Conradi; Aleksandra Brajic; Anna Rita Cantelmo; Ann Bouché; Joanna Kalucka; Andreas Pircher; Ulrike Brüning; Laure-Anne Teuwen; Stefan Vinckier; Bart Ghesquière; Mieke Dewerchin; Peter Carmeliet
      Abstract: Abstract Blockade of the glycolytic activator PFKFB3 in cancer cells (using a maximum tolerable dose of 70 mg/kg of the PFKFB3 blocker 3PO) inhibits tumor growth in preclinical models and is currently being tested as a novel anticancer treatment in phase I clinical trials. However, a detailed preclinical analysis of the effects of such maximum tolerable dose of a PFKFB3 blocker on the tumor vasculature is lacking, even though tumor endothelial cells are hyper-glycolytic. We report here that a high dose of 3PO (70 mg/kg), which inhibits cancer cell proliferation and reduces primary tumor growth, causes tumor vessel disintegration, suppresses endothelial cell growth for protracted periods, (model-dependently) aggravates tumor hypoxia, and compromises vascular barrier integrity, thereby rendering tumor vessels more leaky and facilitating cancer cell intravasation and dissemination. These findings contrast to the effects of a low dose of 3PO (25 mg/kg), which induces tumor vessel normalization, characterized by vascular barrier tightening and maturation, but reduces cancer cell intravasation and metastasis. Our findings highlight the importance of adequately dosing a glycolytic inhibitor for anticancer treatment.
      PubDate: 2017-09-05
      DOI: 10.1007/s10456-017-9573-6
  • Endothelial progenitor cells in multiple myeloma neovascularization: a
           brick to the wall
    • Authors: Maria Margarida Tenreiro; Maria Leonor Correia; Maria Alexandra Brito
      Abstract: Abstract Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow that leads to events such as bone destruction, anaemia and renal failure. Despite the several therapeutic options available, there is still no effective cure, and the standard survival is up to 4 years. The evolution from the asymptomatic stage of monoclonal gammopathy of undetermined significance to MM and the progression of the disease itself are related to cellular and molecular alterations in the bone marrow microenvironment, including the development of the vasculature. Post-natal vasculogenesis is characterized by the recruitment to the tumour vasculature of bone marrow progenitors, known as endothelial progenitor cells (EPCs), which incorporate newly forming blood vessels and differentiate into endothelial cells. Several processes related to EPCs, such as recruitment, mobilization, adhesion and differentiation, are tightly controlled by cells and molecules in the bone marrow microenvironment. In this review, the bone marrow microenvironment and the mechanisms associated to the development of the neovasculature promoted by EPCs are discussed in detail in both a non-pathological scenario and in MM. The latest developments in therapy targeting the vasculature and EPCs in MM are also highlighted. The identification and characterization of the pathways relevant to the complex setting of MM are of utter importance to identify not only biomarkers for an early diagnosis and disease progression monitoring, but also to reveal intervention targets for more effective therapy directed to cancer cells and the endothelial mediators relevant to neovasculature development.
      PubDate: 2017-08-24
      DOI: 10.1007/s10456-017-9571-8
  • Frizzled-5: a high affinity receptor for secreted frizzled-related
           protein-2 activation of nuclear factor of activated T-cells c3 signaling
           to promote angiogenesis
    • Authors: Yuri K. Peterson; Patrick Nasarre; Ingrid V. Bonilla; Eleanor Hilliard; Jennifer Samples; Thomas A. Morinelli; Elizabeth G. Hill; Nancy Klauber-DeMore
      Abstract: Abstract Secreted frizzled-related protein 2 (SFRP2) is a pro-angiogenic factor expressed in the vasculature of a wide variety of human tumors, and modulates angiogenesis via the calcineurin-dependent nuclear factor of activated T-cells cytoplasmic 3 (NFATc3) pathway in endothelial cells. However, until now, SFRP2 receptor for this pathway was unknown. In the present study, we first used amino acid alignments and molecular modeling to demonstrate that SFRP2 interaction with frizzled-5 (FZD5) is typical of Wnt/FZD family members. To confirm this interaction, we performed co-immunofluorescence, co-immunoprecipitation, and ELISA binding assays, which demonstrated SFRP2/FZD5 binding. Functional knock-down studies further revealed that FZD5 is necessary for SFRP2-induced tube formation and intracellular calcium flux in endothelial cells. Using protein analysis on endothelial cell nuclear extracts, we also discovered that FZD5 is required for SFRP2-induced activation of NFATc3. Our novel findings reveal that FZD5 is a receptor for SFRP2 and mediates SFRP2-induced angiogenesis via calcineurin/NFATc3 pathway in endothelial cells.
      PubDate: 2017-08-24
      DOI: 10.1007/s10456-017-9574-5
  • Prox1-GFP/Flt1-DsRed transgenic mice: an animal model for simultaneous
           live imaging of angiogenesis and lymphangiogenesis
    • Authors: Wei Zhong; Xinbo Gao; Shuangyong Wang; Kyuyeon Han; Masatsugu Ema; Susanne Adams; Ralf H. Adams; Mark I. Rosenblatt; Jin-Hong Chang; Dimitri T. Azar
      Abstract: Abstract The roles of angiogenesis in development, health, and disease have been studied extensively; however, the studies related to lymphatic system are limited due to the difficulty in observing colorless lymphatic vessels. But recently, with the improved technique, the relative importance of the lymphatic system is just being revealed. We bred transgenic mice in which lymphatic endothelial cells express GFP (Prox1-GFP) with mice in which vascular endothelial cells express DsRed (Flt1-DsRed) to generate Prox1-GFP/Flt1-DsRed (PGFD) mice. The inherent fluorescence of blood and lymphatic vessels allows for direct visualization of blood and lymphatic vessels in various organs via confocal and two-photon microscopy and the formation, branching, and regression of both vessel types in the same live mouse cornea throughout an experimental time course. PGFD mice were bred with CDh5CreERT2 and VEGFR2lox knockout mice to examine specific knockouts. These studies showed a novel role for vascular endothelial cell VEGFR2 in regulating VEGFC-induced corneal lymphangiogenesis. Conditional deletion of vascular endothelial VEGFR2 abolished VEGFA- and VEGFC-induced corneal lymphangiogenesis. These results demonstrate the potential use of the PGFD mouse as a powerful animal model for studying angiogenesis and lymphangiogenesis.
      PubDate: 2017-08-09
      DOI: 10.1007/s10456-017-9572-7
  • Pulsatile high-dose treatment with antiangiogenic tyrosine kinase
           inhibitors improves clinical antitumor activity
    • Authors: Maria Rovithi; Henk M. W. Verheul
      PubDate: 2017-04-18
      DOI: 10.1007/s10456-017-9555-8
  • A novel strategy to enhance angiogenesis in vivo using the small
           VEGF-binding peptide PR1P
    • Authors: Avner Adini; Irit Adini; Zai-long Chi; Ratmir Derda; Amy E. Birsner; Benjamin D. Matthews; Robert J. D’Amato
      Abstract: Abstract Therapeutic angiogenesis is an experimental frontier in vascular biology that seeks to deliver angiogenic growth factors to ischemic or injured tissues to promote targeted formation of new blood vessels as an alternative approach to surgical revascularization procedures. Vascular endothelial growth factor (VEGF) is a potent angiogenic signal protein that is locally upregulated at sites of tissue injury. However, therapies aimed at increasing VEGF levels experimentally by injecting VEGF gene or protein failed to improve outcomes in human trials in part due to its short half-life and systemic toxicity. We recently designed a novel 12-amino acid peptide (PR1P) whose sequence was derived from an extracellular VEGF-binding domain of the pro-angiogenic glycoprotein prominin-1. In this study, we characterized the molecular binding properties of this novel potential therapeutic for targeted angiogenesis and provided the foundation for its use as an angiogenic molecule that can potentiate endogenous VEGF. We showed that PR1P bound VEGF directly and enhanced VEGF binding to endothelial cells and to VEGF receptors VEGFR2 and neuropilin-1. PR1P increased angiogenesis in the murine corneal micropocket assay when combined with VEGF, but had no activity without added VEGF. In addition, PR1P also enhanced angiogenesis in murine choroidal neovascularization and wound-healing models and augmented reperfusion in a murine hind-limb ischemia model. Together our data suggest that PR1P enhanced angiogenesis by potentiating the activity of endogenous VEGF. In so doing, this novel therapy takes advantage of endogenous VEGF gradients generated in injured tissues and may improve the efficacy of and avoid systemic toxicity seen with previous VEGF therapies.
      PubDate: 2017-04-10
      DOI: 10.1007/s10456-017-9556-7
  • Pro-angiogenic capacities of microvesicles produced by skin wound
    • Authors: Mays Merjaneh; Amélie Langlois; Sébastien Larochelle; Chanel Beaudoin Cloutier; Sylvie Ricard-Blum; Véronique J. Moulin
      Abstract: Abstract Wound healing is a very highly organized process where numerous cell types are tightly regulated to restore injured tissue. Myofibroblasts are cells that produce new extracellular matrix and contract wound edges. We previously reported that the human myofibroblasts isolated from normal wound (WMyos) produced microvesicles (MVs) in the presence of the serum. In this study, MVs were further characterized using a proteomic strategy and potential functions of the MVs were determined. MV proteins isolated from six WMyo populations were separated using two-dimensional differential gel electrophoresis. Highly conserved spots were selected and analyzed using mass spectrometry resulting in the identification of 381 different human proteins. Using the DAVID database, clusters of proteins involved in cell motion, apoptosis and adhesion, but also in extracellular matrix production (21 proteins, enrichment score: 3.32) and in blood vessel development/angiogenesis (19 proteins, enrichment score: 2.66) were identified. Another analysis using the functional enrichment analysis tool FunRich was consistent with these results. While the action of the myofibroblasts on extracellular matrix formation is well known, their angiogenic potential is less studied. To further characterize the angiogenic activity of the MVs, they were added to cultured microvascular endothelial cells to evaluate their influence on cell growth and migration using scratch test and capillary-like structure formation in Matrigel®. The addition of a MV-enriched preparation significantly increased endothelial cell growth, migration and capillary formation compared with controls. The release of microvesicles by the wound myofibroblasts brings new perspectives to the field of communication between cells during the normal healing process.
      PubDate: 2017-04-08
      DOI: 10.1007/s10456-017-9554-9
  • Blood flow can signal during angiogenesis not only through
           mechanotransduction, but also by affecting growth factor distribution
    • Authors: Siavash Ghaffari; Richard L. Leask; Elizabeth A. V. Jones
      Abstract: Abstract Growth factors, such as VEGF, promote the sprouting of new blood vessels. Growth factors are generally produced far from the endothelium, and the transport of these proteins is often assumed to occur through diffusion. When sprouting occurs in a perfused vascular bed, however, interstitial flow is present that can modify protein transport. We recently developed a technique to analyze flow dynamics and vascular remodeling simultaneously in avian embryos. In this study, we extend our technique to model interstitial flow through the porous matrix of the mesenchymal tissue and use this to investigate how flow in the blood vessels affects the distribution of growth factors in the mesenchyme, using VEGF as a prototypical angiogenic molecule. We find that flow controls sprouting location and elongation, both through the direct action of mechanical force and through indirect effects on growth factor distribution. Most importantly, we find that the distribution of VEGF is regulated by interstitial flow, and the effect of diffusion of VEGF is negligible.
      PubDate: 2017-04-03
      DOI: 10.1007/s10456-017-9553-x
  • Effects of nintedanib on the microvascular architecture in a lung fibrosis
    • Authors: Maximilian Ackermann; Yong Ook Kim; Willi L. Wagner; Detlef Schuppan; Cristian D. Valenzuela; Steven J. Mentzer; Sebastian Kreuz; Detlef Stiller; Lutz Wollin; Moritz A. Konerding
      Abstract: Abstract Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, has anti-fibrotic, anti-inflammatory, and anti-angiogenic activity. We explored the impact of nintedanib on microvascular architecture in a pulmonary fibrosis model. Lung fibrosis was induced in C57Bl/6 mice by intratracheal bleomycin (0.5 mg/kg). Nintedanib was started after the onset of lung pathology (50 mg/kg twice daily, orally). Micro-computed tomography was performed via volumetric assessment. Static lung compliance and forced vital capacity were determined by invasive measurements. Mice were subjected to bronchoalveolar lavage and histologic analyses, or perfused with a casting resin. Microvascular corrosion casts were imaged by scanning electron microscopy and synchrotron radiation tomographic microscopy, and quantified morphometrically. Bleomycin administration resulted in a significant increase in higher-density areas in the lungs detected by micro-computed tomography, which was significantly attenuated by nintedanib. Nintedanib significantly reduced lung fibrosis and vascular proliferation, normalized the distorted microvascular architecture, and was associated with a trend toward improvement in lung function and inflammation. Nintedanib resulted in a prominent improvement in pulmonary microvascular architecture, which outperformed the effect of nintedanib on lung function and inflammation. These findings uncover a potential new mode of action of nintedanib that may contribute to its efficacy in idiopathic pulmonary fibrosis.
      PubDate: 2017-03-10
      DOI: 10.1007/s10456-017-9543-z
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