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  • 1. Beställ onlineKöp publikationen >>
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Investigating mechanisms of angiogenesis in health and disease using zebrafish models2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Angiogenesis, the growth of blood vessels from an existing vasculature, can occur by sprouting from preexisting vessels or by vessel splitting (intussusception). Pathological angiogenesis drives choroidal neovascularization (CNV) in age related macular degeneration (AMD) which is commonly restricted under the retinal pigment epithelium (RPE), called occult CNV, but may also involve vessels penetrating through the RPE into the sub-retinal space. Pathological vessels are poorly developed, insufficiently perfused and highly leaky, phenotypes that are considered to drive disease progression and lead to poor prognosis. Currently, a number of anti-angiogenic drugs exists, the majority of which target vascular endothelial factor (VEGF), but although they often are highly beneficial for treating eye diseases in the short-term, they are generally of limited efficacy in other diseases such as cancer, and also have poorer efficacy when used for treatment of eye diseases in the long-term. A better understanding of the mechanisms underlying pathological angiogenesis can generate new targets for treatment leading to development of better drugs for cancer and retinopathies, but perhaps also other angiogenesis-dependent diseases, in the future. In this thesis mechanisms involved in developmental angiogenesis or pathological angiogenesis in the choroid, cornea or melanoma was identified. These findings highlight the need to further elaborate our knowledge related to angiogenesis in different tissues/conditions for a more targeted, and potentially effective treatment of diseases in the future.

    In paper I, we for the first time identified the choriocapillaries (CCs) in adult zebrafish and found that occult CNV could be induced by exposing the fish to severe hypoxia. Interestingly, we found that occult CNV relied on intussusception, involving not only de novo generation of intussusceptive pillars but also a previously poorly understood mechanism called pillar splitting. This involved HIF-VEGF-VEGFR2 signaling and evidence that this also occurred in both rats and humans suffering from AMD suggested that the mechanism was conserved and clinically relevant.

    In contrast, we found in paper II that the development of CCs in the zebrafish relies on sprouting angiogenesis, involve continuous remodeling, and delayed maturation of the vasculature in 2D. The initial development was found to occur by a unique process of tissuewide synchronized vasculogenesis. As expected, VEGFA via VEGFR2 was also critical for the development of these vessels in the zebrafish embryo, but surprisingly this was independent on hypoxia-inducible factor (HIF)-1.

    Inflammatory nuclear factor-kB (NF-kB) signaling is involved in the progression of angiogenesis, but this signaling pathway has mainly been studied in the inflammatory cells and the role of NF-kB in the endothelial cells during angiogenesis is poorly understood. In paper III, we found that blocking NF-kB signaling using a specific IKK2 blocker IMD0354, specifically blocks pathological as well as developmental angiogenesis by targeting endothelial cell NF-kB signaling in the endothelial cells. Using a rat model for suture-induced corneal neovascularization, IMD0354 treatment lead to reduced production of inflammatory C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 5 (CXCL5) and VEGF, and thereby reduced pathological corneal angiogenesis in this model.

    Using the zebrafish tumor xenograft model in paper IV, we found an association between Microphthalmia associated transcription factor (MITF) and pigment epithelium derived factor (PEDF), which was involved in pathological tumor angiogenesis and metastasis. Similarly, in paper V we used zebrafish transplantation models to study and investigate the use of biocompatible polymers for the delivery of pro-angiogenic FGF-2 as a potential treatment strategy for ischemic diseases such as myocardial infarction (MI). Conclusively, this thesis provides new insights into diverse fields of angiogenic assays using zebrafish, and reveals new mechanisms of angiogenesis in health and disease. This work will hopefully provide a foundation for further studies into occult CNV related to AMD, a process that has not been possible to study previously in pre-clinical models. In addition, zebrafish xenograft or other transplantation models used in this work will likely be important to study cancer biology and to develop more attractive pharmaceutical preparations based on biocompatible hydrogels formulated as microspheres in the future.

    Delarbeten
    1. Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis
    Öppna denna publikation i ny flik eller fönster >>Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis
    Visa övriga...
    2018 (Engelska)Ingår i: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, nr 2, s. 267-285Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-kappa B signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-kappa B activation through selective blockade of the IKK complex I kappa B kinase beta (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNF alpha-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-alpha expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-kappa B by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-kappa B signaling in the development of pathologic corneal neovascularization.

    Ort, förlag, år, upplaga, sidor
    Springer Netherlands, 2018
    Nyckelord
    Cornea; Neovascularization; NF-kappa B; IMD0354; IKK2; VEGF
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-147373 (URN)10.1007/s10456-018-9594-9 (DOI)000428924500007 ()29332242 (PubMedID)2-s2.0-85041334437 (Scopus ID)
    Anmärkning

    Funding Agencies|Swedish Research Council [2012-2472]; Swedish Foundation Stiftelsen Synframjandets Forskningsfond/Ogonfonden; Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Jeanssons Stiftelser

    Tillgänglig från: 2018-05-18 Skapad: 2018-05-18 Senast uppdaterad: 2019-05-01Bibliografiskt granskad
    2. Regulatory and Functional Connection of Microphthalmia-Associated Transcription Factor and Anti-Metastatic Pigment Epithelium Derived Factor in Melanoma
    Öppna denna publikation i ny flik eller fönster >>Regulatory and Functional Connection of Microphthalmia-Associated Transcription Factor and Anti-Metastatic Pigment Epithelium Derived Factor in Melanoma
    Visa övriga...
    2014 (Engelska)Ingår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 6, s. 529-542Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor ( MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.

    Ort, förlag, år, upplaga, sidor
    Neoplasia, 2014
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-110497 (URN)10.1016/j.neo.2014.06.001 (DOI)000340553600007 ()25030625 (PubMedID)
    Anmärkning

    Funding Agencies|Ministerio de Ciencia y Competitividad of Spain [SAF-2010-19256, SAF-2011-24225, SAF-2012-32117, FIS 11/02568, RD09/0076/0101, PT13/0010/0012, PI12/01552]; LiU-Cancer; Svenska Sallskapet for Medicinsk Forskning; Ake Wibergs Stiftelse; Goesta Fraenkels Stifelse; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer

    Tillgänglig från: 2014-09-15 Skapad: 2014-09-12 Senast uppdaterad: 2018-12-07
    3. Adjustable delivery of pro-angiogenic FGF-2 by alginate: collagen microspheres
    Öppna denna publikation i ny flik eller fönster >>Adjustable delivery of pro-angiogenic FGF-2 by alginate: collagen microspheres
    Visa övriga...
    2018 (Engelska)Ingår i: BIOLOGY OPEN, ISSN 2046-6390, Vol. 7, nr 3, artikel-id UNSP bio027060Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Therapeutic induction of blood vessel growth (angiogenesis) in ischemic tissues holds great potential for treatment of myocardial infarction and stroke. Achieving sustained angiogenesis and vascular maturation has, however, been highly challenging. Here, we demonstrate that alginate: collagen hydrogels containing therapeutic, pro-angiogenic FGF-2, and formulated as microspheres, is a promising and clinically relevant vehicle for therapeutic angiogenesis. By titrating the amount of readily dissolvable and degradable collagen with more slowly degradable alginate in the hydrogel mixture, the degradation rates of the biomaterial controlling the release kinetics of embedded proangiogenic FGF-2 can be adjusted. Furthermore, we elaborate a microsphere synthesis protocol allowing accurate control over sphere size, also a critical determinant of degradation/release rate. As expected, alginate: collagen microspheres were completely biocompatible and did not cause any adverse reactions when injected in mice. Importantly, the amount of pro-angiogenic FGF-2 released from such microspheres led to robust induction of angiogenesis in zebrafish embryos similar to that achieved by injecting FGF-2-releasing cells. These findings highlight the use of microspheres constructed from alginate: collagen hydrogels as a promising and clinically relevant delivery system for pro-angiogenic therapy.

    Ort, förlag, år, upplaga, sidor
    COMPANY OF BIOLOGISTS LTD, 2018
    Nyckelord
    Hydrogels; Microspheres; Angiogenesis; Vasculature; Zebrafish
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-147419 (URN)10.1242/bio.027060 (DOI)000429100500002 ()29449216 (PubMedID)
    Anmärkning

    Funding Agencies|Svenska Sallskapet for Medicinsk Forskning; Ake-Wiberg Foundation; Goesta Fraenkel Foundation; Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Carmen och Bertil Ragners Stiftelse; KI Stiftelser och fonder; Loo och Hans Ostermans Stiftelse for Medicinsk Forskning; Vetenskapsradet; Linkoping University

    Tillgänglig från: 2018-05-17 Skapad: 2018-05-17 Senast uppdaterad: 2018-12-07
  • 2.
    Ali, Zaheer
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Cui, Dongmei
    Sun Yat Sen Univ, Peoples R China.
    Yang, Yunlong
    Fudan Univ, Peoples R China.
    Tracey-White, Dhani
    UCL Inst Ophthalmol, England.
    Vazquez Rodriguez, Gabriela
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Moosajee, Mariya
    UCL Inst Ophthalmol, England.
    Ju, Rong
    Sun Yat Sen Univ, Peoples R China.
    Li, Xuri
    Sun Yat Sen Univ, Peoples R China.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Synchronized tissue-scale vasculogenesis and ubiquitous lateral sprouting underlie the unique architecture of the choriocapillaris2020Ingår i: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 457, nr 2, s. 206-214Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature.

  • 3.
    Ali, Zaheer
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Islam, Anik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Sherrell, Peter
    Imperial Coll London, England.
    Le-Moine, Mark
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Lolas, Georgios
    Univ Athens, Greece.
    Syrigos, Konstantinos
    Univ Athens, Greece.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Adjustable delivery of pro-angiogenic FGF-2 by alginate: collagen microspheres2018Ingår i: BIOLOGY OPEN, ISSN 2046-6390, Vol. 7, nr 3, artikel-id UNSP bio027060Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Therapeutic induction of blood vessel growth (angiogenesis) in ischemic tissues holds great potential for treatment of myocardial infarction and stroke. Achieving sustained angiogenesis and vascular maturation has, however, been highly challenging. Here, we demonstrate that alginate: collagen hydrogels containing therapeutic, pro-angiogenic FGF-2, and formulated as microspheres, is a promising and clinically relevant vehicle for therapeutic angiogenesis. By titrating the amount of readily dissolvable and degradable collagen with more slowly degradable alginate in the hydrogel mixture, the degradation rates of the biomaterial controlling the release kinetics of embedded proangiogenic FGF-2 can be adjusted. Furthermore, we elaborate a microsphere synthesis protocol allowing accurate control over sphere size, also a critical determinant of degradation/release rate. As expected, alginate: collagen microspheres were completely biocompatible and did not cause any adverse reactions when injected in mice. Importantly, the amount of pro-angiogenic FGF-2 released from such microspheres led to robust induction of angiogenesis in zebrafish embryos similar to that achieved by injecting FGF-2-releasing cells. These findings highlight the use of microspheres constructed from alginate: collagen hydrogels as a promising and clinically relevant delivery system for pro-angiogenic therapy.

  • 4.
    Ali, Zaheer
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Mukwaya, Anthonny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Biesemeier, Antje
    Univ Tubingen, Germany.
    Ntzouni, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ramskold, Daniel
    Karolinska Inst, Sweden.
    Giatrellis, Sarantis
    Karolinska Inst, Sweden.
    Mammadzada, Parviz
    Karolinska Inst, Sweden.
    Cao, Renhai
    Karolinska Inst, Sweden.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Univ Missouri, MO 65211 USA.
    Marass, Michele
    Max Planck Inst Lung and Heart Res, Germany.
    Gerri, Claudia
    Max Planck Inst Lung and Heart Res, Germany.
    Hildesjö, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Taylor, Michael
    Univ Wisconsin, WI 53706 USA.
    Deng, Qiaolin
    Karolinska Inst, Sweden.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Bayer AB, Sweden.
    del Peso, Luis
    Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
    Kvanta, Anders
    Karolinska Inst, Sweden.
    Sandberg, Rickard
    Karolinska Inst, Sweden.
    Schraermeyer, Ulrich
    Univ Tubingen, Germany.
    Andre, Helder
    Karolinska Inst, Sweden.
    Steffensen, John F.
    Univ Copenhagen, Denmark.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Kele, Julianna
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Univ Autonoma Madrid, Spain; UAM, Spain.
    Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization2019Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, nr 7, s. 1402-1418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective—

    Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.

    Approach and Results—

    Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.

    Conclusions—

    Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.

    Visual Overview—

    An online visual overview is available for this article.

  • 5.
    Fernandez-Barral, Asuncion
    et al.
    University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain .
    Luis Orgaz, Jose
    University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain Kings Coll London, England .
    Baquero, Pablo
    University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain University of Glasgow, Scotland .
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Moreno, Alberto
    CSIC UAM Madrid, Spain University of Dundee, Scotland .
    Tiana, Maria
    University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain .
    Gomez, Valenti
    University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain UCL, England .
    Riveiro-Falkenbach, Erica
    University of Complutense Madrid, Spain Institute Invest I 12, Spain .
    Canadas, Carmen
    Capio Fdn Jimenez Diaz, Spain .
    Zazo, Sandra
    Capio Fdn Jimenez Diaz, Spain .
    Bertolotto, Corine
    CHU Nice, France CHU Nice, France .
    Davidson, Irwin
    University of Strasbourg, France .
    Luis Rodriguez-Peralto, Jose
    University of Complutense Madrid, Spain Institute Invest I 12, Spain .
    Palmero, Ignacio
    CSIC UAM Madrid, Spain .
    Rojo, Federico
    Capio Fdn Jimenez Diaz, Spain .
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    del Peso, Luis
    University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain .
    Jimenez, Benilde
    University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain Institute Invest I 12, Spain .
    Regulatory and Functional Connection of Microphthalmia-Associated Transcription Factor and Anti-Metastatic Pigment Epithelium Derived Factor in Melanoma2014Ingår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 6, s. 529-542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor ( MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.

  • 6.
    Lennikov, Anton
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Laboratory of Biomedical Cell Technologies, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
    Mirabelli, Pierfrancesco
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Mukwaya, Anthony
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Schaupper, Mira
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Thangavelu, Muthukumar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lachota, Mieszko
    Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis2018Ingår i: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, nr 2, s. 267-285Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-kappa B signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-kappa B activation through selective blockade of the IKK complex I kappa B kinase beta (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNF alpha-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-alpha expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-kappa B by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-kappa B signaling in the development of pathologic corneal neovascularization.

  • 7.
    Liu, Na
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Xi An Jiao Tong Univ, Peoples R China.
    Cui, Weiyingqi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jiang, Xia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Hebei Med Univ, Peoples R China.
    Zhang, Zhiyong
    Fourth Mil Med Univ, Peoples R China.
    Gnosa, Sebastian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi. Linköpings universitet, Medicinska fakulteten.
    Blockhuys, Stephanie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lam, Eric W-F
    Imperial Coll London, England.
    Zhao, Zengren
    Hebei Med Univ, Peoples R China.
    Ping, Jie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Xie, Ning
    Xi An Jiao Tong Univ, Peoples R China.
    Kopsida, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Wang, Xin
    Fourth Mil Med Univ, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer2019Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 104, nr 5, s. 1153-1164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose

    To explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms.

    Methods and Materials

    Rho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial.

    Results

    RhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors.

    Conclusions

    RhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.

  • 8.
    Mukwaya, Anthony
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Lindvall, Jessica M.
    Stockholm University, Sweden.
    Xeroudaki, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Karolinska Institute, Sweden.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    A microarray whole-genome gene expression dataset in a rat model of inflammatory corneal angiogenesis2016Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 3, artikel-id UNSP 160103Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In angiogenesis with concurrent inflammation, many pathways are activated, some linked to VEGF and others largely VEGF-independent. Pathways involving inflammatory mediators, chemokines, and micro-RNAs may play important roles in maintaining a pro-angiogenic environment or mediating angiogenic regression. Here, we describe a gene expression dataset to facilitate exploration of pro-angiogenic, pro-inflammatory, and remodelling/normalization-associated genes during both an active capillary sprouting phase, and in the restoration of an avascular phenotype. The dataset was generated by microarray analysis of the whole transcriptome in a rat model of suture-induced inflammatory corneal neovascularisation. Regions of active capillary sprout growth or regression in the cornea were harvested and total RNA extracted from four biological replicates per group. High quality RNA was obtained for gene expression analysis using microarrays. Fold change of selected genes was validated by qPCR, and protein expression was evaluated by immunohistochemistry. We provide a gene expression dataset that may be re-used to investigate corneal neovascularisation, and may also have implications in other contexts of inflammation-mediated angiogenesis.

  • 9.
    Mukwaya, Anthony
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Xeroudaki, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Factors regulating capillary remodeling in a reversible model of inflammatory corneal angiogenesis2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, s. 1-15, artikel-id 32137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Newly formed microcapillary networks arising in adult organisms by angiogenic and inflammatory stimuli contribute to pathologies such as corneal and retinal blindness, tumor growth, and metastasis. Therapeutic inhibition of pathologic angiogenesis has focused on targeting the VEGF pathway, while comparatively little attention has been given to remodeling of the new microcapillaries into a stabilized, functional, and persistent vascular network. Here, we used a novel reversible model of inflammatory angiogenesis in the rat cornea to investigate endogenous factors rapidly invoked to remodel, normalize and regress microcapillaries as part of the natural response to regain corneal avascularity. Rapid reversal of an inflammatory angiogenic stimulus suppressed granulocytic activity, enhanced recruitment of remodelling macrophages, induced capillary intussusception, and enriched pathways and processes involving immune cells, chemokines, morphogenesis, axonal guidance, and cell motility, adhesion, and cytoskeletal functions. Whole transcriptome gene expression analysis revealed suppression of numerous inflammatory and angiogenic factors and enhancement of endogenous inhibitors. Many of the identified genes function independently of VEGF and represent potentially new targets for molecular control of the critical process of microvascular remodeling and regression in the cornea.

  • 10.
    Ward, Rebecca
    et al.
    Univ Coll Dublin, Ireland.
    Ali, Zaheer
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Slater, Kayleigh
    Univ Coll Dublin, Ireland.
    Reynolds, Alison L.
    Univ Coll Dublin, Ireland; Univ Coll Dublin, Ireland.
    Jensen, Lasse
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Kennedy, Breandan N.
    Univ Coll Dublin, Ireland.
    Pharmacological restoration of visual function in a zebrafish model of von-Hippel Lindau disease2020Ingår i: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 457, nr 2, s. 226-234Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Von Hippel-Lindau (VHL) syndrome is a rare, autosomal dominant disorder, characterised by hypervascularised tumour formation in multiple organ systems. Vision loss associated with retinal capillary hemangioblastomas remains one of the earliest complications of VHL disease. The mortality of Vhl(-/-) mice in utero restricted modelling of VHL disease in this mammalian model. Zebrafish harbouring a recessive germline mutation in the vhl gene represent a viable, alternative vertebrate model to investigate associated ocular loss-of-function phenotypes. Previous studies reported neovascularisation of the brain, eye and trunk together with oedema in the vhl(-/-) zebrafish eye. In this study, we demonstrate vhl(-/-) zebrafish almost entirely lack visual function. Furthermore, hyaloid vasculature networks in the vhl(-/-) eye are improperly formed and this phenotype is concomitant with development of an ectopic intraretinal vasculature. Sunitinib malate, a multi tyrosine kinase inhibitor, market authorised for cancer, reversed the ocular behavioural and morphological phenotypes observed in vhl(-/-) zebrafish. We conclude that the zebrafish yid gene contributes to an endogenous molecular barrier that prevents development of intraretinal vasculature, and that pharmacological intervention with sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal vessels in vhl(-/-) zebrafish.

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