Jens Kroll

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (40)236.65 Total impact

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    ABSTRACT: JUNB, a subunit of the AP-1 transcription factor complex, mediates gene regulation in response to a plethora of extracellular stimuli. Previously, JUNB was shown to act as a critical positive regulator of blood vessel development and homeostasis as well as a negative regulator of proliferation, inflammation and tumour growth. Here, we demonstrate that the oncogenic miR-182 is a novel JUNB target. Loss-of-function studies by morpholino-mediated knockdown and the CRISPR/Cas9 technology identify a novel function for both JUNB and its target miR-182 in lymphatic vascular development in zebrafish. Furthermore, we show that miR-182 attenuates foxo1 expression indicating that strictly balanced Foxo1 levels are required for proper lymphatic vascular development in zebrafish. In conclusion, our findings uncover with the Junb/miR-182/Foxo1 regulatory axis a novel key player in governing lymphatic vascular morphogenesis in zebrafish.
    Scientific Reports 10/2015; 5. DOI:10.1038/srep15007 · 5.58 Impact Factor

  • Diabetologie und Stoffwechsel 04/2015; 10(S 01). DOI:10.1055/s-0035-1549511 · 0.33 Impact Factor

  • Diabetologie und Stoffwechsel 04/2015; 10(S 01). DOI:10.1055/s-0035-1549636 · 0.33 Impact Factor
  • Nicole Woik · Jens Kroll ·
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    ABSTRACT: Blood vessels have been described a long time ago as passive circuits providing sufficient blood supply to ensure proper distribution of oxygen and nutrition. Blood vessels are mainly formed during embryonic development and in the early postnatal period. In the adult, blood vessels are quiescent, but can be activated and subsequently induced under pathophysiological conditions, such as ischemia and tumor growth. Surprisingly, recent data have suggested an active function for blood vessels, named angiocrine signaling, releasing trophogens which regulate organ development and organ regeneration including in the pancreas, lung, tumor cells, liver and bone. Lung development is driven by hypoxia as well as an intense endothelial-epithelial interaction, and important mechanisms contributing to these processes have recently been identified. This review aims to summarize recent developments and concepts about embryonic pulmonary vascular development and lung regeneration. We discuss hypoxia-inducible factor HIF-2α and vascular endothelial growth factor VEGF as important mediators in lung development and focus on endothelial-epithelial interactions and angiocrine signaling mechanisms.
    Cellular and Molecular Life Sciences CMLS 04/2015; 72(14). DOI:10.1007/s00018-015-1907-1 · 5.81 Impact Factor
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    ABSTRACT: Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180)4 is a bipartite guanine nucleotide exchange factor for the monomeric GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1). Elmo1/Dock180 regulates Rac1 activity in a specific spatiotemporal manner in endothelial cells (ECs) during zebrafish development and acts downstream of the Netrin-1/Unc5-homolog B (Unc5B) signaling cascade. However, mechanistic details on the pathways by which Elmo1/Dock180 regulates endothelial function and vascular development remained elusive. In this study we aimed to analyze the vascular function of Elmo1 and Dock180 in human ECs and during vascular development in zebrafish embryos. In vitro overexpression of Elmo1 and Dock180 in ECs reduced caspase-3/7 activity and annexin V-positive cell number upon induction of apoptosis. This protective effect of Elmo1 and Dock180 is mediated by activation of Rac1, p21 activated kinase (PAK) and AKT/protein kinase B (AKT) signaling. In zebrafish, Elmo1 and Dock180 overexpression reduced the total apoptotic cell and apoptotic EC number and promoted the formation of blood vessels during embryogenesis. In conclusion, Elmo1 and Dock180 protect ECs from apoptosis by the activation of the Rac1/PAK/AKT signaling cascade in vitro and in vivo. Thus, Elmo1 and Dock180 facilitate blood vessel formation by stabilization of the endothelium during angiogenesis. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 01/2015; 290(10). DOI:10.1074/jbc.M114.633701 · 4.57 Impact Factor
  • Jakob Nikolas Kather · Jens Kroll ·
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    ABSTRACT: Corneal neovascularization (NV) refers to the growth of blood vessels and/or lymphatics into the physiologically avascular cornea, which occurs in several pathological processes. In mouse models, corneal NV can be artificially induced to investigate mechanisms of corneal pathologies. However, mouse models of corneal NV are not restricted to cornea-specific research, but also are widely used to investigate general mechanisms of angiogenesis. Because the cornea is transparent and easily accessible, corneal NV models are among the most useful in vivo models in angiogenesis research. The three different approaches that are used to study corneal NV in mice are based on direct application of proangiogenic or antiangiogenic transmitters, external injury to the cornea, or genetically engineered mice, which spontaneously develop corneal NV. The aim of this review is to compare the scope and limitations of the different approaches for corneal NV in mice. Our main focus is to highlight the potential of transgenic spontaneous models of corneal NV. Transgenic models do not require any experimental interference and make it possible to investigate different interconnected proangiogenic signaling cascades. As a result, transgenic models are highly useful for disease-centered angiogenesis research. In summary, transgenic models of corneal NV will complement and advance existing ocular NV assays, and help to discover new angiogenesis-related treatment strategies for ocular and extraocular diseases. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
    Investigative Ophthalmology &amp Visual Science 11/2014; 55(11):7637-51. DOI:10.1167/iovs.14-15430 · 3.40 Impact Factor
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    ABSTRACT: Objective: Nucleoside diphosphate kinase B (NDPKB) participates in the activation of heterotrimeric and monomeric G proteins, which are pivotal mediators in angiogenic signaling. The role of NDPKB in angiogenesis has to date not been defined. Therefore, we analyzed the contribution of NDPKB to angiogenesis and its underlying mechanisms in well-characterized in vivo and in vitro models. Approach and results: Zebrafish embryos were depleted of NDPKB by morpholino-mediated knockdown. These larvae displayed severe malformations specifically in vessels formed by angiogenesis. NDPKB-deficient (NDPKB(-/-)) mice were subjected to oxygen-induced retinopathy. In this model, the number of preretinal neovascularizations in NDPKB(-/-) mice was strongly reduced in comparison with wild-type littermates. In accordance, a delayed blood flow recovery was detected in the NDPKB(-/-) mice after hindlimb ligation. In in vitro studies, a small interfering RNA-mediated knockdown of NDPKB was performed in human umbilical endothelial cells. NDPKB depletion impaired vascular endothelial growth factor (VEGF)-induced sprouting and hampered the VEGF-induced spatial redistributions of the VEGF receptor type 2 and VE-cadherin at the plasma membrane. Concomitantly, NDPKB depletion increased the permeability of the human umbilical endothelial cell monolayer. Conclusions: This is the first report to show that NDPKB is required for VEGF-induced angiogenesis and contributes to the correct localization of VEGF receptor type 2 and VE-cadherin at the endothelial adherens junctions. Therefore, our data identify NDPKB as a novel molecular target to modulate VEGF-dependent angiogenesis.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2014; 34(10). DOI:10.1161/ATVBAHA.114.304239 · 6.00 Impact Factor
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    ABSTRACT: Hyperglycemia causes micro- and macrovascular complications in diabetic patients. Elevated glucose (gluc) concentrations lead to increased formation of the highly reactive dicarbonyl methylglyoxal (MG); yet, the early consequences of MG for development of vascular complications in vivo is poorly understood. In this study zebrafish was used as a model organism to analyze early vascular effects and mechanisms of MG in vivo. High tissue glucose increased MG concentrations in tg(fli:EGFP) zebrafish embryos and rapidly induced several additional malformed and uncoordinated blood vessel structures that originated out of existing intersomitic blood vessels. However, larger blood vessels including the dorsal aorta and common cardinal vein were not affected. Expression silencing of MG degrading enzyme glyoxalase 1 (glo1) elevated MG concentrations and induced a similar vascular hyperbranching phenotype in zebrafish. MG enhanced phosphorylation of VEGF receptor 2 and its downstream target Akt/PKB. Pharmacological inhibitors for VEGF receptor 2 and Akt/PKB as well as MG scavenger aminoguanidine and glo1 activation prevented MG induced hyperbranching of intersomitic blood vessels. Taken together, MG acts on smaller blood vessels in zebrafish via the VEGF receptor signalling cascade, thereby describing a new mechanism that can explain vascular complications under hyperglycemia and elevated MG concentrations.
    Diabetes 08/2014; 64(1). DOI:10.2337/db14-0352 · 8.10 Impact Factor
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    ABSTRACT: Purpose: Corneal neovascularization can cause loss of vision. The introduction of anti-VEGF therapy has been a major improvement in therapeutic options. Recently, we established Kelch-like Ect2-interacting protein (KLEIP/KLHL20) knockout mice as a model of spontaneous corneal neovascular dystrophy. The aim of the present study was to characterize corneal neovascularization in progressive corneal dystrophy in KLEIP(-/-) mice, to evaluate the efficacy of anti-VEGF therapy, and to identify novel molecular regulators in this experimental model. Methods: Corneal neovascularization was assessed by immunohistochemistry. Vascular endothelial growth factor signaling was inhibited by injection of a blocking antibody. Microarrays were used to measure expression of mRNA and microRNA (miRNA) in dystrophic corneae. Results were validated by immunohistochemistry and Western blotting. Results: Blood vessels and lymphatics grew from the limbus toward the dystrophic epithelium in corneae of KLEIP(-/-) mice. Blocking VEGF signaling did not reduce phenotype progression. Correspondingly, microarray analysis revealed no upregulation of canonical vascular growth factors in late dystrophy. During phenotype progression, angiopoietin-1 expression increased while miR-204 expression decreased. Bioinformatic analysis identified a binding site for miR-204 in the angiopoietin-1 gene. Validation by in vitro experiments confirmed regulation of angiopoietin-1 by miR-204. Conclusions: Vascular endothelial growth factor does not act as a major player in corneal neovascularization in KLEIP(-/-) mice. However, the proangiogenic factor angiopoietin-1 was strongly upregulated in late-stage phenotype, correlating with loss of miR-204 expression. Correspondingly, we identified miR-204 as a novel regulator of angiopoietin-1 in vitro. These findings may explain the incomplete efficacy of anti-VEGF therapy in the clinic and may provide new candidates for pharmaceutical intervention.
    Investigative Ophthalmology &amp Visual Science 06/2014; 55(7). DOI:10.1167/iovs.13-13619 · 3.40 Impact Factor
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    ABSTRACT: Respiratory distress syndrome (RDS) caused by preterm delivery is a major clinical problem with limited mechanistic insight. Late stage embryonic lung development is driven by hypoxia and hypoxia inducible transcription factors Hif-1α and Hif-2α, which act as important regulators for lung development. Expression of BTB-kelch protein KLEIP (Kelch-like ECT2 interacting protein; also named Klhl20) is controlled by two hypoxia response elements and KLEIP regulates stabilization and transcriptional activation of Hif-2α. Based on the data, we hypothesised an essential role for KLEIP in murine lung development and function. Therefore, we have performed a functional, histological, mechanistic and interventional study in embryonic and neonatal KLEIP(-/-) mice. Here we show that half of the KLEIP(-/-) neonates die due to respiratory failure that is caused by insufficient aeration, septal thickness, reduced glycogenolysis, type II pneumocyte immaturity and reduced surfactant production. Expression analyses in E18.5 lungs identified KLEIP in lung capillaries and strongly reduced mRNA and protein levels for Hif-2α and VEGF, which is associated with embryonic endothelial cell apoptosis and lung bleedings. Betamethasone injection in pregnant females prevented respiratory failure in KLEIP(-/-) neonates, normalized lung maturation, aeration and function and increased neonatal Hif-2α expression. Thus, the experimental study shows that respiratory failure in KLEIP(-/-) neonates is determined by insufficient angiocrine Hif-2α/VEGF signaling and that betamethasone activates this new identified signaling cascade in late stage embryonic lung development.
    Disease Models and Mechanisms 05/2014; 7(6). DOI:10.1242/dmm.014266 · 4.97 Impact Factor
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    ABSTRACT: β1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated Brag2-silencing reduced EC angiogenic sprouting and migration. Brag2-siRNA transfection differentially affected α5β1- and αVβ3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on β1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the αVβ3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of α5β1-integrin, while reducing surface expression of αVβ3-integrin. Mechanistically, Brag2-mediated αVβ3-integrin-recycling and β1-integrin endocytosis and specifically of the active/matrix-bound α5β1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via β1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, β1-integrin endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Furthermore, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating β1-integrin internalization and link for the first time the process of β1-integrin endocytosis with angiogenesis.
    Archiv für Kreislaufforschung 03/2014; 109(2):404. DOI:10.1007/s00395-014-0404-2 · 5.41 Impact Factor
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    ABSTRACT: Protein kinase D isoenzymes (PKDs, Prkds) are serine threonine kinases that belong to the CAMK superfamily. PKD1 is expressed in endothelial cells and is a major mediator of biological responses downstream of the VEGFRs that are relevant for angiogenesis such as endothelial cell migration, proliferation and tubulogenesis in vitro. PKDs also play a critical role in tumor development and progression, including tumor angiogenesis. However, given the plethora of signaling modules that drive angiogenesis, the precise role of PKD1 in both physiological and tumor angiogenesis in vivo has not been worked out so far. This study aimed at dissecting the contribution of PKD1 to physiological blood vessel formation, PKD1 was found to be widely expressed during zebrafish development. As far as physiological angiogenesis was concerned, morpholino-based silencing of PKD1 expression moderately reduced the formation of the intersomitic vessels and the dorsal longitudinal anastomotic vessel in tg(fli1:EGFP) zebrafish. In addition, silencing of PKD1 resulted in reduced formation of the parachordal lymphangioblasts that serves as a precursor for the developing thoracic duct. Interestingly, tumor angiogenesis was completely abolished in PKD1 morphants using the zebrafish/tumor xenograft angiogenesis assay. Our data in zebrafish demonstrate that PKD1 contributes to the regulation of physiological angiogenesis and lymphangiogenesis during zebrafish development and is essential for tumor angiogenesis.
    PLoS ONE 08/2013; 8(7):e68033. DOI:10.1371/journal.pone.0068033 · 3.23 Impact Factor
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    ABSTRACT: Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (≤12 weeks) and old (≥52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 ± 2.2 vs. 55.4 ± 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 ± 1.6 vs. 77.2 ± 3.1%; p < 0.05) and 64% (40.4 ± 7.9 vs. 66.4 ± 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice.
    Gerontology 06/2013; 59(5). DOI:10.1159/000351628 · 3.06 Impact Factor
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    Sandra J Stoll · Susanne Bartsch · Jens Kroll ·
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    ABSTRACT: HOXC9 belongs to the family of homeobox transcription factors, which are regulators of body patterning and development. HOXC9 acts as a negative regulator on blood endothelial cells but its function on lymphatic vessel development has not been studied. The hyaluronan receptor homologs stabilin 1 and stabilin 2 are expressed in endothelial cells but their role in vascular development is poorly understood. This study was aimed at investigating the function of HOXC9, stabilin 2 and stabilin 1 in lymphatic vessel development in zebrafish and in endothelial cells. Morpholino-based expression silencing of HOXC9 repressed parachordal lymphangioblast assembly and thoracic duct formation in zebrafish. HOXC9 positively regulated stabilin 2 expression in zebrafish and in HUVECs and expression silencing of stabilin 2 phenocopied the HOXC9 morphant vascular phenotype. This effect could be compensated by HOXC9 mRNA injection in stabilin 2 morphant zebrafish embryos. Stabilin 1 also regulated parachordal lymphangioblast and thoracic duct formation in zebrafish but acts independently of HOXC9. On a cellular level stabilin 1 and stabilin 2 regulated endothelial cell migration and in-gel sprouting angiogenesis in endothelial cells. HOXC9 was identified as novel transcriptional regulator of parachordal lymphangioblast assembly and thoracic duct formation in zebrafish that acts via stabilin 2. Stabilin 1, which acts independently of HOXC9, has a similar function in zebrafish and both receptors control important cellular processes in endothelial cells.
    PLoS ONE 03/2013; 8(3):e58311. DOI:10.1371/journal.pone.0058311 · 3.23 Impact Factor
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    ABSTRACT: Objective: Histone deacetylases (HDACs) modulate gene expression by deacetylation of histone and nonhistone proteins. Several HDACs control angiogenesis, but the role of HDAC9 is unclear. Methods and results: Here, we analyzed the function of HDAC9 in angiogenesis and its involvement in regulating microRNAs. In vitro, silencing of HDAC9 reduces endothelial cell tube formation and sprouting. Furthermore, HDAC9 silencing decreases vessel formation in a spheroid-based Matrigel plug assay in mice and disturbs vascular patterning in zebrafish embryos. Genetic deletion of HDAC9 reduces retinal vessel outgrowth and impairs blood flow recovery after hindlimb ischemia. Consistently, overexpression of HDAC9 increases endothelial cell sprouting, whereas mutant constructs lacking the catalytic domain, the nuclear localization sequence, or sumoylation site show no effect. To determine the mechanism underlying the proangiogenic effect of HDAC9, we measured the expression of the microRNA (miR)-17-92 cluster, which is known for its antiangiogenic activity. We demonstrate that silencing of HDAC9 in endothelial cells increases the expression of miR-17-92. Inhibition of miR-17-20a rescues the sprouting defects induced by HDAC9 silencing in vitro and blocking miR-17 expression partially reverses the disturbed vascular patterning of HDAC9 knockdown in zebrafish embryos. Conclusions: We found that HDAC9 promotes angiogenesis and transcriptionally represses the miR-17-92 cluster.
    Arteriosclerosis Thrombosis and Vascular Biology 01/2013; 33(3). DOI:10.1161/ATVBAHA.112.300415 · 6.00 Impact Factor
  • Jakob Nikolas Kather · Jens Kroll ·
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    ABSTRACT: The angiogenic cascade is a multi-step process essential for embryogenesis and other physiological and pathological processes. Rho family GTPases are binary molecular switches and serve as master regulators of various basic cellular processes. Rho GTPases are known to exert important functions in angiogenesis and vascular physiology. These functions demand a tight and context-specific control of cellular processes requiring superordinate control by a multitude of guanine nucleotide exchange factors (GEFs). GEFs display various features enabling them to fine-tune the actions of Rho GTPases in the vasculature: (1) GEFs regulate specific steps of the angiogenic cascade; (2) GEFs show a spatio-temporally specific expression pattern; (3) GEFs differentially regulate endothelial function depending on their subcellular location; (4) GEFs mediate crosstalk between complex signaling cascades and (5) GEFs themselves are regulated by another layer of interacting proteins. The aim of this review is to provide an overview about the role of GEFs in regulating angiogenesis and vascular function and to point out current limitations as well as clinical perspectives.
    Experimental Cell Research 12/2012; 319(9). DOI:10.1016/j.yexcr.2012.12.015 · 3.25 Impact Factor
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    ABSTRACT: Rationale: Formation and remodeling of the vasculature during development and disease involve a highly conserved and precisely regulated network of attractants and repellants. Various signaling pathways control the behavior of endothelial cells, but their posttranscriptional dose titration by microRNAs is poorly understood. Objective: To identify microRNAs that regulate angiogenesis. Methods and results: We show that the highly conserved microRNA family encoding miR-10 regulates the behavior of endothelial cells during angiogenesis by positively titrating proangiogenic signaling. Knockdown of miR-10 led to premature truncation of intersegmental vessel growth in the trunk of zebrafish larvae, whereas overexpression of miR-10 promoted angiogenic behavior in zebrafish and cultured human umbilical venous endothelial cells. We found that miR-10 functions, in part, by directly regulating the level of fms-related tyrosine kinase 1 (FLT1), a cell-surface protein that sequesters vascular endothelial growth factor, and its soluble splice variant sFLT1. The increase in FLT1/sFLT1 protein levels upon miR-10 knockdown in zebrafish and in human umbilical venous endothelial cells inhibited the angiogenic behavior of endothelial cells largely by antagonizing vascular endothelial growth factor receptor 2 signaling. Conclusions: Our study provides insights into how FLT1 and vascular endothelial growth factor receptor 2 signaling is titrated in a microRNA-mediated manner and establishes miR-10 as a potential new target for the selective modulation of angiogenesis.
    Circulation Research 09/2012; 111(11). DOI:10.1161/CIRCRESAHA.112.279711 · 11.02 Impact Factor
  • Sandra Jasmin Stoll · Jens Kroll ·
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    ABSTRACT: The members of the HOX transcription factor family are important basic regulators of morphogenesis and development and several HOX proteins have also been identified as essential regulators of physiological and pathologic angiogenesis. HOXC9 is highly expressed in quiescent endothelial cells and keeps the vasculature in a resting state via inhibition of interleukin-8 production. HOXC9 overexpression in zebra-fish negatively regulated vascular development which can be rescued by exogenous interleukin-8. The further understanding of the HOXC9-IL-8 signaling axis and the identification of other HOXC9 targets in the vasculature will provide important insights into mechanisms promoting endothelial cell activation during physiological angiogenesis. It will also be beneficial to understand pathophysiological angiogenesis regulation and thus provide important new directions for the development of novel anti-angiogenic therapeutic strategies.
    Trends in cardiovascular medicine 07/2012; 22(1):7-11. DOI:10.1016/j.tcm.2012.06.002 · 2.91 Impact Factor
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    ABSTRACT: The BTB-kelch protein KLEIP/KLHL20 is an actin binding protein that regulates cell-cell contact formation and cell migration. The aim of our study was to characterize KLEIP's function in ocular health and disease in mice. KLEIP(-/-) mice were generated, and corneas were examined histologically and stained for keratin-1, loricrin, keratin-12, keratin-14, CD31, LYVE-1, F4/80, E-cadherin, and Ki67. Corneal abrasions were performed after eyelid opening. Corneas of KLEIP(+/+) and KLEIP(-/-) mice were indistinguishable at birth. After eyelid opening corneal epithelial hyperplasia started to manifest in KLEIP(-/-) mice, showing a progressive epithelial metaplasia leading to total corneal opacity. In KLEIP(-/-) mice the initial stratified squamous corneal epithelium was altered to an epidermal histo-architecture showing several superficial keratinized cells, cell infiltrations into the stroma, and several apoptotic cells. Skin markers keratin 1 and loricrin were positive, and surface disease was accompanied by deep stromal vascularization. Expression analysis for E-cadherin in KLEIP(-/-) corneas showed acellular areas in the squamous epithelium, indicating a progressive fragile corneal integrity. Removal of the virgin epithelium accelerated strongly development of the epithelial and stromal alterations, identifying mechanical injuries as the major trigger for corneal dystrophy formation and scarification in KLEIP(-/-) mice. The data identify KLEIP as an important molecule regulating corneal epithelial integrity.
    Investigative ophthalmology & visual science 04/2012; 53(6):3260-8. DOI:10.1167/iovs.12-9676 · 3.40 Impact Factor
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    K Jörgens · J-L Hillebrands · H-P Hammes · J Kroll ·
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    ABSTRACT: Diabetes mellitus causes several vascular complications in patients, such as macrovascular problems including myocardial infarction, peripheral artery diseases and stroke and microvascular problems including nephropathy and retinopathy. Likewise, diabetes mellitus is associated with other complications such as neuropathy and delayed wound healing. The zebrafish has been used for decades as a model organism for studies in developmental biology. In fact several common and important developmental mechanisms have been identified in zebrafish which are similar in mammals. The zebrafish has short generation intervals and zebrafish embryos are transparent and therefore provide unique imaging opportunities. In combination with genetic manipulations, including gene silencing protocols by using morpholinos, mutant or transgenic fish lines, the zebrafish has become one of the most important models in developmental biology. Over and above, zebrafish is also an established model organism for several pathophysiological conditions which are related to human diseases. For instance, zebrafish is used as an inflammation and regeneration model because of its ability to partially compensate for organ loss (e. g., heart and fins). It is also used for drug screening, in tumor biology, for systems biology, congenital and hereditary disease, and in infection [1].
    Experimental and Clinical Endocrinology & Diabetes 03/2012; 120(4):186-7. DOI:10.1055/s-0032-1304565 · 1.56 Impact Factor

Publication Stats

2k Citations
236.65 Total Impact Points


  • 2007-2015
    • Universität Heidelberg
      • • Faculty of Medicine Mannheim and Clinic Mannheim
      • • Center for Biomedicine and Medical Technology Mannheim
      • • Department of Vascular Biology
      Heidelburg, Baden-Württemberg, Germany
  • 2009-2011
    • Deutsches Krebsforschungszentrum
      • • Division of Vascular Oncology and Metastasis
      • • Division of Molecular Immunology
      Heidelburg, Baden-Württemberg, Germany
  • 2006-2007
    • Clinic for Tumor Biology Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1998-2003
    • Universität Ulm
      • • Department of Internal Medicine
      • • Clinic of Internal Medicine II
      Ulm, Baden-Württemberg, Germany