Angiogenesis (Angiogenesis)

Publications in this journal

• Article: Venous malformations mutant Tie2-R849W attenuates VEGF-A-induced angiogenesis through impairing STAT3 signaling pathway.

  Yi-Hsien Huang, Ming-Ping Wu, Shin-Chen Pan, Wu-Chou Su, Yi-Wen Chen, and Li-Wha Wu
  Angiogenesis 01/2013; 16:207-222.
• Article: Bone marrow cells participate in tumor vessel formation that supports the growth of Ewing’s sarcoma in the lung

  Zhichao Zhou, Keri Schadler Stewart, Ling Yu, Eugenie S. Kleinerman
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  ABSTRACT: An MHC-mismatch bone marrow (BM) transplant Ewing’s sarcoma mouse model was used to investigate whether BM cells participate in the vessel formation that support Ewing’s sarcoma lung metastasis. BM cells from H-2Kb/d donor mice were transplanted into sublethally irradiated H-2Kd recipient mice. Donor BM cells were identified using the H-2Kb marker. Engraftment was confirmed by identifying the H-2Kb IL-1β-type specific polymorphism. After engraftment highly lung metastatic TC71-PM4 cells were injected intravenously. Mice were sacrificed 10weeks after tumor cell injection. Hematoxylin-and-eosin staining was performed to identify lung metastatic foci. These tumors were then evaluated using immunohistochemical analysis. H-2Kb-positive cells were found in lung metastases but not in normal lung, liver or spleen tissues. Injection of CM-Dil-labeled BM cells into tumor bearing and control mice showed that nonspecific organ migration occurred at 24h, but that these cells were absent 1week later in control mice. These data suggest that the migration of the H-2Kb BM cells to lung nodules was specific because these cells were observed 14weeks after transplantation. Co-localization of H-2Kb and CD31 or VE-Cadherin demonstrated that some endothelial cells were BM-derived. Co-localization of H-2Kb and Desmin, smooth muscle actin (α-SMA) or PDGFR-β indicated that a fraction of pericytes was also BM-derived. These results suggest that BM cells participate in the vascular formation that supports the growth of Ewing’s sarcoma lung metastases. BM cells migrated to the metastatic tumor and differentiated into endothelial cells and pericytes. These data indicated that targeting this process may have therapeutic potential. KeywordsBone marrow cells–Vasculogenesis–Metastasis–Ewing’s sarcoma–Neovascularization
  Angiogenesis 04/2012; 14(2):125-133.
• Article: A study of metabolites as intermediate effectors in angiogenesis

  Brenda Murray, D.J. Wilson
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  ABSTRACT: Metabolites released from hypoxic tissues have been reported as angiogenic factors in circumstances of reduced tissue oxygenation or an increased rate of metabolism. However, in more recent reports their possible role in angiogenesis prior to the induction of hypoxia-inducible genes appears to have been neglected. In a systematic attempt to evaluate their role, metabolites common to the glycolytic and oxidative pathways (nicotinamide adenine dinucleotide, adenosine diphosphate and adenosine triphosphate), exclusively glycolytic metabolites (pyruvate and lactic acid) and exclusively oxidative metabolites (malate, succinate, fumarate and citrate) were tested to assess their effects upon in vivo angiogenesis and in vitro endothelial cell migration and proliferation. In addition, adenosine was tested due to its proposed role in hypoxia-induced angiogenesis. The angiogenic effects in vivo were examined using the chick chorioallantoic membrane assay and in vitro on chick embryonic capillary endothelial cells using a phagokinetic track/migration assay and crystal violet dye binding/proliferation assay. Metabolites common to the glycolytic and oxidative metabolic pathways and exclusively glycolytic metabolites produced an angiogenic response in vivo and in vitro on endothelial cell proliferation and migration, whereas exclusively oxidative metabolites, with the exception of malate, did not. Adenosine caused an increased proliferation of blood vessels in vivo and stimulated endothelial cell migration and proliferation. Overall, these results implicate metabolites as effectors in angiogenesis and it is proposed that they have a role which is possibly independent of the upregulation of hypoxia-inducible genes.
  Angiogenesis 04/2012; 4(1):71-77.
• Article: Angiogenesis in normal and neoplastic ovaries

  S. Ramakrishnan, I.V. Subramanian, Y. Yokoyama, M. Geller
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  ABSTRACT: Ovarian physiology is intricately connected to hormonally regulated angiogenic response. Recent advances in the post genomic revolution have significantly impacted our understanding of ovarian function. In an angiogenesis perspective, the ovary offers a unique opportunity to unravel the molecular orchestration of blood vessel development and regression under normal conditions. A majority of ovarian cancers develop from the single layer of epithelium surrounding the ovaries. Angiogenesis is critical for the development of ovarian cancer and its peritoneal dissemination. The present review summarizes recent findings on the angiogenic response in neoplastic ovaries and discusses the prospects of using anti-angiogenic approaches to treat ovarian cancer.
  Angiogenesis 04/2012; 8(2):169-182.
• Article: cDNA microarray analysis of the gene expression profile of VEGF-activated human umbilical vien endothelial cells

  Mayumi Abe, Yasufumi Sato
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  ABSTRACT: Vascular endothelial growth factor (VEGF) is one of the most important factors that stimulate angiogenesis and vascular permeability. To clarify the role of VEGF, we analysed a human cDNA chip containing 7267 human genes to identify genes induced by VEGF in human umbilical vein endothelial cells (HUVECs). One hundred thirty-nine cDNAs, including ninety-nine previously known and forty poorly characterized or novel sequences, were increased more than two-fold by VEGF within twenty-four hours of stimulation. Among them, only five are known to regulate angiogenesis: cyclooxygenase 2 (COX2), heparin-binding epidermal growth factor-like growth factor, early growth response 1 (EGR 1), CYR61, and angiopoietin 2. Fifty-three genes induced within the first two hours were thought to be directly induced by VEGF. Of these, Down syndrome candidate region 1 (maximum induction = 6.1-fold) was the most profoundly induced, followed by Mif1 (KIAA0025; 5.5-fold), COX2 (4.7-fold), EGR 3 (3.7-fold), EGR 2 (3.2-fold), bactericidal/permeability-increasing protein (3.1-fold), and CD1B antigen, b polypeptide (3.1-fold). In addition to the genes mentioned above, there were many poorly characterized or novel genes induced by VEGF. Further analysis of these genes may aid in the elucidation of the molecular mechanisms of angiogenesis or vascular permeability stimulated by VEGF.
  Angiogenesis 04/2012; 4(4):289-298.
• Article: PPARγ ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis

  Ahmad Aljada, Laura O’Connor, Yu-Yen Fu, Shaker A. Mousa
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  ABSTRACT: ObjectiveTo study the effect of peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, pioglitazone and rosiglitazone, on vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-induced angiogenesis and on endothelial cell migration. MethodsChick chorioallantoic membrane (CAM) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on VEGF- and bFGF-induced angiogenesis. In addition, the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8mm pore filter to a feeder layer containing vitronectin as chemoattractant. ResultsPioglitazone and rosiglitazone inhibited the pro-angiogenic effects of bFGF and VEGF in the CAM model significantly (P<0.001) to the same extent. Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone (P<0.001). ConclusionsThese results suggest that PPARγ ligands, pioglitazone and rosiglitazone, in addition to their important regulatory role in adipogenesis and inflammation, possess anti-angiogenic properties. Thus, PPARγ ligands may be useful in the treatment of diabetic retinopathy, macular degeneration, and other ocular disorders and may lower the risk to develop cancer in diabetic patients.
  Angiogenesis 04/2012; 11(4):361-367.
• Article: Involvement of VEGFR-2 (kdr/flk-1) but not VEGFR-1 (flt-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro

  Pieter Koolwijk, Erna Peters, Bea van der Vecht, Carsten Hornig, Herbert A. Weich, Kari Alitalo, Daniel J. Hicklin, Yan Wu, Larry Witte, Victor W.M. van Hinsbergh
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  ABSTRACT: Different forms of vascular endothelial growth factor (VEGF) and their cellular receptors (VEGFR) are associated with angiogenesis, as demonstrated by the lethality of VEGF-A, VEGFR-1 or VEGFR-2 knockout mice. Here we have used an in vitro angiogenesis model, consisting of human microvascular endothelial cells (hMVEC) cultured on three-dimensional (3D) fibrin matrices to investigate the roles of VEGFR-1 and VEGFR-2 in the process of VEGF-A and VEGF-C-induced tube formation. Soluble VEGFR-1 completely inhibited the tube formation induced by the combination of VEGF-A and TNFα (VEGF-A/TNFα). This inhibition was not observed when tube formation was induced by VEGF-C/TNFα or bFGF/TNFα. Blocking monoclonal antibodies specific for VEGFR-2, but not antibodies specifically blocking VEGFR-1, were able to inhibit the VEGF-A/TNFα-induced as well as the VEGF-C/TNFα-induced tube formation in vitro. PlGF-2, which interacts only with VEGFR-1, neither induced tube formation in combination with TNFα, nor inhibited or stimulated by itself the VEGF-A/TNFα-induced tube formation in vitro. These data indicate that VEGF-A or VEGF-C activation of the VEGFR-2, and not of VEGFR-1, is involved in the formation of capillary-like tubular structures of hMVEC in 3D fibrin matrices used as a model of repair-associated or pathological angiogenesis in vitro.
  Angiogenesis 04/2012; 4(1):53-60.
• Article: Vascular biology in implantation and placentation

  Berthold Huppertz, Louis L.H. Peeters
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  ABSTRACT: Pregnancy leads to dramatic changes of the vascular system of the mother and enables the development of a completely new vascular system within the growing embryo including the formation of the placenta as the exchange organ between both circulations. Besides a general adaptation of the maternal blood system, the uterine spiral arteries display the greatest changes. Within placental villi angiogenesis as well as vasculogenesis can be found already a few weeks after implantation. Both systems in parallel will determine the blood flow within the placental villi and the intervillous space. Finally, compromised blood flow on either side of the placental membrane will not only lead to fetal malnutrition, but will also trigger morphological changes of the villous trees. This review tries to cover all the above-mentioned topics and will try to depict the consequences of poor placentation on mother and fetus.
  Angiogenesis 04/2012; 8(2):157-167.
• Article: Angiogenesis treatment, new concepts on the horizon

  Robert J. Griffin, Grietje Molema, Ruud P.M. Dings
  Angiogenesis 04/2012; 9(2):67-72.
• Article: Single and combined effects of αvβ3- and α5β1-integrins on capillary tube formation in a human fibrinous matrix

  Nancy Laurens, Marten A. Engelse, Clarissa Jungerius, Clemens W. Löwik, Victor W. M. van Hinsbergh, Pieter Koolwijk
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  ABSTRACT: The fibrinous exudate of a wound or tumor stroma facilitates angiogenesis. We studied the involvement of RGD-binding integrins during tube formation in human plasma-derived fibrin clots and human purified fibrin matrices. Capillary-like tube formation by human microvascular endothelial cells in a 3D plasma-derived fibrinous matrix was induced by FGF-2 and TNF-α and depended largely on cell-bound u-PA and plasmin activities. While tube formation was minimally affected by the addition of either the αvβ3-integrin inhibiting mAb LM609 or the α5-integrin inhibiting mAb IIA1, the general RGD-antagonist echistatin completely inhibited this process. Remarkably, when αvβ3- and α5β1-integrins were inhibited simultaneously, tube formation was reduced by 78%. It was accompanied by a 44% reduction of u-PA antigen accumulation and 41% less production of fibrin degradation products. αvβ5-integrin-blocking antibodies further enhanced the inhibition by mAb LM609 and mAb IIA1 to 94%, but had no effect by themselves. αv-specific cRGD only inhibited angiogenesis when α5β1-integrin was simultaneously blocked. Endostatin mimicked the effect of α5β1-integrin and inhibited tube formation only in the presence of LM609 or cRGD (73 and 80%, respectively). Comparable results were obtained when purified fibrin matrices were used instead of the plasma-derived fibrinous matrices. These data show that blocking of tube formation in a fibrinous exudate requires the simultaneous inhibition of αvβ3- and α5β1-integrins. This may bear impact on attempts to influence angiogenesis in a fibrinous environment.
  Angiogenesis 04/2012; 12(3):275-285.
• Article: Progestogen only contraception and endometrial break through bleeding

  Oliver P. Milling Smith, Hilary O.D. Critchley
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  ABSTRACT: Progestogen only contraceptives (POC) provide a safe and effective method of fertility regulation. Unfortunately, they are commonly associated with the problem of endometrial break through bleeding (BTB), often leading to discontinuation of use. An increase in endometrial vascular fragility has been demonstrated as an important mechanism that contributes to BTB but our understanding of the interaction between exogenous steroid use and endometrial vasculature remains incomplete. This review sets out to describe a number of commonly used POC, their effects on endometrial morphology and possible molecular and cellular mechanisms that may lead to unscheduled bleeding.
  Angiogenesis 04/2012; 8(2):117-126.
• Article: Cooperation between integrin ανβ3 and VEGFR2 in angiogenesis

  Payaningal R. Somanath, Nikolay L. Malinin, Tatiana V. Byzova
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  ABSTRACT: The cross-talk between receptor tyrosine kinases and integrin receptors are known to be crucial for a number of cellular functions. On endothelial cells, an interaction between integrin αvβ3 and VEGFR2 seems to be particularly important process during vascularization. Importantly, the functional association between VEGFR2 and integrin αvβ3 is of reciprocal nature since each receptor is able to promote activation of its counterpart. This mutually beneficial relationship regulates a number of cellular activities involved in angiogenesis, including endothelial cell migration, survival and tube formation, and hematopoietic cell functions within vasculature. This article discusses several possible mechanisms reported by different labs which mediate formation of the complex between VEGFR-2 and αvβ3 on endothelial cells. The pathological consequences and regulatory events involved in this receptor cross-talk are also presented.
  Angiogenesis 04/2012; 12(2):177-185.
• Article: Recent advances in endometrial angiogenesis research

  Jane E. Girling, Peter A.W. Rogers
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  ABSTRACT: This review summarises recent research into the mechanisms and regulation of endometrial angiogenesis. Understanding of when and by what mechanisms angiogenesis occurs during the menstrual cycle is limited, as is knowledge of how it is regulated. Significant endometrial endothelial cell proliferation occurs at all stages of the menstrual cycle in humans, unlike most animal models where a more precise spatial relationship exists between endothelial cell proliferation and circulating levels of oestrogen and progesterone. Recent stereological data has identified vessel elongation as a major endometrial angiogenic mechanism in the mid-late proliferative phase of the cycle. In contrast, the mechanisms that contribute to post-menstrual repair and secretory phase remodelling have not yet been determined. Both oestrogen and progesterone/progestins appear to have paradoxical actions, with recent studies showing that under different circumstances both can promote as well as inhibit endometrial angiogenesis. The relative contribution of direct versus indirect effects of these hormones on the vasculature may help to explain their pro- or anti-angiogenic activities. Recent work has also identified the hormone relaxin as a player in the regulation of endometrial angiogenesis. While vascular endothelial growth factor (VEGF) is fundamental to endometrial angiogenesis, details of how and when different endometrial cell types produce VEGF, and how production and activity is controlled by oestrogen and progesterone, remains to be elucidated. Evidence is emerging that the different splice variants of VEGF play a major role in regulating endometrial angiogenesis at a local level. Intravascular neutrophils containing VEGF have been identified as having a role in stimulating endometrial angiogenesis, although other currently unidentified mechanisms must also exist. Future studies to clarify how endometrial angiogenesis is regulated in the human, as well as in relevant animal models, will be important for a better understanding of diseases such as breakthrough bleeding, menorrhagia, endometriosis and endometrial cancer.
  Angiogenesis 04/2012; 8(2):89-99.
• Article: Discovery and development of anti-angiogenic peptides: A structural link

  Ruud P.M. Dings, Irina Nesmelova, Arjan W. Griffioen, Kevin H. Mayo
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  ABSTRACT: Cancer is a disease promoted by excess angiogenesis. Interference with this process poses an attractive approach to controling aberrant tumor growth, a hypothesis first proposed in the early 1970s that led to world-wide focus on identifying and developing angiogenesis inhibitors, which currently number in the hundreds. This review surveys the discovery and development of anti-angiogenic protein fragments and peptides, with a slant towards understanding their structure–function relationships to aid in the design of better therapeutic agents.
  Angiogenesis 04/2012; 6(2):83-91.
• Article: Fibrin fragment E stimulates the proliferation, migration and differentiation of human microvascular endothelial cells in vitro

  C.A. Bootle-Wilbraham, S. Tazzyman, W.D. Thompson, C.M. Stirk, C.E. Lewis
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  ABSTRACT: Various factors involved in haemostasis also regulate the development of new blood vessels by a process called angiogenesis. Enzymatic cleavage of fibrin yields a variety of fibrin degradation products, particularly in areas of intense angiogenesis such as in healing wounds and active atherosclerotic plaques. One of these, fibrin fragment E (FnE), is a potent angiogenic factor in the chick chorioallantoic membrane assay of angiogenesis. Here, we extend these studies to show that FnE stimulates the proliferation, migration and differentiation of human dermal microvascular endothelial cells (HuDMECs) in vitro, both in the absence and presence of such additional endothelial growth factors as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We also show that these stimulatory effects occur at concentrations of the protein known to be present in angiogenic tissues in vivo. FnE enhanced the angiogenic effects of VEGF or bFGF, indicating a possible synergy between the signalling pathways used by these three angiogenic factors.
  Angiogenesis 04/2012; 4(4):269-275.
• Article: Improved quantification of angiogenesis in the rat aortic ring assay

  Silvia Blacher, Laetitia Devy, Mike F. Burbridge, Guy Roland, Gordon Tucker, Agnes Noël, Jean-Michel Foidart
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  ABSTRACT: In vitro angiogenesis assays are essential for the identification of potential angiogenic agents and screening for pharmacological inhibitors. Among these assays, the rat aortic ring model developed by Nicosia bridges the gap between in vivo and in vitro models. The quantification of angiogenesis on this system must be applicable to characterise vascular networks of various states of complexity. We present here an improved computer-assisted image analysis which allows: (1) the determination of the aortic ring area and its factor shape; (2) the number of microvessels, the total number of branchings, the maximal microvessel length and the microvessel distribution; (3) the total number of isolated fibroblast-like cells and their distribution. We show that this method is suitable to quantify spontaneous angiogenesis as well as to analyse a complex microvascular network induced by various concentrations of vascular endothelial growth factor (VEGF). In addition, by evaluating a new parameter, the fibroblast-like cell distribution, our results show that: (1) during spontaneous angiogenic response, maximal fibroblast-like cell migration delimits microvascular outgrowth; and (2) the known angiogenic inhibitor Batimastat prevents endothelial cell sprouting without completely blocking fibroblast-like cell migration. Finally, this new method of quantification is of great interest to better understand angiogenesis and to test pro- or anti-angiogenic agents.
  Angiogenesis 04/2012; 4(2):133-142.