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Showing papers by "Kari Alitalo published in 2005"


Journal ArticleDOI
14 Dec 2005-Nature
TL;DR: The lymphatic vasculature forms a vessel network that drains interstitial fluid from tissues and returns it to the blood in an important role in the pathogenesis of several diseases, including cancer, lymphoedema and various inflammatory conditions.
Abstract: The lymphatic vasculature forms a vessel network that drains interstitial fluid from tissues and returns it to the blood. Lymphatic vessels are also an essential part of the body's immune defence. They have an important role in the pathogenesis of several diseases, such as cancer, lymphoedema and various inflammatory conditions. Recent biological and technological developments in lymphatic vascular biology will lead to a better understanding and treatment of these diseases.

1,127 citations


Journal ArticleDOI
TL;DR: This review will discuss recent advances in angiogenesis research and provide an overview of the molecular players involved in lymphangiogenesis.
Abstract: The discovery of the vascular endothelial growth factor (VEGF) family members VEGF, VEGF-B, placental growth factor (PlGF), VEGF-C and VEGF-D and their receptors VEGFR-1, -2 and -3 has provided tools for studying the vascular system in development as well as in diseases ranging from ischemic heart disease to cancer. VEGF has been established as the prime angiogenic molecule during development, adult physiology and pathology. PlGF may primarily mediate arteriogenesis, the formation of collateral arteries from preexisting arterioles, with potential future therapeutic use in for example occlusive atherosclerotic disease. VEGF-C and VEGF-D are primarily lymphangiogenic factors, but they can also induce angiogenesis in some conditions. While many studies have addressed the role of angiogenesis and the blood vasculature in human physiology, the lymphatic vascular system has until recently attracted very little attention. In this review, we will discuss recent advances in angiogenesis research and provide an overview of the molecular players involved in lymphangiogenesis.

770 citations


Journal ArticleDOI
TL;DR: It is suggested that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction, and Correction of defective lymphang iogenesis may benefit the treatment of asthma and other inflammatory airway diseases.
Abstract: Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis without angiogenesis, whereas adenoviral VEGF had the opposite effect. After antibiotic treatment of the infection, inflammation and remodeling of blood vessels quickly subsided, but lymphatic vessels persisted. Together, these findings suggest that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.

566 citations


Journal ArticleDOI
TL;DR: These studies define ephrinB2 as an essential regulator of lymphatic development and indicate that interactions with PDZ domain effectors are required to mediate its functions.
Abstract: The transmembrane ligand ephrinB2 and its cognate Eph receptor tyrosine kinases are important regulators of embryonic blood vascular morphogenesis. However, the molecular mechanisms required for ephrinB2 transduced cellular signaling in vivo have not been characterized. To address this question, we generated two sets of knock-in mice: ephrinB2DeltaV mice expressed ephrinB2 lacking the C-terminal PDZ interaction site, and ephrinB2(5F) mice expressed ephrinB2 in which the five conserved tyrosine residues were replaced by phenylalanine to disrupt phosphotyrosine-dependent signaling events. Our analysis revealed that the homozygous mutant mice survived the requirement of ephrinB2 in embryonic blood vascular remodeling. However, ephrinB2DeltaV/DeltaV mice exhibited major lymphatic defects, including a failure to remodel their primary lymphatic capillary plexus into a hierarchical vessel network, hyperplasia, and lack of luminal valve formation. Unexpectedly, ephrinB2(5F/5F) mice displayed only a mild lymphatic phenotype. Our studies define ephrinB2 as an essential regulator of lymphatic development and indicate that interactions with PDZ domain effectors are required to mediate its functions.

442 citations


Journal ArticleDOI
TL;DR: It is shown that VEGF-C produced by tumor cells induced extensive lymphatic sprouting towards the tumor cells as well as dilation of the draining lymphatic vessels, suggesting an active role of lymphatic endothelial cells in lymphatic metastasis, which may require the targeting of both tumor lymphangiogenesis and tumor cell invasion.
Abstract: Lymphangiogenic growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to promote lymphatic metastasis by inducing tumor-associated lymphangiogenesis. In this study, we have investigated how tumor cells gain access into lymphatic vessels and at what stage tumor cells initiate metastasis. We show that VEGF-C produced by tumor cells induced extensive lymphatic sprouting towards the tumor cells as well as dilation of the draining lymphatic vessels, suggesting an active role of lymphatic endothelial cells in lymphatic metastasis. A significant increase in lymphatic vessel growth occurred between 2 and 3 weeks after tumor xenotransplantation, and lymph node metastasis occurred at the same stage. These processes were blocked dose-dependently by inhibition of VEGF receptor 3 (VEGFR-3) signaling by systemic delivery of a soluble VEGFR-3-immunoglobulin (Ig) fusion protein via adenoviral or adeno-associated viral vectors. However, VEGFR-3-Ig did not suppress lymph node metastasis when the treatment was started at a later stage after the tumor cells had already spread out, suggesting that tumor cell entry into lymphatic vessels is a key step during tumor dissemination via the lymphatics. Whereas lymphangiogenesis and lymph node metastasis were significantly inhibited by VEGFR-3-Ig, some tumor cells were still detected in the lymph nodes in some of the treated mice. This indicates that complete blockade of lymphatic metastasis may require the targeting of both tumor lymphangiogenesis and tumor cell invasion.

386 citations


Journal ArticleDOI
TL;DR: Recombinant adeno-associated virus-mediated gene transfer of sVEGFR3-Fc may represent a feasible therapeutic strategy for blockade of lymphogenous metastasis in human prostate and melanoma tumor models established from lymph node metastases via in vivo selection.
Abstract: The presence of metastases in regional lymph nodes is a strong indicator of poor patient survival in many types of cancer. It has recently been shown that the lymphangiogenic growth factor, vascular endothelial growth factor-C (VEGF-C), and its receptor, VEGF receptor-3 (VEGFR3), may play a pivotal role in the promotion of metastasis to regional lymph nodes. In this study, human prostate and melanoma tumor models that preferentially metastasize to the lymph nodes following s.c. tumor cell implantation were established from lymph node metastases via in vivo selection. Melanoma tumor cell sublines established from lymph node metastasis express higher amounts of VEGF-C than the parental tumor cells. The inhibition of tumor-derived VEGF-C with a soluble VEGFR3 decoy receptor, sVEGFR3-Fc, expressed via a recombinant adeno-associated viral vector, potently blocks tumor-associated lymphangiogenesis and tumor metastasis to the lymph nodes, when the treatment was initiated before the tumor implantation. In addition, sVEGFR3-Fc serum levels required for efficient blockade of lymph node metastases are strictly dependent on the VEGF-C levels generated by the primary tumor. Recombinant adeno-associated virus-mediated gene transfer of sVEGFR3-Fc may represent a feasible therapeutic strategy for blockade of lymphogenous metastasis.

258 citations


Journal ArticleDOI
TL;DR: New advances in understanding of the roles of these axonal pathfinding molecules in vascular remodeling and vessel guidance are summarized, indicating that neuronal axons and vessel sprouts use common molecular mechanisms for navigation in the body.
Abstract: The development of the embryonic blood vascular and lymphatic systems requires the coordinated action of several transcription factors and growth factors that target endothelial and periendothelial cells. However, according to recent studies, the precise "wiring" of the vascular system does not occur without an ordered series of guidance decisions involving several molecules initially discovered for axons in the nervous system, including ephrins, netrins, slits, and semaphorins. Here, we summarize the new advances in our understanding of the roles of these axonal pathfinding molecules in vascular remodeling and vessel guidance, indicating that neuronal axons and vessel sprouts use common molecular mechanisms for navigation in the body.

243 citations


Journal ArticleDOI
15 Jun 2005-Blood
TL;DR: It is revealed that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1(+)) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels.

238 citations


Journal ArticleDOI
15 Jun 2005-Blood
TL;DR: The concept that Ang1 therapy may be useful in settings of tissue edema is reinforced, as Ang1 activated lymphatic vessel endothelial proliferation, vessel enlargement, and generation of long endothelial cell filopodia that eventually fused, leading to new sprouts and vessel development.

235 citations


Journal ArticleDOI
TL;DR: This work has shown how, starting from a subgroup of embryonic venous endothelial cells, the whole lymphatic system forms in a stepwise manner, which should lead to the development of better diagnostic methods and treatments of lymphatic disorders and tumor metastasis.
Abstract: The field of lymphatic research has been recently invigorated by the identification of genes and mechanisms that control various aspects of lymphatic development. We are beginning to understand how, starting from a subgroup of embryonic venous endothelial cells, the whole lymphatic system forms in a stepwise manner. The generation of genetically engineered mice with defects in different steps of the lymphangiogenic program has provided models that are increasing our understanding of the lymphatic system in health and disease. This knowledge, in turn, should lead to the development of better diagnostic methods and treatments of lymphatic disorders and tumor metastasis.

225 citations


Journal ArticleDOI
TL;DR: It is shown that Tie1 phosphorylation is induced by multiple angiopoietin proteins and that the activation is amplified via Tie2, and should be important in dissecting the signal transduction pathways and biological functions of Tie1.
Abstract: The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and angiopoietin dose dependence when compared with Tie2. The phosphorylation of overexpressed Tie1 was weakly induced by COMP-Ang1 also in transfected cells that do not express Tie2. When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. Tie1 phosphorylation was also induced by native Ang1 and Ang4, although less efficiently than with COMP-Ang1. In conclusion, we show that Tie1 phosphorylation is induced by multiple angiopoietin proteins and that the activation is amplified via Tie2. These results should be important in dissecting the signal transduction pathways and biological functions of Tie1.

Journal ArticleDOI
TL;DR: The data provide for the first time evidence that HIF-1 may play a role in bacterial infections, and reveal that a B henselae infection resulted in the activation of genes typical for the cellular response to hypoxia.
Abstract: Background— Bartonella species are the only known bacterial pathogens causing vasculoproliferative disorders in humans (bacillary angiomatosis [BA]). Cellular and bacterial pathogenetic mechanisms underlying the induction of BA are largely unknown. Methods and Results— Activation of hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in angiogenesis, was detected in Bartonella henselae–infected host cells in vitro by immunofluorescence, Western blotting, electrophoretic mobility shift, and reporter gene assays and by immunohistochemistry in BA tissue lesions in vivo. Gene microarray analysis revealed that a B henselae infection resulted in the activation of genes typical for the cellular response to hypoxia. HIF-1 was essential for B henselae–induced expression of vascular endothelial growth factor as shown by inhibition with the use of HIF-1–specific short-interfering RNA. Moreover, infection with B henselae resulted in increased oxygen consumption, cellular hypoxia, and decreased A...

Journal ArticleDOI
TL;DR: The results show that AAV‐mediated transduction of a stabilized form of HIF‐1 α can circumvent the problems associated with overexpression of individual angiogenic growth factors, and should offer a potent alternative for pro‐angiogenic gene therapy.
Abstract: Therapeutic angiogenesis provides a potential alternative for the treatment of cardiovascular ischemic diseases. Vascular endothelial growth factor (VEGF) is an important component of the angiogenic response to ischemia. Here we used adeno-associated virus (AAV) gene delivery to skeletal muscle to examine the effects of VEGF vs. a stabilized form of hypoxia-inducible factor-1alpha (HIF-1alpha). The recombinant AAVs were injected into mouse tibialis anterior muscle, and their effects were analyzed by immunohistochemistry and functional assays. These analyses showed that stabilized HIF-1alpha markedly increase capillary sprouting and proliferation, whereas VEGF164 or VEGF120 induced only proliferation of endothelial cells without formation of proper capillary structures. The Evans Blue permeability assay indicated that, unlike VEGF, HIF-1alpha overexpression did not increase vascular leakiness in the transduced muscle. Doppler ultrasound imaging showed that vascular perfusion in the HIF-1alpha treated muscles was significantly enhanced when compared to the controls and not further improved by co-expression of the arteriogenic growth factors angiopoietin-1 or platelet-derived growth factor-B. Our results show that AAV-mediated transduction of a stabilized form of HIF-1alpha can circumvent the problems associated with overexpression of individual angiogenic growth factors. HIF-1alpha should thus offer a potent alternative for pro-angiogenic gene therapy.

Journal ArticleDOI
TL;DR: An overview of the molecular players involved in lymphangiogenesis is provided, with special emphasis on recently discovered molecular mechanisms.

Journal ArticleDOI
TL;DR: Findings establish BM as a significant effector organ in corneal disorders associated with neovascularization as well as establishing its hematopoietic origin from the BM.
Abstract: PURPOSE. Bone-marrow (BM)- derived hematopoietic precursor cells are thought to participate in the growth of blood vessels during postnatal vasculogenesis. In this investigation, multichannel laser scanning confocal microscopy and quantitative image analysis were used to study the fate of BM-derived hematopoietic precursor cells in corneal neovascularization. METHODS. A BM-reconstituted mouse model was used in which the BM from enhanced green fluorescent protein (GFP)-positive mice was transplanted into C57BL/6 mice. Basic fibroblast growth factor (bFGF) was used to induce corneal neovascularization in mice. The vasculogenic potential of adult BM-derived cells and their progeny were tested in this in vivo model. Seventy-two histologic sections selected by systematic random sampling from four mice were immunostained and imaged with a confocal microscope and analyzed with image-analysis software. RESULTS. BM-derived endothelial cells did not contribute to bFGF-induced neovascularization in the cornea. BM-derived periendothelial vascular mural cells (pericytes) were detected at sites of neovascularization, whereas endothelial cells of blood vessels originated from preexisting blood vessels in limbal capillaries. Fifty three percent of all neovascular pericytes originated from BM, and 47% of them originated from preexisting corneoscleral limbus capillaries. Ninety-six percent and 92% of BM-derived pericytes also expressed CD45 and CD11ib, respectively, suggesting their hematopoietic origin from the BM. CONCLUSIONS. Pericytes of new corneal vessels have a dual source: BM and preexisting limbal capillaries. These findings establish BM as a significant effector organ in corneal disorders associated with neovascularization.

Journal ArticleDOI
TL;DR: This study shows no proatherogenic effects of adenovirus-mediated gene transfers of VEGF-A, -B, -C, or -D in the LDLR/apoB48-deficient hypercholesterolemic mice, in which lipoprotein profile and atherosclerosis closely resemble those in human disease.
Abstract: Background— The role of vascular endothelial growth factors (VEGFs) in large arteries has been proposed to be either vasculoprotective or proatherogenic. Because VEGF family members are used for human therapy, it is important to know whether they could enhance atherogenesis. We tested the effects of the members of the VEGF gene family on atherogenesis in LDL-receptor/apolipoprotein (apo) B48 double-knockout (LDLR/apoB48) mice using systemic adenoviral gene transfer. Methods and Results— Six groups of LDLR/apoB48-deficient mice (n=110) were kept 3 months on a Western-type diet. After 6 weeks of diet, mice were injected via tail vein with recombinant adenoviruses expressing VEGF-A, -B, -C, or -D or LacZ (1×109 PFU) or rhVEGF-A protein (2 μg/kg) and euthanized 6 weeks later. Also, older mice (n=36) were injected after 4 months on the diet and euthanized 6 weeks later (total time on the diet, 22 weeks) to evaluate the effects of gene transfers on the development of more mature lesions. Aortas were analyzed fo...

Journal ArticleDOI
TL;DR: Adenovirus-mediated PlGF-2 gene transfer to vascular tissue increases endogenous VEGF-A expression and produces significant angiogenesis, and is a potentially useful candidate for the induction of therapeutic Angiogenesis in vivo.
Abstract: Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family that binds specifically to VEGF receptor (VEGFR)-1. However, the mechanism of PlGF- and VEGFR-1-mediated angiogenesis has remained unclear and some in vitro studies suggest that VEGF-A/VEGFR-2 signaling may also play a role in PlGF-mediated angiogenesis. To clarify these issues we evaluated angiogenic responses in a well-characterized periadventitial angiogenesis model using adenovirus-mediated PlGF-2 (AdvPlGF-2) gene transfer. We also investigated the roles of VEGFR-1 and VEGFR-2 in PlGF-2-mediated angiogenesis. Using a periadventitial collar technique, AdvPlGF-2 (1 x 10(9) plaque-forming units/ml) was transferred to the adventitia of New Zealand White rabbits alone or together with adenoviruses encoding soluble VEGFR-1 (sVEGFR-1) or soluble VEGFR-2 (sVEGFR-2). Adenoviruses encoding LacZ were used as controls. All animals were killed 7 days after gene transfer. Increased neo-vessel formation, upregulation of endogenous VEGF-A expression, and a significant inflammatory response were seen in AdvPlGF-2-transduced arteries. The neo-vessels were large and well perfused. sVEGFR-1 and sVEGFR-2 suppressed the angiogenic response of PlGF-2 by 80 and 71.7%, respectively. We conclude that adenovirus-mediated PlGF-2 gene transfer to vascular tissue increases endogenous VEGF-A expression and produces significant angiogenesis. Both sVEGFR-1 and sVEGFR-2 can inhibit PlGF-2-mediated angiogenesis. PlGF-2 is a potentially useful candidate for the induction of therapeutic angiogenesis in vivo.

Book ChapterDOI
TL;DR: Studies on the effects of endostatin on cultured endothelial cells suggest that the antimigratory and antiproliferative properties of this molecule are the major mechanisms underlying its antiangiogenic potential.
Abstract: The growth and survival of a malignant tumor are dependent on the formation and maintenance of its own microvasculature, a process termed angiogenesis. Inhibition of this phenomenon is an emerging strategy in cancer therapy. The extracellular matrix surrounding the vascular endothelial cells contains cryptic protein domains, which are exposed by changes in the proteolytic homeostasis of the tumor microenvironment. These fragments transmit local signals, which regulate vascular endothelial cell proliferation and migration. Endostatin, the proteolytic fragment of collagen type XVIII, is a potent inhibitor of tumor angiogenesis in various mouse models and is currently in clinical trials for therapeutic use in human cancer. Multiple cell surface receptors have been described for endostatin, but the signals transmitted by these receptors resulting in the inhibition of angiogenesis have so far been poorly characterized. Studies on the effects of endostatin on cultured endothelial cells suggest that the antimigratory and antiproliferative properties of this molecule are the major mechanisms underlying its antiangiogenic potential. These effects may be a consequence of endostatin modulation of endothelial cell–matrix interactions and pericellular proteolysis.

Patent
07 Mar 2005
TL;DR: In this paper, materials and methods for modulating angiogenesis were described, and compositions of the invention provide antibody substances specific for two or more PDGF/VEGF family members, which are useful for modifying angiogenogenesis and lymphangiogenesis in a subject.
Abstract: The present invention relates to materials and methods for modulating angiogenesis. The compositions of the invention provide antibody substances specific for two or more PDGF/VEGF family members, which are useful for modulating angiogenesis and lymphangiogenesis in a subject.

Patent
07 Mar 2005
TL;DR: In this article, materials and methods for antagonizing the function of vascular endothelial growth factor receptors, platelet derived growth factor receptor and other receptors are presented. But none of these methods can be used to antagonize the functions of other receptors.
Abstract: The present invention provides materials and methods for antagonizing the function of vascular endothelial growth factor receptors, platelet derived growth factor receptors and other receptors. Soluble binding constructs able to bind vascular endothelial growth factors, platelet derived growth factors, and other ligands are provided.

Patent
08 Mar 2005
TL;DR: In this paper, methods and compositions that may be used in disrupting the association of smooth muscle cells with lymphatic endothelial cells and in correcting the valvular dysfunction in veins and lymphatic vessels are presented.
Abstract: The present invention is directed to methods and compositions that may be used in disrupting the association of smooth muscle cells with lymphatic endothelial cells and in correcting the valvular dysfunction in veins and lymphatic vessels. Such compositions are useful for therapeutic and prophylactic treatment of impaired lymphatic and venous function, particularly for the treatment of lymphedema distichiasis or chronic venous insufficiency.

Journal ArticleDOI
TL;DR: It is concluded that in the periadventitial space Ang1 shows angiogenic activity and is a potentially useful factor for the induction of therapeutic vascular growth in vivo.
Abstract: This study was performed to evaluate angiogenic responses of angiopoietin-1 (Ang1) in vivo after adenovirus-mediated gene transfer in the periadventitial space of the rabbit carotid arteries using a collar technique. Adenoviruses encoding LacZ and vascular endothelial growth factor (VEGF) receptor-1-Ig fusion protein (VEGF-R1-Ig) adenoviruses were used as controls. Increased neovessel formation was seen in adventitia of the Ang1 transduced arteries 7 days after the gene transfer. Neovessels in the Ang1 transduced arteries were large in size and well perfused. Ang1 binds to Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) receptors, which were expressed in the endothelium of the neovessels. When VEGF-R1-Ig was used with Ang1, it resulted in a decrease in the number of neovessels, which implies that VEGF-A or some other VEGF-R1 ligand(s) play a crucial role in angiogenesis occurring in response to Ang1. There were no significant differences in the total number of capillaries in the adventitia of the VEGF-R1-Ig transduced arteries as compared to LacZ controls. Neointima formation was not increased in the Ang1 transduced arteries as compared to the controls. We conclude that in the periadventitial space Ang1 shows angiogenic activity and is a potentially useful factor for the induction of therapeutic vascular growth in vivo.

Journal Article
TL;DR: It is concluded that angiogenesis induced by colorectal carcinoma cells is regulated by Src kinase and that heterogeneous endothelial cells from distinct anatomic sites may be differentially activated by coloresceptic cancer cells.
Abstract: 2024 A number of signaling pathways regulate expression of and response to pro-angiogenic factors. Because the protein tyrosine kinase, Src has been implicated in both of these processes, we hypothesized that Src is a critical mediator of angiogenesis induced by colorectal carcinoma cells. To examine Src-mediated angiogenic properties, temperature-sensitive SV40 Tag immortalized endothelial cells from both the colon (CEC) and liver (HEC) were stimulated with conditioned media from HT29 human colorectal carcinoma cells previously treated with a selective Src kinase inhibitor, PP2, or DMSO control. Endothelial proliferation was determined by MTT; migration was determined by modified Boyden chamber assay. To asses the ability of Src to regulate growth factor-induced endothelial activation, the above assays were repeated in the presence of 1) 2% FBS, 2) EGF, 3) bFGF, 4) VEGF-A or 5) HGF either in the presence or absence of a selective Src inhibitor. For protein analysis, HEC pretreated with PP2 or DMSO were stimulated with EGF and lysed at various time points. Total and phosphorylated forms of Akt, Erk, and Src were assessed by western blotting and densitometry. Conditioned media from HT29 colorectal carcinoma cells induced a ∼2-fold increase in proliferation and migration in the CEC and >3-fold increase in proliferation and migration HEC respectively. The conditioned media from the Src-inhibited colorectal carcinoma cells failed to induce significant proliferation or migration in either cell line. Likewise, EGF, bFGF, VEGF, and HGF induced a 5.0-, 3.7-, 4.4-, and 3.9-fold increase in migration in HEC respectively and a 3.3-, 2.4-, 2.7- and 4.0-fold increase in migration in CEC respectively. In contrast, while EGF and bFGF caused ∼2-fold increase in proliferation in both HEC and CEC, VEGF failed to increase proliferation above control values. HGF induced a 1.5-fold increase in CEC proliferation, but failed to induce proliferation in HEC. Pretreatment with the selective Src inhibitor abrogated endothelial proliferation and migration induced by all factors. EGF treatment of HEC induced a 2-fold increase in Src kinase activity, a >5-fold increase in phosphorylated Erk and ∼3 fold increase in phosphorylated Akt, all of which were effectively blocked by Src inhibition. We therefore conclude that angiogenesis induced by colorectal carcinoma cells is regulated by Src kinase and that heterogeneous endothelial cells from distinct anatomic sites may be differentially activated by colorectal carcinoma cells.

Patent
27 Jun 2005
TL;DR: In this paper, materials and methods involving tie receptors and Angiopoietin ligands for modulating female fertility in mammals, including humans, were described. But none of these methods were tested on humans.
Abstract: The present invention provides materials and methods involving Tie receptors and Angiopoietin ligands for modulating female fertility in mammals, including humans. Materials and methods for inhibiting fertility (e.g., for contraception) or for enhancing fertility (e.g., treating infertility) are contemplated.

Patent
07 Mar 2005
TL;DR: In this paper, materials and methods for antagonizing the function of vascular endothelial growth factor receptors, platelet derived growth factor receptor and other receptors are presented. But none of these methods can be used to antagonize the functions of other receptors.
Abstract: The present invention provides materials and methods for antagonizing the function of vascular endothelial growth factor receptors, platelet derived growth factor receptors and other receptors. Soluble binding constructs able to bind vascular endothelial growth factors, platelet derived growth factors, and other ligands are provided.


Journal ArticleDOI
TL;DR: Bronchoscopic instillation of surfactant improves oxygenation and prognosis following severe RI in lung transplant recipients and represents a non-invasive therapeutic alternative to extra corporeal membrane oxygenation to significantly improve clinical outcome in RI.
Abstract: improved pulmonary compliance and gas exchange after lung transplantation. Aim: We report our clinical experience of FOB instillation of surfactant in severe RI after human lung transplantation. Methods: Retrospective review of 92 consecuetive lung or heart lung transplants performed at a single institution. Severe RI was defined as diffuse roentgenographic alveolar infiltrates, worsening hypoxaemia and decreased lung compliance within 72 hours of lung transplantation. One 5 ml vial of surfactant (Beractant Bovine Lung Extract, Abbott, Australasia Ptd. Ltd, 20mg/ml phospholipid) was instilled into each segmental bronchus upon diaqnosis of RI. Results: Five patients (all bilateral sequential) of mean age 49 years were diagnosed with RI and surfactant administered at a mean of 42 hours (range 2.3–98) post transplant. Mean graft ischaemic time was 414 minutes (range 232–625) and cardiopulmonary bypass time 167 minutes (range 0–210). Mean oxygen index (PaO2mmHg/FiO2) pre and 48 hours post surfactant was 70 and 223 respectively. Significant resolution of radiological infiltrates was evident in all cases within 24 hours. Successful extubation occurred at a mean of 15.8 days and survival is 100% at 16.2 months (range 1–49). Conclusions: Bronchoscopic instillation of surfactant improves oxygenation and prognosis following severe RI in lung transplant recipients. It represents a non-invasive therapeutic alternative to extra corporeal membrane oxygenation to significantly improve clinical outcome in RI.

Patent
31 May 2005
TL;DR: PDGF-D, a member of the PDGF/VEGF family of growth factors, as well as the nucleotide sequence encoding it, methods for producing it, antibodies and other antagonists to it, transfected and transformed host cells expressing it, pharmaceutical compositions containing it, and uses thereof in medical and diagnostic applications, including methods for stimulating growth of a connective tissue or healing a wound in a mammal.
Abstract: PDGF-D, a new member of the PDGF/VEGF family of growth factors, as well as the nucleotide sequence encoding it, methods for producing it, antibodies and other antagonists to it, transfected and transformed host cells expressing it, pharmaceutical compositions containing it, and uses thereof in medical and diagnostic applications, including methods for stimulating growth of a connective tissue or healing a wound in a mammal, which methods comprise administering to the mammal an effective amount of PDGF-D polypeptides or polynucleotides encoding the PDGF-D polypeptides.

Patent
08 Mar 2005
TL;DR: In this article, a method of modulating, regulating and/or stabilizing angiogenesis in a mammal was proposed, in which an active PDGF-D or a polynucleotide encoding anactive PDGFD was administered to the mammal.
Abstract: A method of modulating, regulating and/or stabilizing angiogenesis in a mammal in which an active PDGF-D or a polynucleotide encoding an active PDGF-D is administered to the mammal. The PDGF-D is advantageously co-adminstered with an angiogenic growth factor, such as a member of the VEGF family of growth factors. The claimed method inhibits leakage of blood vessels and is useful, inter alia, for treatment of edemas.

Patent
24 Feb 2005
TL;DR: In this article, the authors present materials and methods for preventing stenosis or restenosis of a blood vessel using Vascular Endothelial Growth Factor C (VEGF-C) and/or vascular endothelial growth Factor D (VEGF-D) genes or proteins.
Abstract: The present invention provides materials and methods for preventing stenosis or restenosis of a blood vessel using Vascular Endothelial Growth Factor C (VEGF-C) and/or Vascular Endothelial Growth Factor D (VEGF-D) genes or proteins.