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1.
Development ; 137(8): 1285-95, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20223757

ABSTRACT

Tie1 is an endothelial receptor tyrosine kinase that is essential for development and maintenance of the vascular system; however, the role of Tie1 in development of the lymphatic vasculature is unknown. To address this question, we first documented that Tie1 is expressed at the earliest stages of lymphangiogenesis in Prox1-positive venous lymphatic endothelial cell (LEC) progenitors. LEC Tie1 expression is maintained throughout embryonic development and persists in postnatal mice. We then generated two lines of Tie1 mutant mice: a hypomorphic allele, which has reduced expression of Tie1, and a conditional allele. Reduction of Tie1 levels resulted in abnormal lymphatic patterning and in dilated and disorganized lymphatic vessels in all tissues examined and in impaired lymphatic drainage in embryonic skin. Homozygous hypomorphic mice also exhibited abnormally dilated jugular lymphatic vessels due to increased production of Prox1-positive LECs during initial lymphangiogenesis, indicating that Tie1 is required for the early stages of normal lymphangiogenesis. During later stages of lymphatic development, we observed an increase in LEC apoptosis in the hypomorphic embryos after mid-gestation that was associated with abnormal regression of the lymphatic vasculature. Therefore, Tie1 is required for early LEC proliferation and subsequent survival of developing LECs. The severity of the phenotypes observed correlated with the expression levels of Tie1, confirming a dosage dependence for Tie1 in LEC integrity and survival. No defects were observed in the arterial or venous vasculature. These results suggest that the developing lymphatic vasculature is particularly sensitive to alterations in Tie1 expression.


Subject(s)
Embryonic Development/genetics , Lymphangiogenesis/genetics , Lymphatic System/embryology , Receptors, TIE/physiology , Animals , Apoptosis , Blood Vessels/embryology , Blood Vessels/physiology , DNA Primers , DNA Probes , Gene Expression Regulation, Developmental , In Situ Hybridization , Lymphangiogenesis/physiology , Lymphatic System/physiology , Mice , Mice, Knockout , Mice, Mutant Strains , Phenotype , Polymerase Chain Reaction , Receptor Protein-Tyrosine Kinases/deficiency , Receptor Protein-Tyrosine Kinases/genetics , Receptors, TIE/deficiency , Receptors, TIE/genetics , Reverse Transcriptase Polymerase Chain Reaction
2.
Reproduction ; 138(6): 883-93, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19755482

ABSTRACT

Angiogenesis, lymphangiogenesis and vascular maturation occur on a regular, physiological basis in human endometrium. These processes form part of a continuum of vascular remodelling involving numerous regulatory factors. Key factors include vascular endothelial growth factor (VEGF)A, VEGFC and VEGFD, and their associated receptors VEGFR1, VEGFR2 and VEGFR3. A second group of vascular regulatory proteins belongs to the angiopoietin (ANG)-TIE system. Although members of the VEGF family and the ANG-TIE system are represented in the endometrium, our understanding of how these different molecules interact to regulate remodelling of the blood and lymphatic vasculature present in the endometrium is still limited. A review of the current information is provided.


Subject(s)
Angiopoietins/physiology , Endometrium/blood supply , Neovascularization, Physiologic/genetics , Receptors, TIE/physiology , Vascular Endothelial Growth Factor A/physiology , Angiopoietins/genetics , Angiopoietins/metabolism , Animals , Endometrium/metabolism , Endometrium/physiology , Female , Humans , Lymphangiogenesis/genetics , Lymphangiogenesis/physiology , Models, Biological , Multigene Family/physiology , Neovascularization, Physiologic/physiology , Receptors, TIE/genetics , Receptors, TIE/metabolism , Signal Transduction/genetics , Signal Transduction/physiology , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
3.
Arterioscler Thromb Vasc Biol ; 29(5): 630-8, 2009 May.
Article in English | MEDLINE | ID: mdl-19164813

ABSTRACT

Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRbeta- dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-beta-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.


Subject(s)
Neovascularization, Physiologic/physiology , Pericytes/physiology , Signal Transduction/physiology , Adherens Junctions/physiology , Angiopoietins/physiology , Animals , Lysophospholipids/physiology , Mice , Mice, Knockout , Neovascularization, Pathologic/physiopathology , Receptor, Notch3 , Receptor, Platelet-Derived Growth Factor beta/physiology , Receptors, Notch/physiology , Receptors, TIE/physiology , Sphingosine/analogs & derivatives , Sphingosine/physiology
4.
Cell Mol Life Sci ; 64(15): 1915-29, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17458498

ABSTRACT

Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system.


Subject(s)
Lymphangiogenesis/physiology , Lymphatic Vessels/physiology , Angiopoietins/physiology , Animals , Cells, Cultured , Endothelial Cells/physiology , Growth Substances/physiology , Humans , Lymphatic Vessels/cytology , Models, Biological , Receptors, TIE/physiology , Receptors, Vascular Endothelial Growth Factor/physiology , Vascular Endothelial Growth Factor A/physiology , Vesicular Transport Proteins/physiology
5.
Am J Physiol Heart Circ Physiol ; 291(4): H1635-45, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16714355

ABSTRACT

Angiopoietins are ligands for endothelial cell-specific Tie-2 receptors. Whereas angiopoietin-1 (Ang-1) activates these receptors and promotes cell survival, migration, and sprouting, little information is available regarding how Ang-2 influences these cells. In this study, we evaluated signaling pathways and biological effects of physiological concentrations of Ang-2 in cultured human umbilical vein endothelial cells. Ang-2 at 150 and 300 ng/ml elicited a transient (reaching peak values within 15 min of exposure) increase in the phosphorylation of Tie-2 receptors, protein kinase B (Akt), ERK1/2, and p38 members of the mitogen-activated protein kinases. However, unlike Ang-1, Ang-2 significantly inhibited JNK/SAPK phosphorylation. When vascular endothelial growth factor (VEGF) was present along with Ang-2, ERK1/2 phosphorylation was inhibited, whereas augmentation of Ang-1-induced ERK1/2 phosphorylation was triggered by VEGF. Ang-2 treatment had no effect on cell migration and in vitro wound healing but significantly attenuated serum deprivation-induced apoptosis and promoted survival. These effects were completely reversed by phosphatidylinositol 3 (PI3)-kinase and ERK1/2 inhibitors but were augmented by an inhibitor of the p38 pathway. These results suggest that Ang-2 promotes endothelial cell survival through the ERK1/2 and PI3-kinase pathways and that this angiopoietin is not a strong promoter of endothelial cell migration. We also conclude that the nature of interactions in terms of ERK1/2 activation between Ang-2 and VEGF is different from that of Ang-1 and VEGF.


Subject(s)
Angiopoietin-2/physiology , Endothelium, Vascular/physiology , Signal Transduction/physiology , Apoptosis/physiology , Cell Movement/physiology , Cell Survival/physiology , Cells, Cultured , Endothelial Cells/physiology , Endothelium, Vascular/cytology , Humans , Mitogen-Activated Protein Kinase 3/physiology , Mitogen-Activated Protein Kinases/physiology , Phosphatidylinositol 3-Kinases/physiology , Phosphorylation , Proto-Oncogene Proteins c-akt/physiology , Receptors, TIE/physiology , Vascular Endothelial Growth Factor A/physiology
6.
Histol Histopathol ; 21(5): 557-66, 2006 05.
Article in English | MEDLINE | ID: mdl-16493585

ABSTRACT

There is much evidence that rheumatoid arthritis is closely linked to angiogenesis. Important angiogenic mediators have been demonstrated in synovium and tenosynovium of rheumatoid joints. VEGF (Vascular Endothelial Growth Factor), expressed in response to soluble mediators such as cytokines and growth factors and its receptors are the best characterized system in the angiogenesis regulation of rheumatoid joints. Moreover, other angiogenic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-15, IL-18, angiogenin, platelet activating factor (PAF), angiopoietin, soluble adhesion molecules, endothelial mediator (endoglin) play an important role in angiogenesis in rheumatoid arthritis. On the other hand, endostatin, thrombospondin-1 and -2 are angiogenic inhibitors in rheumatoid arthritis. The persistence of inflammation in rheumatoid joints is a consequence of an imbalance between these inducers and inhibitors of angiogenesis.


Subject(s)
Angiogenesis Inhibitors/physiology , Angiogenic Proteins/physiology , Arthritis, Rheumatoid/physiopathology , Neovascularization, Pathologic , Angiopoietins/physiology , Animals , Arthritis, Rheumatoid/pathology , CD40 Antigens/physiology , CD40 Ligand/physiology , Chemokines/physiology , Endothelium, Vascular/cytology , Endothelium, Vascular/physiology , Growth Substances/physiology , Humans , Hypoxia/physiopathology , Receptors, TIE/physiology , Vascular Endothelial Growth Factor A/physiology
7.
Clin Genet ; 64(4): 282-92, 2003 Oct.
Article in English | MEDLINE | ID: mdl-12974730

ABSTRACT

The basic science and development of therapies targeting the blood vascular system has enjoyed much focus due to the knowledge of the molecular mechanisms behind its development and roles in disease. However, the closely associated lymphatic system, while also being responsible for a number of serious and debilitating diseases, has not garnered as much attention due to the lack of specific molecular markers, thereby limiting this field to no more than descriptive analysis. Within the past decade, great strides have been taken to identify a number of molecular signatures unique to the lymphatic system. To this end, the timeline for lymphatic development has now been redefined at the molecular level, and diseases associated with lymphatics now have a molecular basis. With this knowledge, the current modes of treatment for disease such as lymphedema, lymphangiomas, and metastatic progression can now be augmented with potential molecular therapies that have currently been tested in a number of animal models. Much like the therapeutics that have been associated with vasculogenesis and angiogenesis, manipulation of the molecular pathways that define lymphatic development may lead to better clinical outcomes associated with developmental defects and disease.


Subject(s)
Lymphangiogenesis , Lymphatic Diseases/genetics , Lymphatic System/growth & development , Models, Biological , Angiopoietin-2/physiology , DNA-Binding Proteins/physiology , Forkhead Transcription Factors , Genetic Markers , Homeodomain Proteins/physiology , Humans , Receptors, TIE/physiology , Transcription Factors/physiology , Tumor Suppressor Proteins , Vascular Endothelial Growth Factor Receptor-3/physiology
8.
Expert Opin Ther Targets ; 7(4): 527-41, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12885272

ABSTRACT

Angiogenesis, the process of blood vessel formation, is crucial for malignant tumour growth and metastases; therefore, it has become an attractive target for anticancer therapy. Theoretically applicable to most solid tumours, this therapy may be advantageous over existing cytotoxic therapy, since it is directed at genetically stable endothelium growing within tumours rather than at malignant cells, which acquire resistance to treatment. Many promising angiogenesis inhibitors have been developed, although their activity has yet to be demonstrated in human clinical trials. To improve therapeutic benefit, this may require further insight into tumour angiogenesis, development of appropriate surrogate markers of activity, treatment of early stage neoplastic disease and probably a combination of different classes of antiangiogenesis agents to overcome redundant mechanisms of angiogenesis control.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Drug Design , Neovascularization, Pathologic/drug therapy , Angiogenesis Inhibitors/therapeutic use , Angiogenic Proteins/antagonists & inhibitors , Angiogenic Proteins/physiology , Angiopoietins/physiology , Animals , Cell Division , Clinical Trials as Topic , Endostatins/pharmacology , Endostatins/therapeutic use , Endothelium, Vascular/physiology , Humans , Integrins/physiology , Matrix Metalloproteinase Inhibitors , Matrix Metalloproteinases/physiology , Mice , Neoplasms/blood supply , Neoplasms/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Physiologic/drug effects , Platelet Factor 4/physiology , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/physiology , Receptors, TIE/drug effects , Receptors, TIE/physiology , Recombinant Fusion Proteins/pharmacology , Recombinant Fusion Proteins/therapeutic use , Thalidomide/pharmacology , Thalidomide/therapeutic use , Thrombospondins/physiology
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