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George D Yancopoulos – 1st expert on this subject based on the ideXlab platform
expression of tie1 tie2 and Angiopoietins 1 2 and 4 in kaposi s sarcoma and cutaneous angiosarcomaAmerican Journal of Pathology, 2000Co-Authors: Lawrence F Brown, Bruce J Dezube, Kathi Tognazzi, Harold F Dvorak, George D YancopoulosAbstract:
The Angiopoietins are recently described growth factors for vascular endothelium. The Tie1 and Tie2 receptors are expressed by endothelium. Acquired immune deficiency syndrome (AIDS)-associated Kaposi’s sarcoma (KS) and cutaneous angiosarcoma are malignancies of endothelial origin. KS involves primarily the skin and mucosal surfaces and is common in AIDS patients. In an effort to determine whether the Angiopoietins and Tie receptors play a role in the pathobiology of angiosarcoma and KS, we studied the expression of Angiopoietin-1, Angiopoietin-2, Angiopoietin-4, Tie1, and Tie2 mRNAs in biopsies of KS from 12 AIDS patients, in biopsies of cutaneous angiosarcoma from two patients, and in control biopsies of normal skin from three volunteers by in situ hybridization. Strong expression of Angiopoietin-2, Tie1, and Tie2 mRNAs was detected in the tumor cells of KS and cutaneous angiosarcomas, in contrast to the focal low-level expression in normal skin biopsies. Focal low-level expression of Angiopoietin-1 was seen in KS, cutaneous angiosarcomas, and in normal skin. Focal low-level expression of Angiopoietin-4 was identified in a minority of KS lesions. These findings suggest that the Angiopoietins and Tie receptors may play an important role in the pathobiology of KS and cutaneous angiosarcoma and identify additional potential targets for therapeutic intervention in these vascular malignancies.
in situ expression of Angiopoietins in astrocytomas identifies Angiopoietin 2 as an early marker of tumor angiogenesisExperimental Neurology, 1999Co-Authors: David Zagzag, George D Yancopoulos, Andrea Hooper, David R Friedlander, Wai Chan, Jocelyn Holash, Stanley J Wiegand, Martin GrumetAbstract:
Abstract Angiopoietin-1 (Ang-1) and its naturally occurring antagonist Angiopoietin-2 (Ang-2) are novel ligands that regulate tyrosine phosphorylation of the Tie2/Tek receptor on endothelial cells. Proper regulation of Tie2/Tek is absolutely required for normal vascular development, seemingly by regulating vascular remodeling and endothelial cell interactions with supporting pericytes/smooth muscle cells. We investigated the expression of Ang-1 and Ang-2 in human astrocytomas by in situ hybridization and compared them to the distribution of pericytes/smooth muscle cells by immunohistochemistry for α-smooth muscle actin (SMA). Ang-1 mRNA was localized in tumor cells and Ang-2 mRNA was detected in endothelial cells of hyperplastic and nonhyperplastic tumor vessels. Ang-2 was also expressed in partially sclerotic vessels and in vascular channels surrounded by tumor cells in brain adjacent to the tumor. Neither Ang-1 nor Ang-2 was detected in normal brain. Dynamic changes in SMA expression during glioma tumorigenesis appear to progress from fragmentation in early vascular hyperplasia to subsequent reassociation and enhanced expression in later stages of vascular proliferation in hyperplastic complexes in high-grade gliomas. All these vessels displaying dynamic changes in SMA immunoreactivity also expressed Ang-2 mRNA. Moreover, SMA immunoreactive intratumoral vascular channels lacking morphological evidence of hyperplasia also showed upregulation of Ang-2. These results suggest that Angiopoietins are involved in the early stage of vascular activation and in advanced angiogenesis, and they identify Ang-2 as an early marker of glioma-induced neovascularization. The association between Ang-2 expression and alterations in SMA immunoreactivity suggests a role for Ang-2 in tumor-associated activation of pericytes/smooth muscle cells.
Increased Vascularization in Mice Overexpressing Angiopoietin-1Science, 1998Co-Authors: Chitra Suri, Hao Zhou, Joyce Mcclain, Gavin Thurston, Donald M. Mcdonald, Eben H. Oldmixon, Thomas N. Sato, George D YancopoulosAbstract:
The Angiopoietins and members of the vascular endothelial growth factor (VEGF) family are the only growth factors thought to be largely specific for vascular endothelial cells. Targeted gene inactivation studies in mice have shown that VEGF is necessary for the early stages of vascular development and that Angiopoietin-1 is required for the later stages of vascular remodeling. Here it is shown that transgenic overexpression of Angiopoietin-1 in the skin of mice produces larger, more numerous, and more highly branched vessels. These results raise the possibility that Angiopoietins can be used, alone or in combination with VEGF, to promote therapeutic angiogenesis.
Daniel J. Dumont – 2nd expert on this subject based on the ideXlab platform
Differential response of lymphatic, venous and arterial endothelial cells to Angiopoietin-1 and Angiopoietin-2BMC Cell Biology, 2007Co-Authors: Vicky P. K. H. Nguyen, Stephen H. Chen, Jason Trinh, Brenda L. Coomber, Daniel J. DumontAbstract:
The lymphatic system complements the blood circulatory system in absorption and transport of nutrients, and in the maintenance of homeostasis. Angiopoietins 1 and 2 (Ang1 and Ang2) are regulators of both angiogenesis and lymphangiogenesis through the Tek/Tie-2 receptor tyrosine kinase. The response of endothelial cells to stimulation with either Ang1 or Ang2 is thought to be dependent upon the origin of the endothelial cells. In this study, we examined the effects of the Angiopoietins on lymphatic, venous and arterial primary endothelial cells (bmLEC, bmVEC and bmAEC, respectively), which were isolated and cultured from bovine mesenteric vessels. BmLEC, bmVEC and bmAEC cell populations all express Tie-2 and were shown to express the appropriate cellular markers Prox-1, VEGFR3, and Neuropilin-1 that define the particular origin of each preparation. We showed that while bmLECs responded slightly more readily to Angiopoietin-2 (Ang2) stimulation, bmVECs and bmAECs were more sensitive to Ang1 stimulation. Furthermore, exposure of bmLECs to Ang2 induced marginally higher levels of proliferation and survival than did exposure to Ang1. However, exposure to Ang1 resulted in higher levels of migration in bmLECs than did to Ang2. Our results suggest that although both Ang1 and Ang2 can activate the Tie-2 receptor in bmLECs, Ang1 and Ang2 may have distinct roles in mesenteric lymphatic endothelial cells.
Activation of Tie2 by Angiopoietin-1 and Angiopoietin-2 results in their release and receptor internalizationJournal of Cell Science, 2006Co-Authors: Elena Bogdanovic, Vicky P. K. H. Nguyen, Daniel J. DumontAbstract:
The receptor tyrosine kinase Tie2 is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance. The ligands for Tie2 are the Angiopoietins, of which Angiopoietin-1 and Angiopoietin-2 have been the most studied. Angiopoietin-1 has been characterized as the primary activating ligand for Tie2 whereas the role of Angiopoietin-2 remains controversial; activating Tie2 in some studies and inhibiting Tie2 in others. Our studies were aimed at understanding the regulation of Tie2 in endothelial cells by Angiopoietin-1 and Angiopoietin-2 and revealed that both ligands activated Tie2 in a concentration-dependent manner. Angiopoietin-2 was considerably weaker at activating Tie2 compared with Angiopoietin-1 suggesting that Angiopoietin-2 may be a partial agonist. Activation of Tie2 by these ligands resulted in differential turnover of the receptor where binding of Angiopoietin-1, and to a lesser extent Angiopoietin-2, induced rapid internalization and degradation of Tie2. Furthermore, our binding studies demonstrate that both ligands are differentially released from the endothelial cell surface after receptor activation and accumulate in the surrounding medium. Altogether, these data begin our understanding of the regulation of Tie2 and the activity of the Angiopoietins after engaging the endothelial cell surface.
transgenic expression of Angiopoietin 1 in the liver leads to changes in lymphatic and blood vessel architectureBiochemical and Biophysical Research Communications, 2006Co-Authors: Alexandra L Haninec, Daniel Voskas, Andrew Needles, Allison S Brown, F S Foster, Daniel J. DumontAbstract:
To investigate the possible role of the Angiopoietins in vessel remodelling, we overexpressed one of the Angiopoietins, Angiopoietin-1 (Ang1), in the hepatocytes of mice by means of the conditional binary transgenic system. Animals were examined by Doppler ultrasound, and dissected livers were analyzed by immunohistochemical staining. Double transgenic mice presented with enlarged spleens and kidneys, enlarged, disorganized blood vessels located near the surface of the liver, sprouting, dilation, and disorganization of liver lymphatics, and turbulent flow in about 1/4 of the blood vessels sampled. Most of these characteristics completely resolved within 12 weeks of turning off the expression of the Ang1 transgene, illustrating a dependence on the continual presence of Ang1 for maintenance of the vascular phenotype. Conditional Angiopoietin-1 overexpression in the liver of mice leads to a phenotype highly reminiscent of portal hypertension illustrating that Ang1 can drive both vascular and lymphatic vessel remodelling and may play a role in portal hypertension.
Hiroshi Tamura – 3rd expert on this subject based on the ideXlab platform
angiogenesis in the human corpus luteum changes in expression of Angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancyThe Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Norihiro Sugino, Takashi Suzuki, Aki Sakata, Ichiro Miwa, Hiromi Asada, Toshiaki Taketani, Yoshiaki Yamagata, Hiroshi TamuraAbstract:
Context: Blood vessel stabilization is regulated by Angiopoietins and important for angiogenesis in the corpus luteum. Objective: To study angiogenesis and blood vessel stabilization in the human corpus luteum, changes in expression of Angiopoietin (Ang)-1, Ang-2, and their specific receptor, Tie-2, together with the number of blood vessels and pericytes were examined in the corpus luteum throughout the menstrual cycle and in early pregnancy. Design: The number of blood vessels and pericytes was determined by immunohistochemistry for CD34 and α-smooth muscle actin, respectively. Ang and Tie-2 expression were examined by immunohistochemistry or RT-PCR. Results: The number of blood vessels increased during the early luteal phase, whereas the number of pericytes was small in the early luteal phase and increased in the midluteal phase, suggesting that angiogenesis is undergoing during the early luteal phase and blood vessels are stabilized in the midluteal phase. Blood vessels and pericytes decreased in numbe…