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Lymphatic malformations
Published in Prem Puri, Newborn Surgery, 2017
Emily R. Christison-Lagay, Jacob C. Langer
Overexpression of the isoforms VEGF-C and VEGF-D in transgenic mice induces the formation of hyperplastic lymphatic vessels.6 Kinase-inactivating mutations in the human VEGFR3 gene result in Milroy disease.15–17 Mutations in Sox18 are associated with hypotrichosis–lymphedema–telangiectasia.9 Tie-2-deficient mouse embryos demonstrate normal initial vasculogenesis but have a disorganized vascular network lacking appropriate hierarchical organization.18 Tie-1-deficient models demonstrate decreased endothelial cell integration leading to embryonic edema, hemorrhage, and death, and the Tie-1 receptor has recently been shown to be required for normal embryonic lymphangiogenesis.19,20 Ang1–4, members of the angiopoietin family, likely have roles in vessel stabilization and lymphatic development.21 Mutations in the Fox family of transcription factors have been associated with congenital lymphedema, and this family is thought to play a role in the formation of lymphatic valves.22,23 Mutations or deletions in specific integrin subtypes can lead to abnormal lymphatic development.24 Recently, integrin-α9 was found to be necessary for normal lymphatic valve morphogenesis and may be implicated as a candidate gene for primary lymphedema caused by valve defects.25–27
The management of venous malformations
Published in Peter Gloviczki, Michael C. Dalsing, Bo Eklöf, Fedor Lurie, Thomas W. Wakefield, Monika L. Gloviczki, Handbook of Venous and Lymphatic Disorders, 2017
Jovan N. Markovic, Cynthia K. Shortell
Although the etiology of CVMs remains to be elucidated, data from relatively recent studies suggest that the pathophysiologic mechanisms responsible for the formation of CVMs are caused by dysfunctions in the signaling process(es) responsible for the regulation of the proliferation, differentiation, maturation, adhesion, and apoptosis of vascular cells during the development of the vascular system.10 Vessel development occurs in two different ways: vasculogenesis and angiogenesis.11 The exact mechanisms through which these processes occur remain largely unknown and have just recently begun to be unveiled. Vasculogenesis refers to the process by which endothelial cells are differentiated de novo from mesodermal precursors. It occurs only during embryonic development. In angiogenesis, new vessels are formed from pre-existing ones by budding (sprouting), splitting (intussusception), and fusion (intercalated growth). These new vessels that are formed by angiogenesis (the so-called juvenile system) evolve into mature vessels by the processes of maturation and remodeling.12 These complex processes involve several receptor tyrosine kinases. Some of these receptors and their ligands have been identified (i.e., vascular endothelial growth factors and Tie1 and Tie2).13
Overview of Angiogenesis: Molecular and Structural Features
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
Arye Elfenbein, Michael Simons
The signaling molecules most implicated in this process of vessel remodeling are the angiopoietins, ligands that bind to two unique tyrosine kinases named Tie1 and Tie2. Although four distinct ligands have been identified (Ang-1–4), Ang-1 and Ang-2 are best understood with respect to their effects on vascular remodeling. The first insights into the involvement of angiopoietins in this role were generated by studies of Ang-1 knockout mice, which develop a normal primary vascular system that does not undergo subsequent remodeling (27).
An overview of the molecular and clinical significance of the angiopoietin system in leukemia
Published in Journal of Receptors and Signal Transduction, 2023
Saeed Zaka Khosravi, Samira Molaei Ramshe, Mehdi Allahbakhshian Farsani, Mohammadreza Moonesi, Faroogh Marofi, Majid Farshdousti Hagh
The exact role of Tie-1 in the Ang–Tie system is controversial and is not completely defined. The Tie-2 activation by Ang-1 contributes to Tie-2/Tie-1 heterodimer dissociation, Tie-2 clustering, stimulation of downstream signaling pathway, and Tie-1 phosphorylation in Tie-2-dependent fashion [31,87,90]. Milner et al. stated that Tie-1 could not alter anti-apoptotic or anti-permeability facets of Ang-1 on endothelial cells. They hypothesized that Tie-1 might affect other functional aspects of Ang-1 on endothelial cells [91]. On the other hand, further studies have not found a specific role for Tie-1 in the Ang–Tie-2 signaling system. Some studies recommended Tie-1 as a contributor for the agonistic roles of the Ang-1 and Ang-2 [30,92,93], but conversely, others showed it to be a negative regulator of Tie-2 activation [87,94]. Also, the context-dependent regulatory role of Tie-1 upon Tie-2 signaling is revealed [90]. A recent study shows that inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP) as an Ang-2 regulator along with Tie-1 and Tie-2 shedding inhibition enhances Tie-2 activation [95]. It seems that increased Tie-1 expression is correlated with CLL cell proliferation [42] and shorter survival in CML patients [44]. Tie-1 increased level in AML patients has shown no effect on the outcome of patients (Table 1) [43]. Also, one study has demonstrated Tie-1 expression in AML but not in ALL patients [96]. Taken together, more studies are needed in defining the exact role of Tie-1 in the Ang–Tie system and angiogenesis.
Growth factor signaling pathways in vascular development and disease
Published in Growth Factors, 2019
Angiopoietin signaling has complex, context-specific roles in regulating blood vessel growth and has a central role in maintaining vessel stability (Saharinen, Eklund, and Alitalo 2017). The ligands angiopoietin 1 (ANGPT1) and ANGPT2 signal through two tyrosine kinase receptors: tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1) and TIE2 (TEK) (Saharinen, Eklund, and Alitalo 2017). TIE1 is an orphan receptor normally required for full activation of TIE2 (Korhonen et al. 2016). ANGPT1 is a constitutive agonist of TIE2 and is largely responsible for basal TIE2 activation, promoting EC quiescence and vessel stabilization. In part, ANGPT1/TIE2 achieves this by activating PI3K/AKT signaling, which phosphorylates and expels the Forkhead box O (FOXO) transcription factor FOXO1 from the nucleus. This prevents FOXO1 from promoting the expression of vascular destabilizing genes, which includes ANGPT2 (Daly et al. 2004) (Figure 2). ANGPT2 acts predominantly as a competitive inhibitor of ANGPT1, preventing TIE2 activation (Maisonpierre et al. 1997). In some contexts, ANGPT2 can be a weak agonist (Saharinen, Eklund, and Alitalo 2017) but the physiological relevance of this is not always clear (Mueller and Kontos 2016). ANGPT2 inhibition of TIE2 weakens EC-EC junctions, causing vascular destabilization (Saharinen et al. 2008).
Neovascularization: an attractive but tricky target in thyroid cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Jason Tasoulas, Gerasimos Tsourouflis, Stamatios Theocharis
Ang/Tie pathway induces a quiescent state in ECs and it is involved in vessel normalization [35]. Tie-2 receptor binds Angiopoietin (Ang)-1 and Ang-2. It is reported to participate in the SA cascade at early disease stages (day 10–15), in Ang-2 deficient mice [36]. Interestingly, a recent report about the role of the orphan Tie-1 receptor on tumor growth identified a reversed pattern compared to Tie-2 [37]. Tie-1 deletion affected tumor volume at a later disease stage and was associated with delayed tumor growth, decreased levels of circulating tumor cells, lower rate of metastasis formation and prolonged OS [37]. The antitumor effects of Tie-1 deletion were associated with vessel normalization, which prevents intravasation tumor cells of primary tumor and extravasation on the metastatic site [37].