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Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Angiogenesis is the process underlying the formation and development of new blood vessels vital for the growth and development of new cells, as in wound healing. However, it also plays an important role in tumor growth, development, and metastasis, as it facilitates the transport of oxygen and nutrients to a growing tumor and the removal of waste products through the formation of a supporting vascular network. Angiogenesis is controlled by growth factors such as VEGF, TGF-α, TGF-β, TNF-α, angiogenin, IL-8, and the angiopoietins. One of the primary regulators of tumor angiogenesis is the pro-angiogenic factor VEGF, a potent endothelial cell-specific mitogen which stimulates endothelial cell growth originating in arteries, veins, and lymph drainage vessels (Figure 12.5).
Dopamine in the Immune and Hematopoietic Systems
Published in Nira Ben-Jonathan, Dopamine, 2020
Angiogenesis is a highly regulated process that takes place through two nonexclusive events of microvascular growth: sprouting or splitting [70]. Sprouting differs from splitting angiogenesis by forming entirely new vessels as opposed to splitting existing vessels. As illustrated in Figure 9.6, sprouting proceeds in several well-characterized stages. First, angiogenic factors [VEGF and fibroblast growth factor (FGF)], released from neighboring cells, bind to their respective receptors on endothelial cells and activate signal transduction pathways. Matrix metalloproteinases (MMPs), produced by the endothelial cells are then activated and degrade the extracellular matrix, enabling an escape of endothelial cells from the parental vessel walls. This is followed by their migration and proliferation. The integrins, expressed by endothelial cells, facilitate their adhesion to the extracellular matrix and the formation of solid sprouts that connect to neighboring vessels. Angiopoietin 1 (Ang-1), binding to Tie-2 receptors, stimulates pericyte recruitment and vessel stabilization. Final vessel maturation and stabilization necessitate additional morphological changes that include lumen formation and perfusion, network establishment, remodeling, and pruning to become full-fledged functional vessels.
Angiogenesis and Roles of Adhesion Molecules in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Asmita Hazra, Saptarshi Mandal
The main angiogenic angiopoietin is Ang2, which causes vessel destabilization, initiation of angiogenesis, and transformation of capillaries into inflammatory venules, with increased leakiness and stickiness, in synergism with TNFα. Ang2 is expressed by endothelial cells near the VEGF-expressing epidermal keratinocytes in psoriasis lesions, and the vessel-stabilizing angiopoietin Ang1 is expressed by stromal cells in the vascularized papillary dermis of lesional skin. Their receptors Tie2 and Ang2 could also be upregulated in cultured dermal microvascular endothelial cell upon the addition of angiogenic factors like VEGF or FGF2. Successful antipsoriatic treatment was accompanied by a noticeable reduction of Ang2.
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).
Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies
Published in Expert Opinion on Biological Therapy, 2018
Michael Whitehead, Sanjeewa Wickremasinghe, Andrew Osborne, Peter Van Wijngaarden, Keith R. Martin
The angiopoietin family is involved in the regulation of vascular maturation and neovascularization. Angiopoietin-1 and -2 (Ang1 and 2) are known to have opposing effects when binding to their cognate receptor, the receptor tyrosine kinase Tie2. Ang1 induces Tie2 activation and phosphorylation, thereby promoting vessel stabilization and maturation. In addition, Ang1 has demonstrated anti-inflammatory effects and the ability to inhibit leukocyte adhesion to endothelial cells in animal models [92,93]. By contrast, Ang2 is a context-dependent mediator of the Tie2 pathway and can act as a mild agonist or an antagonist of the receptor. To dephosphorylate and thereby deactivate the Tie2 receptor, Ang2 activates protein tyrosine phosphatase beta or vascular endothelial PTP, which in turn leads to blood vessel destabilization. This destabilization is essential for the normal process of angiogenesis but can lead to endothelial cell apoptosis in the absence of VEGF signaling [94,95].
Changing paradigms for targeted therapies against diffuse infiltrative gliomas: tackling a moving target
Published in Expert Review of Neurotherapeutics, 2019
Candice D. Carpenter, Iyad Alnahhas, Javier Gonzalez, Pierre Giglio, Vinay K. Puduvalli
Several molecules other than VEGF have emerged as relevant mediators of angiogenesis; of these, angiopoietins are associated with robust angiogenesis in tumors [83]. Angiopoietin-2 (Ang-2) is a member of the angiopoietin family that is upregulated in GBM [84,85]. Ang-2 signals primarily through TEK receptor tyrosine kinase (Tie-2) [86]. Studies have shown that increased Ang-2 expression can contribute to resistance to anti-VEGF therapies in GBM through its proangiogenic properties [87]. Dual inhibition of VEGFR and Ang-2 has been shown to inhibit tumor growth and prolong survival compared with VEGFR inhibition alone in murine glioma models [86].