Dopamine in the Immune and Hematopoietic Systems
Nira Ben-Jonathan in 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.
Lymphatic malformations
Prem Puri in Newborn Surgery, 2017
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
Angiogenesis and Roles of Adhesion Molecules in Psoriatic Disease
Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi in Psoriasis and Psoriatic Arthritis, 2017
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.
Novel nano-carriers with N-formylmethionyl-leucyl-phenylalanine-modified liposomes improve effects of C16-angiopoietin 1 in acute animal model of multiple sclerosis
Published in Drug Delivery, 2023
Xiao-Xiao Fu, Han Qu, Jing Wang, Hua-Ying Cai, Hong Jiang, Hao-Hao Chen, Shu Han
The fundamental events during the onset of acute EAE include extensive edema and cellular inflammation due to an impaired blood–brain barrier (BBB). Importantly, integrin αVβ3 permits endothelial cells to interact with many extracellular matrix proteins, including laminin. The synthesized peptide C16, a γ1 chain peptide of laminin-1, can selectively bind the αVβ3 and αVβ1 integrins in endothelial cells to block the interaction between leukocytes and endothelial cells, which ultimately inhibits the transmigration of inflammatory cells (Gaillard et al., 2012). A previous study has also verified that C16 had no effect on the total number of leukocytes, suggesting that C16 is not an immunosuppressant (Han S et al., 2010). As a member of the endothelial growth factor family, angiopoietin 1 (Ang-1) has important roles in the establishment and maintenance of the maturation, stabilization, and integrity of the vascular system (Fang et al., 2013). Moreover, C16 and Ang-1 can synergistically alleviate vascular leakage and inflammation and prevent the demyelination and axonal loss in the EAE rat model (Jiang et al., 2014). However, the solubility of C16 is largely affected by the pH of the solvent, which decreases its bioavailability and may limit its clinical application (Han et al., 2010).
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].
Related Knowledge Centers
- Angiogenesis
- Growth Factor
- Peptide
- Receptor Tyrosine Kinase
- Smooth Muscle
- Vascular Endothelial Growth Factor
- Cytokine
- N-Terminus
- C-Terminus
- Tie1