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
Pulmonary Endothelium in Health and Viral Infections
Sunit K. Singh in Human Respiratory Viral Infections, 2014
Four members have been identified in the angiopoietin family. Three of these members, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4) are expressed in humans. Ang-1 is an oligomeric-secreted glycoprotein that exerts its effects through the receptor TIE2, an endothelial-specific tyrosine kinase. The basic functions of Ang-1 are induction of EC migration, formation of capillary-like structures, inhibition of EC apoptosis, reduction of vascular permeability, and inflammation and maintenance of vascular integrity.38 The expression of Ang-1 and TIE2 is present during development of blood vessels. Ang-1 is expressed and secreted by vascular SMCs, while TIE2 is a transmembrane receptor expressed in ECs. In the adult lung vasculature, Ang-1 expression is reduced significantly, showing minimal presence,57 while the expression of TIE2 remains unaltered.57,58 The second member of the angiopoietin family, Ang-2, is a TIE2 receptor agonist or, mainly, antagonist. Both Ang-1 and Ang-2 appear to have the same affinity for TIE2. Ang-2, however, has a context-specific effect depending on the cell type and condition. In the presence of Ang-1 (i.e., a TIE2 agonist), Ang-2 will mostly act as an antagonist and block TIE2 signaling, preventing cytoprotection. Activation of Ang-2/TIE2 signaling promotes vascular destabilization and VEGF-induced angiogenesis.58,59
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).
Quantile-specific heritability of serum growth factor concentrations
Published in Growth Factors, 2021
VEGF stimulates endothelial cell nitric oxide and prostacyclin production (Hood et al. 1998; Neagoe et al. 2005), increases microvascular permeability (Bates et al. 2002), and prevents endothelial cell apoptosis (Lieb et al. 2009). It is inhibited by the circulating soluble form of the VEGFR1 receptor (sFlt-1) by direct sequestration (Shibuya 2006). Angiopoietin-2 promotes VEGF-induced neovascularization (Lieb et al. 2010). Both angiopoietin-2 and the soluble form of the sTie-2 (growth substances tyrosine kinase) receptor (Reusch et al. 2001) inhibit endothelial Ang-1/Tie-2 signaling (Peters 1998; Reusch et al. 2001), thereby attenuating the signal’s ability to prolong endothelial cell survival, maintainthe endothelium in a quiescent state, and facilitate new vessel maturation (Asahara et al. 1998). VEGF and HGF relate to improved endothelial function whereas sFlt-1 relates to endothelial dysfunction (Lieb et al. 2009).
Anticoagulant treatment and bleeding complications in patients with left ventricular assist devices
Published in Expert Review of Cardiovascular Therapy, 2020
Paul L. den Exter, Saskia L.M.A. Beeres, Jeroen Eikenboom, Frederikus A. Klok, Menno V. Huisman
Factors that contribute to these high bleeding risks are multifactorial and include the routine administration of VKA and antiplatelet therapy, combined with the above described risk of acquired coagulopathies and angiodysplasias. The precise mechanisms for the development of angiodysplasias in LVAD patients are not completely understood. Recent evidence has suggested that angiopoietin 2, a potent angiogenic factor that is stored in endothelial cells within Weibel-Palade bodies, is dysregulated in patients with continuous flow LVADs [76]. Compared to patients with heart failure or orthotopic heart transplantation, serum levels and endothelial expression of angiopoietin 2 were higher in LVAD patients. Elevated levels of angiopoietin 2 increased angiogenesis in vitro, which was normalized with angiopoietin −2 blockade. Whether this represents a pharmaceutical target to prevent bleeding complications in LVAD patients remains to be investigated.
Related Knowledge Centers
- Angiogenesis
- Growth Factor
- Peptide
- Receptor Tyrosine Kinase
- Smooth Muscle
- Vascular Endothelial Growth Factor
- Cytokine
- N-Terminus
- C-Terminus
- Tie1