The endothelial cells forming the inner layer of blood vessels and lymphatic vessels are essential components of the vascular system and participate in the pathogenesis of vascular and lymphatic system diseases. The tyrosine-protein kinase receptors with immunoglobulin and EGF homology domains (Tie) on endothelial cells, along with angiopoietin (Ang) ligands, constitute a receptor signaling system distinct from the vascular endothelial growth factor receptor pathway, necessary for embryonic cardiovascular and lymphatic development. The Ang-Tie axis regulates postnatal vascular generation and remodeling, vascular permeability, and inflammation to maintain vascular homeostasis. Therefore, this system plays a crucial role in many vascular and lymphatic system diseases.
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Composition and Function of the Ang-Tie Axis
The Ang-Tie axis comprises angiopoietins (Ang1, Ang2, and Ang4, with Ang3 being the murine ortholog of Ang4) and tyrosine kinase receptors (Tie1 and Tie2). Ang1 serves as an essential agonist for Tie2, primarily secreted by vascular smooth muscle cells and perivascular cells. It is expressed in tissues such as the lung, skin, muscle, prostate, and ovary, regulated by factors like epidermal growth factor and transforming growth factor beta 2 (TGFβ2). Ang1 induces the formation of Tie clusters at endothelial cell-endothelial cell (EC-EC) junctions, enhancing vascular stability (particularly post-angiogenesis), suppressing tissue fibrosis, and modulating vascular normalization during anti-angiogenic therapy. Conversely, Ang2, expressed by endothelial cells and stored in intracellular Weibel-Palade bodies, acts as a paracrine environment-dependent agonist or antagonist of Tie2. It increases endothelial cell permeability and induces detachment of perivascular cells from the basement membrane, leading to vascular leakage, and immune or cancer cell transendothelial migration. Under normal physiological conditions, Ang2 levels are low, but inflammatory and hypoxic stimuli upregulate its expression, reducing vascular stability and promoting endothelial cell activation, angiogenesis, and remodeling.
Fig. 1 Crystal structures of the ANG2/TIE2 complex and the TIE2 kinase domain (Saharinen P., et al. 2015).
Tie is a type of tyrosine kinase-like receptor, including Tie1 and Tie2, primarily expressed in endothelial cells of blood vessels and lymphatic vessels, with minimal expression in certain hematopoietic cell lineages. Tie1 is an orphan receptor, and its role in vascular development remains unclear; however, studies suggest that Tie1 can exert its biological functions through binding to Tie2. Additionally, literature reports Leukocyte cell-derived chemotaxin-2 (LECT2) as a functional ligand for Tie1, elucidating the crucial role and mechanism of the LECT2/Tie1 signaling pathway in angiogenesis and liver fibrosis processes.
Tie2 undergoes autophosphorylation and activation upon binding with Ang1, then transduces signals to downstream molecules, activating the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway, promoting endothelial cell integrity and reducing permeability, thus inhibiting inflammation. Recent studies have found that Tie2-mediated signaling pathways play a critical role in retinal vascular neovascularization, but the loss of its signaling does not significantly affect the growth and remodeling process of lymphatic vessels after birth. Whereas Tie1 plays a crucial role in regulating lymphatic vessel growth and remodeling processes.
The Ang-Tie axis is involved in regulating the homeostasis of endothelial cells and is associated with many human vascular and lymphatic system-related diseases, making it an attractive target for the development of treatments for vascular and lymphatic system-related diseases.
The Role of the Ang-Tie Axis in Vascular and Lymphatic System-Related Diseases
The Ang-Tie axis is a crucial signaling system involved in regulating the development of blood vessels and lymphatic vessels, maintaining vascular homeostasis, and inhibiting pathological inflammation and tumor angiogenesis reactions. In different disease states, the activity and signaling of the Ang-Tie axis undergo changes, thereby affecting the function of the vascular and lymphatic systems.
Ang-Tie Axis and Inflammation-Induced Vascular Permeability and Remodeling
During inflammation, Ang1 and Ang2 play critical roles in regulating vascular permeability and remodeling. Ang1 activates multiple downstream signaling pathways through Tie2, favoring the stabilization of endothelial cell junctions and maintenance of the cellular cytoskeleton, thereby reducing vascular permeability. Conversely, Ang2 acts synergistically with inflammatory cytokines to promote vascular leakage. The balance between Ang1 and Ang2 is crucial during chronic inflammation, and its imbalance may lead to vascular dysfunction and exacerbation of inflammation.
Ang-Tie Axis and Hemodynamic Shear Stress and Atherosclerosis
Atherosclerosis is a chronic inflammatory disease associated with endothelial cell damage and abnormal hemodynamic shear stress. Non-laminar flow induces Tie1 expression, while laminar flow downregulates Tie1 expression. Tie1 contributes to the development of inflammatory diseases in atherosclerosis formation. On the other hand, laminar shear stress stimulation protects blood vessels from the effects of atherosclerosis by regulating endothelial protein tyrosine phosphatase and downregulating Ang2 expression via miRNA.
Ang-Tie Axis and Neovascularization in the Eye and Lymphatic System
The Ang-Tie axis also plays a significant role in ocular vascular development and the lymphatic system. Genetic polymorphisms of Ang2 and SNP segments of the Tie2 gene associated with retinal neovascular diseases are related to the occurrence and development of diseases. In addition, the inactivation of the Ang-Tie axis may be related to the pathogenesis of glaucoma, and targeting this axis may provide new therapeutic strategies for glaucoma.
Ang-Tie Axis in Tumor Angiogenesis and Metastasis
In tumors, the Ang-Tie axis also participates in regulating the processes of angiogenesis and metastasis. Blockade of Ang2 can reduce tumor cell proliferation and endothelial cell sprouting, thereby inhibiting tumor growth and angiogenesis. On the other hand, the blockade of Ang2 can also reduce the migration ability of tumor cells by decreasing the connections between endothelial cells. Therefore, modulation of the Ang-Tie axis may become a potential target for treating tumors.
Conclusion
The Ang-Tie axis regulates blood and lymphatic vessel development, maintains vascular balance, and inhibits inflammation and tumor angiogenesis. In various diseases, Ang2 is overexpressed, and Tie1 promotes inflammatory and angiogenic signaling in atherosclerosis and tumors. Dysregulation of the Ang-Tie axis disrupts vascular balance by altering Tie2 and Ang2 levels. Recent research has advanced our understanding of the axis in vascular and lymphatic systems, especially its role in inflammation and cardiovascular diseases, where it contributes to vascular dysfunction. Research institutions and pharmaceutical companies are targeting the Ang-Tie axis for novel studies, aiming to develop drugs for vascular diseases.
References
- Saharinen P., et al. The TIE receptor family. Receptor Tyrosine Kinases: Family and Subfamilies. 2015: 743-75.
- Eklund L., et al. Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems. Clinical Science. 2017, 131 (1): 87-103.
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