Angiopoietin–Tie signalling in the cardiovascular and lymphatic systems

Abstract

Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)–Tie system is a second endothelial cell specific ligand–receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang–Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang–Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang–Tie system in vascular development and pathogenesis of vascular diseases.

Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

“…Whereas Tie2 is well characterized as the primary Ang/Tie signaling receptor, the function of the second Tie receptor, Tie1, is much less understood. Tie1 does not bind the angiopoietin ligands and is to this day considered an orphan receptor (18). Yet, Tie1 is essential for vascular development: Tie1-deficient mice have no overt angiogenetic defects, but their vasculature fails to mature and embryos die during late gestation (19,20).…”

Markers and Biomarkers of Endothelium: When Something Is Rotten in the State

“…This pathway is involved in many diseases where the vasculature plays a significant role, such as in cancer, sepsis, diabetes, atherosclerosis, and so forth. Mutations in the TIE2 signaling affect vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma [75]. ECs are specifically enriched for expression of Tie-2, its paralog Tie-1, the tyrosine phosphatase VE-PTP, and its ligand Angpt-2 [57].…”

“…Tie-2 activated by Angpt-1 stimulates Rap1 GTPase, which reduces radial stress fibres via Rac1 and nonmuscle myosin II, independent of VEcadherin. On the other hand, Angpt1-Tie-2 can also recruit VE-PTP into EC-EC contacts, and VE-PTP dephosphorylation of Tie-2 enhances vascular permeability [75]. Moreover, activation of a VEGFR2-dependent signaling pathway causes phosphorylation of the VE-cadherin, with subsequent betaarrestin-dependent endocytosis of VE-cadherin and disassembly of EC-EC junctions [79].…”

“…Moreover, activation of a VEGFR2-dependent signaling pathway causes phosphorylation of the VE-cadherin, with subsequent betaarrestin-dependent endocytosis of VE-cadherin and disassembly of EC-EC junctions [79]. On the other hand, at EC-EC junctions, VE-PTP indirectly dephosphorylates VEGFR2 via a Tie-2-dependent mechanism; this downregulates VE-cadherin tyrosine phosphorylation and promotes EC polarity and lumen formation [75,80]. Thus, endothelial permeability is a result of complex interplay of Angpts, VEGF, their receptors, VE-cadherin, and VE-PTP; targeting VE-PTP can stabilize blood vessels, at least in patients with a wide variety of retinal and choroidal vascular diseases [78].…”

Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019

“…Angiopoietins (ANGPT1 and ANGPT2) also modulate angiogenesis and lymphangiogenesis through the engagement of TIE1 and TIE2 receptors [157]. ANGPT1, expressed by pericytes, supports BEC survival whereas ANGPT2, secreted by BECs, acts autocrinally and paracrinally as the TIE2 ligand to promote angiogenesis and lymphangiogenesis [158]. TIE1 and TIE2 mRNAs are expressed in human lung mast cells and ANGPT1 induces migration of these cells through the engagement of TIE2 [159].…”