Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis
TL;DR: It is shown with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium, and shows that full VEGFR3 signalling is coupled to receptor internalization.
Abstract: In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions. Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.
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TL;DR: The emerging principles of vascular growth provide exciting new perspectives, the translation of which might overcome the current limitations of pro- and antiangiogenic medicine.
2,278 citations
Cites background from "Ephrin-B2 controls VEGF-induced ang..."
...ECs lacking ephrin-B2 reverse signaling are unable to internalize VEGFR2 and VEGFR3 and cannot transmit VEGF signals properly, together impairing sprouting (Sawamiphak et al., 2010; Wang et al., 2010)....
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TL;DR: A durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment.
Abstract: As angiogenesis is essential for tumor growth and metastasis, controlling tumor-associated angiogenesis is a promising tactic in limiting cancer progression. The tumor microenvironment comprises numerous signaling molecules and pathways that influence the angiogenic response. Understanding how these components functionally interact as angiogenic stimuli or as repressors and how mechanisms of resistance arise is required for the identification of new therapeutic strategies. Achieving a durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment.
1,512 citations
TL;DR: In this paper, the authors identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties, which mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis.
Abstract: The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.
1,281 citations
TL;DR: This review outlines the current information on VEGF signal transduction in relation to blood and lymphatic vessel biology and develops treatments to halt blood vessel formation, angiogenesis in diseases that involve tissue growth and inflammation, such as cancer.
Abstract: Vascular endothelial growth factors (VEGFs) are master regulators of vascular development and of blood and lymphatic vessel function during health and disease in the adult. It is therefore important to understand the mechanism of action of this family of five mammalian ligands, which act through three receptor tyrosine kinases (RTKs). In addition, coreceptors like neuropilins (NRPs) and integrins associate with the ligand/receptor signaling complex and modulate the output. Therapeutics to block several of the VEGF signaling components have been developed with the aim to halt blood vessel formation, angiogenesis, in diseases that involve tissue growth and inflammation, such as cancer. In this review, we outline the current information on VEGF signal transduction in relation to blood and lymphatic vessel biology.
995 citations
Cites background from "Ephrin-B2 controls VEGF-induced ang..."
...VEGFR3 internalization and signaling involving RAC1, AKT, and ERK is regulated by ephrin B2 (Wang et al. 2010)....
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TL;DR: The PI3K pathway plays an important role in regulating angiogenesis both in normal tissues and in cancers, and numerous inhibitors targeting the PI3k/AKT/mTOR pathway have been developed, and these agents have been shown to decrease VEGF secretion and angiynthesis.
Abstract: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is activated in the majority of human cancers. This pathway is known to play a key role in numerous cellular functions including proliferation, adhesion, migration, invasion, metabolism, and survival, but in the current review we focus on its role in angiogenesis. PI3K activation may occur via RAS mutation, loss of phosphatase and tensin homolog (PTEN), or by increased expression of growth factor receptors such as epidermal growth factor receptor. There is a connection between the PI3K pathway and angiogenesis. Hypoxia leads to HIF-1α stabilization and is a major stimulus for increased vascular endothelial growth factor (VEGF) production by tumor cells. However, activation of the PI3K/AKT pathway in tumor cells can also increase VEGF secretion, both by hypoxia-inducible factor 1 (HIF-1) dependent and independent mechanisms. The PI3K/AKT pathway also modulates the expression of other angiogenic factors such as nitric oxide and angiopoietins. Numerous inhibitors targeting the PI3K/AKT/mTOR pathway have been developed, and these agents have been shown to decrease VEGF secretion and angiogenesis. The effect of these inhibitors on tumor vasculature can be difficult to predict. The vasculature of tumors is aberrant, leading to sluggish bloodflow and elevated interstitial blood pressure, which can be perpetuated by the high levels of VEGF. Hence, decreasing VEGF expression can paradoxically lead to vascular normalization and improved bloodflow in some tumors. In addition to its importance in cancer, the PI3K pathway also plays an essential role in the formation of normal blood vessels during development. Embryos with kinase-dead p110α catalytic subunit of PI3K develop vascular defects. Stimulation of endothelial cells by VEGF leads to activation of the PI3K pathway within these cells, which is important for cell migration. Sustained endothelial activation of AKT1 has been shown to induce the formation of structurally abnormal blood vessels that recapitulate the aberrations of tumor vessels. Hence, the PI3K pathway plays an important role in regulating angiogenesis both in normal tissues and in cancers.
965 citations
References
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TL;DR: Recent insights have shed light onto VEGFR signal transduction and the interplay between different V EGFRs and VEGF co-receptors in development, adult physiology and disease.
Abstract: Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.
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TL;DR: It is found that the zebrafish fli1 promoter is able to drive expression of enhanced green fluorescent protein (EGFP) in all blood vessels throughout embryogenesis, and these transgenic lines allow detailed analysis of both wild type and mutant embryonic vasculature.
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TL;DR: Dynamin acts at two steps during clathrin coat formation; GTP hydrolysis is probably needed at both steps; Dynasore acts as a potent inhibitor of endocytic pathways known to depend on dynamin by rapidly blocking coated vesicle formation within seconds of dynasore addition.
1,857 citations
TL;DR: The angiogenic growth of blood vessels and lymphatic vessels coordinates several biological processes such as cell proliferation, guided migration, differentiation and cell–cell communication.
Abstract: Blood vessels and lymphatic vessels form extensive networks that are essential for the transport of fluids, gases, macromolecules and cells within the large and complex bodies of vertebrates. Both of these vascular structures are lined with endothelial cells that integrate functionally into different organs, acquire tissue-specific specialization and retain plasticity; thereby, they permit growth during tissue repair or in disease settings. The angiogenic growth of blood vessels and lymphatic vessels coordinates several biological processes such as cell proliferation, guided migration, differentiation and cell-cell communication.
1,856 citations