Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1-10
Open Access
- 1 January 2012
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 302 (1), H215-H223
- https://doi.org/10.1152/ajpheart.00895.2011
Abstract
Angiopoietin (Ang)-2, a ligand of the receptor tyrosine kinase Tie2, is known to be involved in the regulation of embryonic lymphangiogenesis. However, the role of Ang-2 in postnatal pathological lymphangiogenesis, such as inflammation, is largely unknown. We used a combination of imaging, molecular, and cellular approaches to investigate whether Ang-2 is involved in inflammatory lymphangiogenesis. We observed strong and continuous expression of Ang-2 on newly generated lymphatic vessels for 2 wk in sutured corneas of BALB/c mice. This expression was concurrent with an increased number of lymphatic vessels. TNF-α expression also increased, with peak TNF-α expression occurring before peak Ang-2 expression was reached. In vitro experiments showed that TNF-α stimulates Ang-2 and Tie2 and ICAM-1 expression on human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BECs). Ang-2 alone did not affect the biological behavior of LECs, whereas Ang-2 combined with TNF-α significantly promoted the proliferation of LECs but not BECs. In mouse models, blockade of Ang-2 with L1-10, an Ang-2-specific inhibitor, significantly inhibited lymphangiogenesis but promoted angiogenesis. These results clearly indicate that Ang-2 acts as a crucial regulator of inflammatory lymphangiogenesis by sensitizing the lymphatic vasculature to inflammatory stimuli, thereby directly promoting lymphangiogenesis. The involvement of Ang-2 in inflammatory lymphangiogenesis provides a strong rationale for the exploitation of anti-Ang-2 treatment in the prevention and treatment of tumor metastasis and transplant rejection.Keywords
This publication has 36 references indexed in Scilit:
- Preoperative serum levels of serum VEGF-C is associated with distant metastasis in colorectal cancer patientsInternational Journal of Colorectal Disease, 2008
- Blockade of VEGFR3-signalling specifically inhibits lymphangiogenesis in inflammatory corneal neovascularisationAlbrecht von Graefes Archiv für Ophthalmologie, 2007
- Inhibition of Inflammatory Lymphangiogenesis by Integrin α5 BlockadeThe American Journal of Pathology, 2007
- Bevacizumab as a Potent Inhibitor of Inflammatory Corneal Angiogenesis and LymphangiogenesisInvestigative Ophthalmology & Visual Science, 2007
- Angiogenic effect of intercellular adhesion molecule-1Journal of Huazhong University of Science and Technology [Medical Sciences], 2007
- Time Course of Angiogenesis and Lymphangiogenesis After Brief Corneal InflammationCornea, 2006
- Roles of Thrombospondin-1 and -2 in Regulating Corneal and Iris AngiogenesisInvestigative Ophthalmology & Visual Science, 2004
- VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitmentJCI Insight, 2004
- TNF-R1 Signaling: A Beautiful PathwayScience, 2002
- Endothelial-Leukocyte Adhesion MoleculesAnnual Review of Immunology, 1993