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Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1-10.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2012 Jan 01; Vol. 302 (1), pp. H215-23. Date of Electronic Publication: 2011 Nov 04. - Publication Year :
- 2012
-
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.
- Subjects :
- Angiopoietin-2 metabolism
Animals
Cell Proliferation drug effects
Cells, Cultured
Cornea blood supply
Cornea immunology
Cornea metabolism
Corneal Neovascularization immunology
Corneal Neovascularization metabolism
Corneal Neovascularization physiopathology
Disease Models, Animal
Endothelial Cells metabolism
Endothelium, Lymphatic immunology
Endothelium, Lymphatic metabolism
Endothelium, Lymphatic physiopathology
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Female
Humans
Inflammation immunology
Inflammation metabolism
Inflammation physiopathology
Inflammation Mediators metabolism
Mice
Mice, Inbred BALB C
Neovascularization, Physiologic drug effects
Time Factors
Tumor Necrosis Factor-alpha metabolism
Angiopoietin-2 antagonists & inhibitors
Anti-Inflammatory Agents pharmacology
Cornea drug effects
Corneal Neovascularization prevention & control
Endothelium, Lymphatic drug effects
Inflammation prevention & control
Lymphangiogenesis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 302
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 22058148
- Full Text :
- https://doi.org/10.1152/ajpheart.00895.2011