Mechanism for IL-1 beta-mediated neovascularization unmasked by IL-1 beta knock-out mice.

Abstract

We have reported that interleukin-1 beta (IL-1 beta) upregulates cardiac expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2), raising the possibility that IL-1 beta plays an important role in VEGF-mediated neovascularization. In this study, we examined the cellular mechanism for ischemia-induced neovascularization using IL-1 beta knock-out (-/-) mice. Recovery of blood perfusion in ischemic hindlimb in IL-1 beta-/- mice was markedly (43% decrease) impaired as compared with the wild-type mice. CD31(+) vessel numbers and Ki-67(+) neo-capillaries were significantly (P < 0.01) decreased 44% and 68%, respectively. IL-1 beta expression was localized in the capillary vessels in ischemic limb muscles. Ischemia-induced expressions of hypoxia-inducible factor 1 alpha (HIF-1 alpha), VEGF, its receptor VEGFR-2 and vascular cell adhesion molecule-1 (VCAM-1) were markedly inhibited in the IL-1 beta-/- mice. Hindlimb ischemia-induced an increase (1.22% out of total nuclear cell) in CD34(-)/B220(-)/CD3(-)/Flk-1(+) hematopoietic stem cell population in peripheral blood in the wild-type mice, whereas in the IL-1 beta-/- mice such increase was only 0.09%. Injection of IL-1 beta protein into the wild-type mice markedly increased the ratio of the CD34(-)/B220(-)/CD3(-)/Flk-1(+) cell population (from 0.03% to 0.7%) in the peripheral blood associated with an increase in the number of endothelial cells. Such IL-1 beta-mediated increases in cell numbers were blocked by co-injection of anti-VEGF antibody. CD34(-)/B220(-)CD3(-)Flk-1(+) cells trans-differentiated into eNOS- and CD31-expressing endothelial cells in vivo and in vitro. This study demonstrates that IL-1 beta plays a key role in ischemia-induced neovascularization by mobilizing CD34(-)/B220(-)CD3(-)Flk-1(+) endothelial precursor cells in a VEGF-dependent manner as well as by upregulating expressions of VEGF, VEGFR-2 and adhesion molecules on endothelial cells.

• Authors: Katsuya Amano, Mitsuhiko Okigaki, Yasushi Adachi, Soichiro Fujiyama, Yasukio Mori, Atsushi Kosaki, Toshiji Iwasaka, Hiroaki Matsubara
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 36 Issue 4 Pg. 469-80 (Apr 2004) ISSN: 0022-2828 [Print] England
• PMID: 15081307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD34
• CD3 Complex
• Hypoxia-Inducible Factor 1, alpha Subunit
• Interleukin-1
• Ki-67 Antigen
• Platelet Endothelial Cell Adhesion Molecule-1
• Transcription Factors
• Vascular Cell Adhesion Molecule-1
• Vascular Endothelial Growth Factor A
• RNA
• Vascular Endothelial Growth Factor Receptor-2
• Leukocyte Common Antigens

Topics

• Animals
• Antigens, CD34 (biosynthesis)
• Blotting, Western
• CD3 Complex (biosynthesis)
• Calibration
• Cell Differentiation
• Cell Separation
• Endothelium, Vascular (metabolism)
• Flow Cytometry
• Hypoxia-Inducible Factor 1, alpha Subunit
• Immunohistochemistry
• Interleukin-1 (genetics, metabolism, physiology)
• Ischemia
• Ki-67 Antigen (biosynthesis)
• Laser-Doppler Flowmetry
• Leukocyte Common Antigens (biosynthesis)
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Neovascularization, Pathologic
• Perfusion
• Platelet Endothelial Cell Adhesion Molecule-1 (biosynthesis)
• RNA (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Transcription Factors (metabolism)
• Up-Regulation
• Vascular Cell Adhesion Molecule-1 (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)