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Overexpression of catalase in myeloid cells causes impaired postischemic neovascularization
Roberto Hodara1, Daiana Weiss, Giji Joseph
1Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Objective:
Myeloid lineage cells (MLCs) such as macrophages are known to play a key role in postischemic neovascularization. However, the role of MLC-derived reactive oxygen species in this process and their specific chemical identity remain unknown.
Methods And Results:
Transgenic mice with MLC-specific overexpression of catalase (Tg(Cat-MLC) mice) were created on a C57BL/6 background. Macrophage catalase activity was increased 3.4-fold compared with wild-type mice. After femoral artery ligation, laser Doppler perfusion imaging revealed impaired perfusion recovery in Tg(Cat-MLC) mice. This was associated with fewer collateral vessels, as assessed by microcomputed tomography angiography, and decreased capillary density. Impaired functional recovery of the ischemic limb was also evidenced by a 50% reduction in spontaneous running activity. The deficient neovascularization was associated with a blunted inflammatory response, characterized by decreased macrophage infiltration of ischemic tissues, and lower mRNA levels of inflammatory markers, such as tumor necrosis factor-α, osteopontin, and matrix mettaloproteinase-9. In vitro macrophage migration was impaired in Tg(Cat-MLC) mice, suggesting a role for H(2)O(2) in regulating the ability of macrophages to infiltrate ischemic tissues.
Conclusions:
MLC-derived H(2)O(2) plays a key role in promoting neovascularization in response to ischemia and is a necessary factor for the development of ischemia-induced inflammation.
Insights
Hydrogen peroxide (H2O2) derived from myeloid lineage cells (MLCs) is crucial for neovascularization and inflammation following ischemia. Impaired H2O2 production in MLCs hinders recovery and reduces collateral vessel formation.
Area of Science:
- Biomedical Science
- Molecular Biology
- Immunology
Background:
- Myeloid lineage cells (MLCs), including macrophages, are vital for neovascularization after ischemia.
- The specific role and chemical nature of reactive oxygen species (ROS) produced by MLCs in this process are not well understood.
Purpose of the Study:
- To investigate the role of MLC-derived hydrogen peroxide (H2O2) in post-ischemic neovascularization.
- To determine if H2O2 is essential for ischemia-induced inflammation and macrophage function.
Main Methods:
- Generated transgenic mice (Tg(Cat-MLC)) with increased catalase activity in MLCs.
- Utilized femoral artery ligation to induce hindlimb ischemia.
- Assessed neovascularization using laser Doppler perfusion imaging and microcomputed tomography angiography.
- Quantified capillary density, limb function (running activity), and inflammatory markers (mRNA levels).
- Evaluated macrophage migration in vitro.
Main Results:
- Tg(Cat-MLC) mice exhibited impaired perfusion recovery and reduced collateral vessel formation compared to wild-type mice.
- Capillary density and functional recovery of ischemic limbs were significantly decreased in Tg(Cat-MLC) mice.
- Neovascularization deficits correlated with a blunted inflammatory response, including reduced macrophage infiltration and lower inflammatory gene expression.
- In vitro studies showed impaired macrophage migration in Tg(Cat-MLC) mice, indicating H2O2's role in macrophage tissue infiltration.
Conclusions:
- MLC-derived H2O2 is a critical mediator of neovascularization following ischemic events.
- H2O2 is essential for the development of ischemia-induced inflammation.
- Targeting MLC-derived H2O2 may offer therapeutic strategies for ischemic diseases.
