TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological...

Area of Science:

• Vascular biology
• Immunology
• Molecular mechanisms of angiogenesis

Background:

• Angiogenesis is crucial for ischemia but can be pathological when driven by inflammation.
• Tripartite-motif-containing protein 2 (TRIM2) was previously found to impair endothelial angiogenic functions in vitro.
• The in vivo role and molecular mechanisms of TRIM2 in angiogenesis require further investigation.

Purpose of the Study:

• To investigate the in vivo role of TRIM2 in inflammation- and hypoxia-induced angiogenesis.
• To elucidate the molecular mechanisms underlying TRIM2's function in angiogenesis.
• To compare TRIM2's effects in different angiogenic contexts.

Main Methods:

• CRISPR/Cas9 gene editing to generate Trim2 knockout mice.
• Periarterial collar model for inflammation-induced angiogenesis.
• Hindlimb ischemia model for hypoxia-mediated angiogenesis.
• In vitro endothelial cell culture with TRIM2 knockdown via shRNA.
• Analysis of macrophage infiltration, neovessel proliferation, and molecular mediators (HIF-1α, eNOS).

Main Results:

• Trim2 knockout mice showed reduced macrophage infiltration and neovascularization in the inflammation model.
• TRIM2 knockdown attenuated inflammation-induced angiogenic mediators like HIF-1α and eNOS phosphorylation in vitro.
• No significant differences in blood flow reperfusion were observed in the hindlimb ischemia model between Trim2 knockout and wildtype mice.
• TRIM2 knockdown in vitro reduced hypoxia-induced HIF-1α but did not affect other angiogenic proteins.

Conclusions:

• TRIM2 is implicated in regulating inflammation-induced angiogenesis, particularly concerning macrophage recruitment and neovessel formation.
• TRIM2's role in angiogenesis appears context-dependent, with limited impact on hypoxia-driven neovascularization.
• These findings contribute to understanding TRIM2's complex role in diverse angiogenic processes.