Myeloid Drp1 deficiency limits revascularization in ischemic muscles via inflammatory macrophage polarization and metabolic reprograming

Shikha Yadav; Vijay C. Ganta; Sudhahar Varadarajan; Vy Ong; Yang Shi; Archita Das; Dipankar Ash; Sheela Nagarkoti; Malgorzata McMenamin; Stephanie Kelley; Tohru Fukai; Masuko Ushio-Fukai

doi:10.1172/jci.insight.177334

Myeloid Drp1 deficiency limits revascularization in ischemic muscles via inflammatory macrophage polarization and metabolic reprograming

Shikha Yadav,¹ Vijay C. Ganta,¹ Sudhahar Varadarajan,¹ Vy Ong,² Yang Shi,² Archita Das,¹ Dipankar Ash,¹ Sheela Nagarkoti,¹ Malgorzata McMenamin,¹ Stephanie Kelley,¹ Tohru Fukai,¹ and Masuko Ushio-Fukai¹

Published November 26, 2024 - More info

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Abstract

Macrophage plays a crucial role in promoting perfusion recovery and revascularization after ischemia through anti-inflammatory polarization, a process essential for the treatment of peripheral arterial disease (PAD). Mitochondrial dynamics, particularly regulated by the fission protein DRP1, are closely linked to macrophage metabolism and inflammation. However, the role of DRP1 in reparative neovascularization remains unexplored. Here we show that DRP1 expression was increased in F4/80⁺ macrophages within ischemic muscle at day 3 after hindlimb ischemia (HLI), an animal model of PAD. Mice lacking Drp1 in myeloid cells exhibited impaired limb perfusion recovery, angiogenesis and muscle regeneration post-HLI. These effects were associated with increased pro-inflammatory M1-like macrophages, p-NFkB and TNFα, and reduced anti-inflammatory M2-like macrophages and p-AMPK in ischemic muscle of myeloid Drp1^–/– mice. In vitro, Drp1-deficient macrophages under hypoxia serum starvation (HSS), an in vitro PAD model, demonstrated enhanced glycolysis via reducing p-AMPK as well as mitochondrial dysfunction, and excessive mitochondrial ROS production, resulting in increased pro-inflammatory M1-gene and reduced anti-inflammatory M2-gene expression. Conditioned media from HSS-treated Drp1^–/– macrophages exhibited increased pro-inflammatory cytokine secretion, leading to suppressed angiogenesis in endothelial cells. Thus, macrophage DRP1 deficiency under ischemia drives pro-inflammatory metabolic reprogramming and macrophage polarization, limiting revascularization in experimental PAD.

Myeloid Drp1 deficiency limits revascularization in ischemic muscles via inflammatory macrophage polarization and metabolic reprograming

Shikha Yadav,¹ Vijay C. Ganta,¹ Sudhahar Varadarajan,¹ Vy Ong,² Yang Shi,² Archita Das,¹ Dipankar Ash,¹ Sheela Nagarkoti,¹ Malgorzata McMenamin,¹ Stephanie Kelley,¹ Tohru Fukai,¹ and Masuko Ushio-Fukai¹

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Myeloid Drp1 deficiency limits revascularization in ischemic muscles via inflammatory macrophage polarization and metabolic reprograming

Shikha Yadav,1 Vijay C. Ganta,1 Sudhahar Varadarajan,1 Vy Ong,2 Yang Shi,2 Archita Das,1 Dipankar Ash,1 Sheela Nagarkoti,1 Malgorzata McMenamin,1 Stephanie Kelley,1 Tohru Fukai,1 and Masuko Ushio-Fukai1

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Shikha Yadav,¹ Vijay C. Ganta,¹ Sudhahar Varadarajan,¹ Vy Ong,² Yang Shi,² Archita Das,¹ Dipankar Ash,¹ Sheela Nagarkoti,¹ Malgorzata McMenamin,¹ Stephanie Kelley,¹ Tohru Fukai,¹ and Masuko Ushio-Fukai¹