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Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia
Published on: June 8, 2019
CCL11 released by GSDMD-mediated macrophage pyroptosis regulates angiogenesis after hindlimb ischemia
Yiwen Wang1, Yang Gao1, Huairui Shi1
1Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
Insights
Gasdermin D (GSDMD) promotes blood flow recovery after hindlimb ischemia by triggering pyroptosis and releasing CCL11 from macrophages, enhancing angiogenesis. This finding offers a new therapeutic target for vascular ischemic diseases.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- Peripheral vascular disease (PVD) presents a significant public health challenge, linked to high disability and mortality rates.
- Gasdermin D (GSDMD) is implicated in pyroptosis and cardiovascular disease pathophysiology.
- The precise role of GSDMD in regulating perfusion recovery following hindlimb ischemia (HLI) requires elucidation.
Purpose of the Study:
- To investigate the function of GSDMD in controlling perfusion recovery after hindlimb ischemia (HLI).
- To clarify the molecular mechanisms by which GSDMD influences angiogenesis in ischemic injury.
Main Methods:
- Utilized a hindlimb ischemia (HLI) mouse model.
- Assessed perfusion recovery and angiogenesis in GSDMD-deficient and wild-type mice.
- Investigated the role of GSDMD in macrophage-mediated angiogenesis and CCL11 production.
- Examined the effects of CCL11 on endothelial function and angiogenesis in vitro and in vivo.
Main Results:
- GSDMD-mediated pyroptosis occurs during HLI, and its absence improves perfusion recovery and angiogenesis.
- GSDMD deletion in macrophages reduces CCL11 levels, a key chemokine for angiogenesis.
- Exogenous CCL11 enhances endothelial function and angiogenesis, effects diminished by CCL11 antibodies.
- GSDMD promotes angiogenesis via CCL11 release from macrophages, improving blood flow post-HLI.
Conclusions:
- GSDMD plays a critical role in regulating angiogenesis and perfusion recovery after ischemic injury.
- The GSDMD-CCL11 axis in macrophages is essential for promoting angiogenesis and blood flow restoration.
- CCL11 emerges as a potential therapeutic target for treating vascular ischemic diseases.
Abstract:
Peripheral vascular disease (PVD) is an emerging public health burden with a high rate of disability and mortality. Gasdermin D (GSDMD) has been reported to exert pyroptosis and play a critical role in the pathophysiology of many cardiovascular diseases. We ought to determine the role of GSDMD in the regulation of perfusion recovery after hindlimb ischemia (HLI). Our study revealed that GSDMD-mediated pyroptosis occurred in HLI. GSDMD deletion aggravated perfusion recovery and angiogenesis in vitro and in vivo. However, how GSDMD regulates angiogenesis after ischemic injury remains unclear. We then found that GSDMD-mediated pyroptosis exerted the angiogenic capacity in macrophages rather than endothelial cells after HLI. GSDMD deletion led to a lower level of CCL11 in mice serum. GSDMD knockdown in macrophages downregulated the expression and decreased the releasing level of CCL11. Furthermore, recombinant CCL11 improved endothelial functions and angiogenesis, which was attenuated by CCL11 antibody. Taken together, these results demonstrate that GSDMD promotes angiogenesis by releasing CCL11, thereby improving blood flow perfusion recovery after hindlimb ischemic injury. Therefore, CCL11 may be a novel target for prevention and treatment of vascular ischemic diseases.
