Adipsin improves diabetic hindlimb ischemia through SERPINE1 dependent angiogenesis

Area of Science:

• Endocrinology and Metabolism
• Vascular Biology
• Regenerative Medicine

Background:

• Adipsin (complement factor D, CFD) is an adipokine known for regulating diabetic cardiovascular complications.
• Its role in diabetic hind-limb ischemia (HLI) remains unclear, prompting investigation into its therapeutic potential.
• Diabetes impairs ischemic recovery, necessitating novel therapeutic strategies.

Purpose of the Study:

• To evaluate the therapeutic effect of Adipsin in a mouse model of type 2 diabetic hind-limb ischemia.
• To elucidate the molecular mechanisms by which Adipsin influences angiogenesis and tissue repair in this context.
• To assess Adipsin's potential for treating peripheral artery disease (PAD) in diabetic patients.

Main Methods:

• Utilized high-fat diet and streptozotocin (HFD/STZ)-induced diabetic mice and Adipsin-transgenic (Adipsin-Tg) mice.
• Established hindlimb ischemia via femoral artery ligation and monitored blood flow recovery using Laser Doppler perfusion imaging.
• Investigated molecular mechanisms using RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS).

Main Results:

• Adipsin expression was suppressed in diabetic mice with HLI but upregulated in non-diabetic mice.
• Adipsin-Tg mice showed significantly improved blood flow recovery, capillary density, and muscle regeneration compared to non-transgenic diabetic mice.
• Adipsin promoted endothelial cell proliferation, migration, and tube formation, enhancing AKT, ERK, and eNOS phosphorylation.

Conclusions:

• Adipsin promotes angiogenesis and recovery of blood perfusion in diabetic HLI by downregulating SERPINE1 via SERBP1 interaction.
• This mechanism involves the activation of the VEGFR2 signaling cascade.
• Adipsin demonstrates novel therapeutic potential for managing PAD in diabetic patients by enhancing angiogenesis and tissue repair.