Paradoxical impairment of angiogenesis, endothelial function and circulating number of endothelial progenitor cells in DPP4-deficient rat after critical limb ischemia.

Abstract

INTRODUCTION:

We hypothesized that dipeptidyl peptidase-IV (DPP4) may impair angiogenesis, endothelial function, and the circulating number of endothelial progenitor cells (EPC) in a model of critical limb ischemia (CLI) through ligating the left femoral artery using DPP4-deficient rats.

METHODS:

Adult male DPP4-deficient (DPP4(D)) rats (n = 18) were equally divided into CLI only (DPP4(D)-CLI) and CLI treated by granulocyte colony-stimulating factor (GCSF) (DPP4(D)-CLI-GCSF). For comparison, age-matched wild-type (WT) Fischer 344 rats (n = 18) were randomized into two groups receiving identical treatment compared to their DPP4-deficient counterparts and labeled as WT-CLI (n = 9) and WT-CLI-GCSF (n = 9), respectively.

RESULTS:

The circulating number of EPCs (CD31(+), CD34(+), CD133, C-kit(+)) was significantly lower in DPP4-deficient than in WT rats on post-CLI days 1 and 4 (all P < 0.01). The ratio of ischemia/normal blood flow was remarkably lower in DPP4(D)-CLI-GCSF rats than in WT-CLI-GCSF animals on post-CLI Day 14 (all P < 0.01). Protein expressions of pro-angiogenic factors (endothelial nitric oxide synthase (eNOS), CXCR4, SDF-1α, vascular endothelial growth factor (VEGF)) were remarkably higher in WT-CLI than in DPP4(D)-CLI rats, and higher in WT-CLI-GCSF than in DPP4(D)-CLI-GCSF animals (all P < 0.01). Moreover, the numbers of small vessel in the ischemic area were substantially higher in WT-CLI-GCSF than in DPP4(D)-CLI-GCSF rats (P < 0.001). Furthermore, vasorelaxation and nitric oxide production of the normal femoral artery were significantly reduced in DPP4-deficient than in WT Fischer rats (all P < 0.01).

CONCLUSIONS:

Contrary to our hypothesis, DPP4-deficient rats were inferior to age-matched WT Fischer rats in terms of angiogenesis, endothelial function, circulating EPC number and response to GCSF, suggesting a positive role of DPP4 in maintaining vascular function and tissue perfusion in this experimental setting.

• Authors: Cheuk-Kwan Sun, Steve Leu, Jiunn-Jye Sheu, Tzu-Hsien Tsai, Hsin-Chin Sung, Yung-Lung Chen, Sheng-Ying Chung, Sheung-Fat Ko, Hsueh-Wen Chang, Hon-Kan Yip
• Journal: Stem cell research & therapy (Stem Cell Res Ther) Vol. 4 Issue 2 Pg. 31 (Mar 21 2013) ISSN: 1757-6512 [Electronic] England
• PMID: 23517567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Surface
• Chemokine CXCL12
• Cxcr4 protein, rat
• Receptors, CXCR4
• Vascular Endothelial Growth Factor A
• Granulocyte Colony-Stimulating Factor
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Dipeptidyl Peptidase 4
• Galactose

Topics

• Animals
• Antigens, Surface (metabolism)
• Blood Flow Velocity (drug effects)
• Chemokine CXCL12 (metabolism)
• Dipeptidyl Peptidase 4 (deficiency, genetics, metabolism)
• Endothelial Progenitor Cells (cytology, drug effects, metabolism)
• Galactose (pharmacology)
• Granulocyte Colony-Stimulating Factor (pharmacology)
• Ischemia (metabolism, pathology, physiopathology)
• Laser-Doppler Flowmetry
• Male
• Neovascularization, Pathologic
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Rats
• Receptors, CXCR4 (metabolism)
• Time Factors
• Vascular Endothelial Growth Factor A (metabolism)
• Vasodilation (drug effects)