| First Author | Thirunavukkarasu M | Year | 2022 |
| Journal | Microvasc Res | Volume | 141 |
| Pages | 104311 | PubMed ID | 34999110 |
| Mgi Jnum | J:341285 | Mgi Id | MGI:7431027 |
| Doi | 10.1016/j.mvr.2022.104311 | Citation | Thirunavukkarasu M, et al. (2022) Gene therapy with Pellino-1 improves perfusion and decreases tissue loss in Flk-1 heterozygous mice but fails in MAPKAP Kinase-2 knockout murine hind limb ischemia model. Microvasc Res 141:104311 |
| abstractText | OBJECTIVES: In the United States, over 8.5 million people suffer from peripheral arterial disease (PAD). Previously we reported that Pellino-1(Peli1) gene therapy reduces ischemic damage in the myocardium and skin flaps in Flk-1 [Fetal Liver kinase receptor-1 (Flk-1)/ Vascular endothelial growth factor receptor-2/VEGFR2] heterozygous (Flk-1(+/)(-)(-)) mice. The present study compares the angiogenic response and perfusion efficiency following hind limb ischemia (HLI) in, Flk-1(+/-) and, MAPKAPKINASE2 (MK2(-/-)) knockout (KO) mice to their control wild type (WT). We also demonstrated the use of Peli1 gene therapy to improve loss of function following HLI. STUDY DESIGN AND METHODS: Femoral artery ligation (HLI) was performed in both Flk-1(+/-) and MK2(-/-) mice along with their corresponding WT. Another set of Flk-1(+/-) and MK2(-/-) were injected with either Adeno-LacZ (Ad.LacZ) or Adeno-Peli1 (Ad.Peli1) after HLI. Hind limb perfusion was assessed by laser doppler imaging at specific time points. A standardized scoring scale is used to quantify the extent of ischemia. Histology analysis performed includes capillary density, fibrosis, pro-angiogenic and anti-apoptotic proteins. RESULTS: Flk-1(+/-) and MK2(-/-) had a slower recovery of perfusion efficiency in the ischemic limbs than controls. Both Flk-1(+/-) and MK2(-/-) KO mice showed decreased capillary density and capillary myocyte ratios with increased fibrosis than their corresponding wild types. Ad.Peli1 injected ischemic Flk-1(+/-) limb showed improved perfusion, increased capillary density, and pro-angiogenic molecules with reduced fibrosis compared to Ad.LacZ group. No significant improvement in perfusion was observed in MK2(-/-) ischemic limb after Ad. Peli1 injection. CONCLUSION: Deletion of Flk-1 and MK2 impairs neovascularization and perfusion following HLI. Treatment with Ad. Peli1 results in increased angiogenesis and improved perfusion in Flk-1(+/-) mice but fails to rectify perfusion in MK2 KO mice. Overall, Peli1 gene therapy is a promising candidate for the treatment of PAD. |
