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

Overview

Journal Microvasc Res

Specialty Cardiology & Vascular Diseases

Date 2022 Jan 9

PMID 34999110

Citations 3

Authors

Mahesh Thirunavukkarasu

Seetur R Pradeep

Gopi Ukani

Salim Abunnaja

Mark Youssef

Diego Accorsi

Santosh Swaminathan

Sue Ting Lim

Virginia Parker

Jacob Campbell

Muhammad Tipu Rishi

J Alexander Palesty

Nilanjana Maulik

Affiliations

Soon will be listed here.

Abstract

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.

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