Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia

Sergio Rey, Kang Ae Lee, C. Joanne Wang, Kshitiz Gupta, Shaoping Chen, Alexandra McMillan, Nupura Bhise, Andre Levchenko, Gregg L. Semenza

Research output: Contribution to journalArticle

Abstract

Ischemia induces the production of angiogenic cytokines and the homing of bone-marrow-derived angiogenic cells (BMDACs), but these adaptive responses become impaired with aging because of reduced expression of hypoxia-inducible factor (HIF)-1α. In this study, we analyzed the effect of augmenting HIF-1α levels in ischemic limb by intramuscular injection of AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, and intravenous administration of BMDACs that were cultured in the presence of the prolyl-4-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to induce HIF-1 expression. The combined therapy increased perfusion, motor function, and limb salvage in old mice subjected to femoral artery ligation. Homing of BMDACs to the ischemic limb was dramatically enhanced by intramuscular AdCA5 administration. DMOG treatment of BMDACs increased cell surface expression of β2 integrins, which mediated increased adherence of BMDACs to endothelial cells. The effect of DMOG was abolished by coadministration of the HIF-1 inhibitor digoxin or by preincubation with a β2 integrin-blocking antibody. Transduction of BMDACs with lentivirus LvCA5 induced effects similar to DMOG treatment. Thus, HIF-1α gene therapy increases homing of BMDACs to ischemic muscle, whereas HIF-1 induction in BMDACs enhances their adhesion to vascular endothelium, leading to synergistic effects of combined therapy on tissue perfusion.

Original languageEnglish (US)
Pages (from-to)20399-20404
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number48
DOIs
StatePublished - Dec 1 2009

Keywords

  • Angiogenesis
  • Cell therapy
  • Hypoxia
  • Prolyl hydroxylation

ASJC Scopus subject areas

  • General

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