Vascular endothelial growth factor165 gene transfer augments circulating endothelial progenitor cells in human subjects

Christoph Kalka, Haruchika Masuda, Tomono Takahashi, Rebecca Gordon, Oren Tepper, Edwin Gravereaux, Ann Pieczek, Hideki Iwaguro, Shin Ichiro Hayashi, Jeffrey M. Isner, Takayuki Asahara

Research output: Contribution to journalArticlepeer-review

197 Scopus citations


Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE- cadherin, CD34, α(v)β3, and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.

Original languageEnglish (US)
Pages (from-to)1198-1202
Number of pages5
JournalCirculation research
Issue number12
StatePublished - Jun 23 2000
Externally publishedYes


  • Endothelial progenitor cells
  • Gene therapy
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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