Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle

Costanza Emanueli, Antonella Zacheo, Alessandra Minasi, Julie Chao, Lee Chao, Maria Bonaria Salis, Tiziana Stacca, Stefania Straino, Maurizio C. Capogrossi, Paolo Madeddu

Research output: Contribution to journalArticlepeer-review


We investigated whether local delivery of the tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the human tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant human tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascularization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B 1 or B 2 receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) human tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the tissue kallikrein-kinin system in vascular biology.

Original languageEnglish
Pages (from-to)2379-2385
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number11
Publication statusPublished - 2000


  • Angiogenesis
  • Gene delivery
  • Kallikrein
  • Kinins
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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