Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia

Brunella Cristofaro, Oliver A. Stone, Andrea Caporali, David Dawbarn, Nicholas Ieronimakis, Morayma Reyes, Paolo Madeddu, David O. Bates, Costanza Emanueli

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Objective: To investigate the novel hypothesis that neurotrophin-3 (NT-3), an established neurotrophic factor that participates in embryonic heart development, promotes blood vessel growth. Methods and results: We evaluated the proangiogenic capacity of recombinant NT-3 in vitro and of NT-3 gene transfer in vivo (rat mesenteric angiogenesis assay and mouse normoperfused adductor muscle). Then, we studied whether either transgenic or endogenous NT-3 mediates postischemic neovascularization in a mouse model of limb ischemia. In vitro, NT-3 stimulated endothelial cell survival, proliferation, migration, and network formation on the basement membrane matrix Matrigel. In the mesenteric assay, NT-3 increased the number and size of functional vessels, including vessels covered with mural cells. Consistently, NT-3 overexpression increased muscular capillary and arteriolar densities in either the absence or the presence of ischemia and improved postischemic blood flow recovery in mouse hind limbs. NT-3-induced microvascular responses were accompanied by tropomyosin receptor kinase C (an NT-3 high-affinity receptor) phosphorylation and involved the phosphatidylinositol 3-kinase-Akt kinase-endothelial nitric oxide synthase pathway. Finally, endogenous NT-3 was shown to be essential in native postischemic neovascularization, as demonstrated by using a soluble tropomyosin receptor kinase C receptor domain that neutralizes NT-3. Conclusion: Our results provide the first insight into the proangiogenic capacity of NT-3 and propose NT-3 as a novel potential agent for the treatment of ischemic disease.

Original languageEnglish (US)
Pages (from-to)1143-1150
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number6
DOIs
StatePublished - Jun 2010

Keywords

  • Angiogenesis
  • Endothelial cells
  • Limb ischemia
  • Neurotrophin-3
  • PI3K/Akt/eNOS

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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