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 (Academic Journal)peer-review

44 Citations (Scopus)

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.

CONCLUSIONS: 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.

Translated title of the contributionNeurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia
Original languageEnglish
Pages (from-to)1143 - 1150
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume30
Issue number6
DOIs
Publication statusPublished - Jun 2010

Bibliographical note

Publisher: Arterioscler Thromb Vasc Biol

Keywords

  • Angiogenic Proteins
  • Animals
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells
  • Genetic Therapy
  • Hindlimb
  • Humans
  • Ischemia
  • Male
  • Mesentery
  • Mice
  • Muscle, Skeletal
  • Neovascularization, Physiologic
  • Nerve Growth Factors
  • Neurotrophin 3
  • Nitric Oxide Synthase Type III
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger
  • Rats
  • Rats, Wistar
  • Receptor, trkC
  • Recombinant Proteins
  • Signal Transduction
  • Time Factors
  • Transfection

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