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 Gil, Paolo Madeddu, David O. Bates, Costanza Emanueli

Research output: Contribution to journalArticle

35 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. 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
Externally publishedYes

Fingerprint

Neurotrophin 3
Angiogenesis Inducing Agents
Ischemia
Extremities
Therapeutics
Phosphatidylinositol 3-Kinase
Nitric Oxide Synthase Type III
Nerve Growth Factors
Basement Membrane
Embryonic Development
Blood Vessels

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia. / Cristofaro, Brunella; Stone, Oliver A.; Caporali, Andrea; Dawbarn, David; Ieronimakis, Nicholas; Reyes Gil, Morayma; Madeddu, Paolo; Bates, David O.; Emanueli, Costanza.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 30, No. 6, 06.2010, p. 1143-1150.

Research output: Contribution to journalArticle

Cristofaro, Brunella ; Stone, Oliver A. ; Caporali, Andrea ; Dawbarn, David ; Ieronimakis, Nicholas ; Reyes Gil, Morayma ; Madeddu, Paolo ; Bates, David O. ; Emanueli, Costanza. / Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2010 ; Vol. 30, No. 6. pp. 1143-1150.
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