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


ABSTRACT: To investigate the novel hypothesis that neurotrophin-3 (NT-3), an established neurotrophic factor that participates in embryonic heart development, promotes blood vessel growth.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.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.

SUBMITTER: Cristofaro B 

PROVIDER: S-EPMC2881585 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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

Cristofaro Brunella B   Stone Oliver A OA   Caporali Andrea A   Dawbarn David D   Ieronimakis Nicholas N   Reyes Morayma M   Madeddu Paolo P   Bates David O DO   Emanueli Costanza C  

Arteriosclerosis, thrombosis, and vascular biology 20100401 6


<h4>Objective</h4>To investigate the novel hypothesis that neurotrophin-3 (NT-3), an established neurotrophic factor that participates in embryonic heart development, promotes blood vessel growth.<h4>Methods and results</h4>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 neovasculari  ...[more]

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