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 contribution | Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia |
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Original language | English |
Pages (from-to) | 1143 - 1150 |
Number of pages | 8 |
Journal | Arteriosclerosis, Thrombosis, and Vascular Biology |
Volume | 30 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 2010 |
Bibliographical note
Publisher: Arterioscler Thromb Vasc BiolKeywords
- 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