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

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.

• Authors: Brunella Cristofaro, Oliver A Stone, Andrea Caporali, David Dawbarn, Nicholas Ieronimakis, Morayma Reyes, Paolo Madeddu, David O Bates, Costanza Emanueli
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 6 Pg. 1143-50 (Jun 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20360537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenic Proteins
• Nerve Growth Factors
• Neurotrophin 3
• RNA, Messenger
• Recombinant Proteins
• neurotropin 3, mouse
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Phosphatidylinositol 3-Kinases
• Receptor, trkC
• Proto-Oncogene Proteins c-akt

Topics

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