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

doi:10.1161/ATVBAHA.109.205468

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

Bristol Medical School (THS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

59 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 contribution	Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia
Original language	English
Pages (from-to)	1143 - 1150
Number of pages	8
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	30
Issue number	6
DOIs	https://doi.org/10.1161/ATVBAHA.109.205468
Publication status	Published - 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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10.1161/ATVBAHA.109.205468

http://atvb.ahajournals.org/cgi/reprint/30/6/1143

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Cristofaro, B., Stone, O. A., Caporali, A., Dawbarn, D., Ieronimakis, N., Reyes, M., Madeddu, P., Bates, D. O., & Emanueli, C. (2010). Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(6), 1143 - 1150. https://doi.org/10.1161/ATVBAHA.109.205468

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title = "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.",

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",

author = "Brunella Cristofaro and Stone, {Oliver A} and Andrea Caporali and David Dawbarn and Nicholas Ieronimakis and Morayma Reyes and Paolo Madeddu and Bates, {David O} and Costanza Emanueli",

note = "Publisher: Arterioscler Thromb Vasc Biol",

year = "2010",

month = jun,

doi = "10.1161/ATVBAHA.109.205468",

language = "English",

volume = "30",

pages = "1143 -- 1150",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1524-4636",

publisher = "Lippincott Williams and Wilkins",

number = "6",

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TY - JOUR

T1 - Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia

AU - Cristofaro, Brunella

AU - Stone, Oliver A

AU - Caporali, Andrea

AU - Dawbarn, David

AU - Ieronimakis, Nicholas

AU - Reyes, Morayma

AU - Madeddu, Paolo

AU - Bates, David O

AU - Emanueli, Costanza

N1 - Publisher: Arterioscler Thromb Vasc Biol

PY - 2010/6

Y1 - 2010/6

N2 - 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.

AB - 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.

KW - Angiogenic Proteins

KW - Animals

KW - Cell Movement

KW - Cell Proliferation

KW - Cell Survival

KW - Cells, Cultured

KW - Disease Models, Animal

KW - Endothelial Cells

KW - Genetic Therapy

KW - Hindlimb

KW - Humans

KW - Ischemia

KW - Male

KW - Mesentery

KW - Mice

KW - Muscle, Skeletal

KW - Neovascularization, Physiologic

KW - Nerve Growth Factors

KW - Neurotrophin 3

KW - Nitric Oxide Synthase Type III

KW - Phosphatidylinositol 3-Kinases

KW - Phosphorylation

KW - Proto-Oncogene Proteins c-akt

KW - RNA, Messenger

KW - Rats

KW - Rats, Wistar

KW - Receptor, trkC

KW - Recombinant Proteins

KW - Signal Transduction

KW - Time Factors

KW - Transfection

U2 - 10.1161/ATVBAHA.109.205468

DO - 10.1161/ATVBAHA.109.205468

M3 - Article (Academic Journal)

C2 - 20360537

SN - 1524-4636

VL - 30

SP - 1143

EP - 1150

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 6

ER -

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

Abstract

Bibliographical note

Keywords

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