Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice

M. B. Salis, G. Graiani, E. Desortes, Ruth B Caldwell, P. Madeddu, C. Emanueli

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Aims/hypothesis. Type 1 diabetes increases the risk of peripheral ischaemia and impairs recovery once ischaemia occurs, probably because the healing process is hampered by diabetes-induced endothelial dysfunction. In normoglycaemic mice subjected to limb ischaemia, blockade of nerve growth factor (NGF) compromises reparative angiogenesis. In the present study, we evaluated if expressional alterations of endogenous NGF system components are associated with diabetes-related impairment in neovascularisation. In addition, we tested whether the correction of NGF liabilities benefits post-ischaemic healing of Type 1 diabetic animals. Methods. Unilateral hindlimb ischaemia was produced in streptozotocin-induced Type 1 diabetic mice. Purified murine NGF (20 μg daily for 14 days) or PBS were injected into ischaemic adductors. Non-diabetic mice given PBS served as controls. Hindlimb blood flow was analysed sequentially for up to 14 days. At necroscopy, adductors were removed for quantification of microvessel density, endothelial cell apoptosis and NGF receptor expression. NGF content was determined by ELISA three days after ischaemia. In vitro, we tested whether NGF protects endothelial cells from apoptosis induced by high glucose and whether vascular endothelial growth factor-A (VEGF-A) is involved in this beneficial effect. Results. Muscles removed from Type 1 diabetic mice showed reduced NGF content and up-regulation of the NGF p75 receptor. NGF supplementation promoted capillarisation and arteriogenesis, reduced apoptosis, and accelerated blood flow recovery. NGF stimulated VEGF-A production by human endothelial cells incubated in high-glucose medium and conferred resistance against high-glucose-induced apoptosis via a VEGF-A-mediated mechanism. Conclusions/interpretation. NGF protects endothelial cells from apoptosis induced by Type 1 diabetes and facilitates reparative neovascularisation. The findings may open up new therapeutic options for the treatment of diabetic complications.

Original languageEnglish (US)
Pages (from-to)1055-1063
Number of pages9
JournalDiabetologia
Volume47
Issue number6
DOIs
StatePublished - Jan 1 2004

Fingerprint

Nerve Growth Factor
Hindlimb
Type 1 Diabetes Mellitus
Ischemia
Apoptosis
Endothelial Cells
Vascular Endothelial Growth Factor A
Nerve Growth Factor Receptor
Glucose
Diabetes Complications
Streptozocin
Microvessels
Up-Regulation
Extremities
Enzyme-Linked Immunosorbent Assay
Muscles

Keywords

  • Apoptosis
  • Endothelial cell
  • Ischaemia
  • Neovascularisation
  • NGF
  • Skeletal muscle
  • Type 1 diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice. / Salis, M. B.; Graiani, G.; Desortes, E.; Caldwell, Ruth B; Madeddu, P.; Emanueli, C.

In: Diabetologia, Vol. 47, No. 6, 01.01.2004, p. 1055-1063.

Research output: Contribution to journalArticle

Salis, M. B. ; Graiani, G. ; Desortes, E. ; Caldwell, Ruth B ; Madeddu, P. ; Emanueli, C. / Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice. In: Diabetologia. 2004 ; Vol. 47, No. 6. pp. 1055-1063.
@article{9d92c566807b407990b30dcaeb23e9f0,
title = "Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice",
abstract = "Aims/hypothesis. Type 1 diabetes increases the risk of peripheral ischaemia and impairs recovery once ischaemia occurs, probably because the healing process is hampered by diabetes-induced endothelial dysfunction. In normoglycaemic mice subjected to limb ischaemia, blockade of nerve growth factor (NGF) compromises reparative angiogenesis. In the present study, we evaluated if expressional alterations of endogenous NGF system components are associated with diabetes-related impairment in neovascularisation. In addition, we tested whether the correction of NGF liabilities benefits post-ischaemic healing of Type 1 diabetic animals. Methods. Unilateral hindlimb ischaemia was produced in streptozotocin-induced Type 1 diabetic mice. Purified murine NGF (20 μg daily for 14 days) or PBS were injected into ischaemic adductors. Non-diabetic mice given PBS served as controls. Hindlimb blood flow was analysed sequentially for up to 14 days. At necroscopy, adductors were removed for quantification of microvessel density, endothelial cell apoptosis and NGF receptor expression. NGF content was determined by ELISA three days after ischaemia. In vitro, we tested whether NGF protects endothelial cells from apoptosis induced by high glucose and whether vascular endothelial growth factor-A (VEGF-A) is involved in this beneficial effect. Results. Muscles removed from Type 1 diabetic mice showed reduced NGF content and up-regulation of the NGF p75 receptor. NGF supplementation promoted capillarisation and arteriogenesis, reduced apoptosis, and accelerated blood flow recovery. NGF stimulated VEGF-A production by human endothelial cells incubated in high-glucose medium and conferred resistance against high-glucose-induced apoptosis via a VEGF-A-mediated mechanism. Conclusions/interpretation. NGF protects endothelial cells from apoptosis induced by Type 1 diabetes and facilitates reparative neovascularisation. The findings may open up new therapeutic options for the treatment of diabetic complications.",
keywords = "Apoptosis, Endothelial cell, Ischaemia, Neovascularisation, NGF, Skeletal muscle, Type 1 diabetes mellitus",
author = "Salis, {M. B.} and G. Graiani and E. Desortes and Caldwell, {Ruth B} and P. Madeddu and C. Emanueli",
year = "2004",
month = "1",
day = "1",
doi = "10.1007/s00125-004-1424-5",
language = "English (US)",
volume = "47",
pages = "1055--1063",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice

AU - Salis, M. B.

AU - Graiani, G.

AU - Desortes, E.

AU - Caldwell, Ruth B

AU - Madeddu, P.

AU - Emanueli, C.

PY - 2004/1/1

Y1 - 2004/1/1

N2 - Aims/hypothesis. Type 1 diabetes increases the risk of peripheral ischaemia and impairs recovery once ischaemia occurs, probably because the healing process is hampered by diabetes-induced endothelial dysfunction. In normoglycaemic mice subjected to limb ischaemia, blockade of nerve growth factor (NGF) compromises reparative angiogenesis. In the present study, we evaluated if expressional alterations of endogenous NGF system components are associated with diabetes-related impairment in neovascularisation. In addition, we tested whether the correction of NGF liabilities benefits post-ischaemic healing of Type 1 diabetic animals. Methods. Unilateral hindlimb ischaemia was produced in streptozotocin-induced Type 1 diabetic mice. Purified murine NGF (20 μg daily for 14 days) or PBS were injected into ischaemic adductors. Non-diabetic mice given PBS served as controls. Hindlimb blood flow was analysed sequentially for up to 14 days. At necroscopy, adductors were removed for quantification of microvessel density, endothelial cell apoptosis and NGF receptor expression. NGF content was determined by ELISA three days after ischaemia. In vitro, we tested whether NGF protects endothelial cells from apoptosis induced by high glucose and whether vascular endothelial growth factor-A (VEGF-A) is involved in this beneficial effect. Results. Muscles removed from Type 1 diabetic mice showed reduced NGF content and up-regulation of the NGF p75 receptor. NGF supplementation promoted capillarisation and arteriogenesis, reduced apoptosis, and accelerated blood flow recovery. NGF stimulated VEGF-A production by human endothelial cells incubated in high-glucose medium and conferred resistance against high-glucose-induced apoptosis via a VEGF-A-mediated mechanism. Conclusions/interpretation. NGF protects endothelial cells from apoptosis induced by Type 1 diabetes and facilitates reparative neovascularisation. The findings may open up new therapeutic options for the treatment of diabetic complications.

AB - Aims/hypothesis. Type 1 diabetes increases the risk of peripheral ischaemia and impairs recovery once ischaemia occurs, probably because the healing process is hampered by diabetes-induced endothelial dysfunction. In normoglycaemic mice subjected to limb ischaemia, blockade of nerve growth factor (NGF) compromises reparative angiogenesis. In the present study, we evaluated if expressional alterations of endogenous NGF system components are associated with diabetes-related impairment in neovascularisation. In addition, we tested whether the correction of NGF liabilities benefits post-ischaemic healing of Type 1 diabetic animals. Methods. Unilateral hindlimb ischaemia was produced in streptozotocin-induced Type 1 diabetic mice. Purified murine NGF (20 μg daily for 14 days) or PBS were injected into ischaemic adductors. Non-diabetic mice given PBS served as controls. Hindlimb blood flow was analysed sequentially for up to 14 days. At necroscopy, adductors were removed for quantification of microvessel density, endothelial cell apoptosis and NGF receptor expression. NGF content was determined by ELISA three days after ischaemia. In vitro, we tested whether NGF protects endothelial cells from apoptosis induced by high glucose and whether vascular endothelial growth factor-A (VEGF-A) is involved in this beneficial effect. Results. Muscles removed from Type 1 diabetic mice showed reduced NGF content and up-regulation of the NGF p75 receptor. NGF supplementation promoted capillarisation and arteriogenesis, reduced apoptosis, and accelerated blood flow recovery. NGF stimulated VEGF-A production by human endothelial cells incubated in high-glucose medium and conferred resistance against high-glucose-induced apoptosis via a VEGF-A-mediated mechanism. Conclusions/interpretation. NGF protects endothelial cells from apoptosis induced by Type 1 diabetes and facilitates reparative neovascularisation. The findings may open up new therapeutic options for the treatment of diabetic complications.

KW - Apoptosis

KW - Endothelial cell

KW - Ischaemia

KW - Neovascularisation

KW - NGF

KW - Skeletal muscle

KW - Type 1 diabetes mellitus

UR - http://www.scopus.com/inward/record.url?scp=3142714528&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3142714528&partnerID=8YFLogxK

U2 - 10.1007/s00125-004-1424-5

DO - 10.1007/s00125-004-1424-5

M3 - Article

VL - 47

SP - 1055

EP - 1063

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 6

ER -