Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles.
Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75(NTR)), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75(NTR) expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75(NTR) gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75(NTR) depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin], BIRC5 (survivin), PTTG1 (securin) and VEZF1. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75(NTR). Collectively, our data newly demonstrate the antiangiogenic action of p75(NTR) and open new avenues for the therapeutic use of p75(NTR) inhibition to combat diabetes-induced microvascular liabilities.
Experimental Cardiovascular Medicine Division, Bristol Heart Institute, University of Bristol, UK.
Andrea
A
Caporali
Elisabetta
E
Pani
Anton J G
AJ
Horrevoets
Nicolle
N
Kraenkel
Atsuhiko
A
Oikawa
Graciela B
GB
Sala-Newby
Marco
M
Meloni
Brunella
B
Cristofaro
Gallia
G
Graiani
Aurelie S
AS
Leroyer
Chantal M
CM
Boulanger
Gaia
G
Spinetti
Sung Ok
SO
Yoon
Paolo
P
Madeddu
Costanza
C
Emanueli
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000378:metabolism*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology*; D006801:Humans; D007511:Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013311:Streptozocin; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020800:Receptor, Nerve Growth Factor; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D013311:Streptozocin; D019001:Nitric Oxide Synthase; D051057:Proto-Oncogene Proteins c-akt