Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs.
BACKGROUND
The neurotrophin nerve growth factor (NGF) regulates neuron survival and differentiation. Implication in neovascularization is supported by statement of NGF and its high-affinity receptor at vascular level and by NGF property of stimulating vascular endothelial cell proliferation. The present study investigated the involvement of endogenous NGF in spontaneous reparative response to ischemia. Mechanisms and therapeutic potential of NGF-induced neovascularization were examined.


RESULTS
Unilateral limb ischemia was produced in CD1 mice by femoral artery resection. By ELISA and immunohistochemistry, we documented that statement of NGF and its high-affinity receptor is upregulated in ischemic muscles. The functional relevance of this phenomenon was assessed by means of NGF-neutralizing antibody. Chronic NGF blockade abrogated the spontaneous capillarization response to ischemia and augmented myocyte apoptosis. Then we tested whether NGF administration may exert curative effects. Repeated NGF injection into ischemic adductors increased capillary and arteriole density, reduced endothelial cell and myofiber apoptosis, and accelerated perfusion recovery, without altering systemic hemodynamics. In normoperfused muscles, NFG-induced capillarization was blocked by vascular endothelial growth factor-neutralizing antibodies, dominant-negative Akt, or NO synthase inhibition.


CONCLUSIONS
These results indicate that NGF plays a functional role in reparative neovascularization. Furthermore, supplementation of the growth factor promotes angiogenesis through a vascular endothelial growth factor-Akt-NO-mediated mechanism. In the setting of ischemia, potentiation of NGF pathway stimulates angiogenesis and arteriogenesis, thereby accelerating hemodynamic recovery. NGF might be envisaged as a utilitarian target for the treatment of ischemic vascular disease.
Emanueli
Costanza
C
Cardiovascular Medicine and Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Sassari, Italy. emanueli@yahoo.com
Salis
Maria B
MB
Pinna
Alessandra
A
Graiani
Gallia
G
Manni
Luigi
L
Madeddu
Paolo
P
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000254:growth & development*; D001160:Arterioles / Q000187:drug effects / Q000254:growth & development; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000097:blood* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015854:Up-Regulation
D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor