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(Circulation. 2002;106:2257.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Nerve Growth Factor Promotes Angiogenesis and Arteriogenesis in Ischemic Hindlimbs

Costanza Emanueli, PhD; Maria B. Salis, PhD; Alessandra Pinna, BS; Gallia Graiani, PhD; Luigi Manni, PhD; Paolo Madeddu, MD

From the Cardiovascular Medicine and Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, Osilo; Department of Internal Medicine (P.M.), University of Sassari; and Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy.

Correspondence to Costanza Emanueli, PhD, Cardiovascular Medicine and Gene Therapy Section, INBB National Laboratory, viale Sant’Antonio, 07033 Osilo, Sassari, Italy. E-mail emanueli{at}yahoo.com

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.

Methods and 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.

Key Words: angiogenesis • ischemia • muscles

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