Nerve Growth Factor Promotes Angiogenesis and Arteriogenesis in Ischemic Hindlimbs

Abstract

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 NGFinduced 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-NOmediated 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.

The Neuropeptide Secretoneurin Acts as a Direct Angiogenic Cytokine In Vitro and In Vivo

“…This interaction seems to be the consequence of the requirement for oxygen supply of nervous tissues and the lack of regenerative capacity of these cells after hypoxic damage; it was demonstrated that nerve growth factor, beside its effect on neurons, has angiogenic activity in a chorioallantoic membrane assay and in the hindlimb ischemia model. 20,21 Furthermore, other members of the family of neuropeptides, such as substance-P and neuropeptide-Y, have been reported to induce angiogenesis. 22,23 VEGF, on the other hand, a classical endothelial mitogen, has been shown to exert trophic functions on neuronal cells and to improve nerve function in ischemic and diabetic neuropathy by acting directly on Schwann cells, in addition to angiogenic effects on nerve vasculature.…”

Regulation of myogenic stem cell behaviour by vessel cells: The "ménage à trois" of satellite cells, periendothelial cells and endothelial cells

“…34 Finally, Nerve Growth Factor (NGF) has been shown to enhance angiogenesis and arteriogenesis after ischemia in vivo while it protects ECs and myofibres from apoptosis in vitro. 35 All these studies suggest the existence of regulatory mechanisms through which blood vessel recruitment can be coupled dimensional model. 46 All these data provide evidence that active satellite cells/myogenic cells possess a potent proangiogenic effect that may participate in revascularization of damaged muscle.…”

Endocannabinoids inhibit release of nerve growth factor by inflammation-activated mast cells

“…Post-traumatic or -ischemic inflammation may be associated with progressive cell loss and proliferation of non-specific cell elements, such as fibroblasts [36], as well as with neoangiogenesis [37]. The latter would either take place in response to vasoactive stimuli which occur in the inflammatory process, or by hypoxia and is nevertheless fuelled by overproduction of proangiogenic molecules, such as NGF [37].…”

“…The latter would either take place in response to vasoactive stimuli which occur in the inflammatory process, or by hypoxia and is nevertheless fuelled by overproduction of proangiogenic molecules, such as NGF [37].…”