NGF Activates Similar Intracellular Signaling Pathways in Vascular Smooth Muscle Cells as PDGF-BB But Elicits Different Biological Responses

Abstract

Abstract-The signaling pathways that regulate smooth muscle cell migration and proliferation are incompletely understood. Smooth muscle cells express at least 3 families of receptor tyrosine kinases that mediate cell migration: platelet-derived growth factor (PDGF) receptors, the trk family of neurotrophin receptors, and insulin-like growth factor 1 receptor. The neurotrophin, nerve growth factor (NGF), and insulin-like growth factor 1 induce the migration but not the proliferation of smooth muscle cells, whereas PDGF-BB stimulates both responses. To determine whether distinct signaling pathways downstream of receptor tyrosine kinases specifically mediate smooth muscle cell migration or proliferation, the ligand-induced activation of different signaling pathways in smooth muscle cells was examined. NGF induces prolonged activation of the Shc/MAP kinase pathway and phospholipase C␥ compared with PDGF-BB. The activation of phosphatidylinositol-3 kinase, however, was 10-fold greater in response to PDGF-BB compared with NGF. Insulin-like growth factor 1 activates only phosphatidylinositol-3 kinase. Pharmacological inhibitors of phosphatidylinositol-3 kinase, Wortmannin and LY294002, inhibit PDGF-BB and NGF-induced migration, whereas an inhibitor of MAP kinase kinase, PD98059, has no effect. Our results suggest that (1) different receptor tyrosine kinases use similar patterns of activation of signaling pathways to mediate distinct biological outcomes of cell migration and proliferation, (2) NGF activates signaling proteins in smooth muscle cells similar to those activated during NGF-induced neuronal differentiation, and (3) the combinatorial effects of different signaling pathways are important for the regulation of smooth muscle cell migration and proliferation. Further studies using mutant trk receptors will help to define the signal transduction pathways mediating NGF-induced smooth muscle cell migration. A rterial injury, as occurs in atherosclerosis and balloon angioplasty, results in the migration of medial smooth muscle cells into the intima. This is followed by a period of proliferation, resulting in the formation of a neointimal lesion. 1 Ligand-induced activation of several receptor tyrosine kinases has been implicated in the migration and proliferation of smooth muscle cells in the neointima after vascular injury. Growth factors, such as platelet-derived growth factor (PDGF) and insulin-like growth factor 1 (IGF-1), and their receptors show increased expression in the arterial wall after balloon angioplasty. 2-6 However, the biological responses elicited by these 2 agonists are different in that PDGF mediates both smooth muscle cell proliferation and migration whereas IGF-1 specifically induces only smooth muscle cell migration. 7 Ligand binding to the PDGF and IGF-1 receptor tyrosine kinases induces autophosphorylation of tyrosines within the cytoplasmic domain of the receptors, resulting in the recruitment and activation of specific signaling molecules that may mediate the migration and proliferation of ...

Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors

“…BDNF induces vessel sprouting and supports a long-lasting augmentation in vessel integrity and stability. Although best characterized by their survival, differentiative, and synaptic effects on neurons, the neurotrophins are emerging as ligands capable of regulating several components of the vascular bed, exhibiting direct effects upon both endothelial (26) and vascular smooth muscle cells (32,35).…”

Nerve Growth Factor Suppresses Prostate Tumor Growth

“…Human and rat vascular smooth muscle cells have been shown to express NGF receptor, Trk A (13). In addition, the smooth muscle cell migration induced by NGF is comparable to the migratory effects obtained in vitro with platelet-derived growth factor-BB (PDGF-BB), indicating that the neurotrophin NGF is a potent chemoattractant for cultured vascular smooth muscle cells (13). Furthermore, peripheral nerves have been reported to provide a template that determines the organotypic pattern of blood vessel branching and arterial differentiation in the skin (14).…”

Nerve Growth Factor Promotes Angiogenesis and Arteriogenesis in Ischemic Hindlimbs

“…NGF was extracted from mouse submaxillary glands, following the method of Bocchini et al 20 Third, the mechanisms implicated in the proangiogenic action of NGF were investigated. Mice were given the following treatments for 7 days: (1) daily injection of NGF (20 g in 20 L PBS) or PBS into normoperfused adductors (nϭ5 each group); (2) intramuscular NGF plus VEGF neutralizing antibody (2.5 g IP twice a week, R&D Systems, Minneapolis, Minn) or control IgG (nϭ5 each group); (3) intramuscular NGF plus the NO synthase inhibitor L-nitroarginine methyl ester (L-NAME) or the inactive isomer (D-NAME) (both at 1.4 nmol/kg per day in drinking water, SigmaAldrich, nϭ5 each group); and (4) intramuscular NGF plus adenovirus carrying dominant-negative Akt (Ad.Akt 308/547 , prepared at the Kimmel Cancer Center, Philadelphia, Pa) or reporter gene Luciferase (Ad.Luc) (each at 5ϫ10 6 pfu in a single intramuscular injection, nϭ5 each group).…”

“…Nerve growth factor (NGF), the first isolated member of a growing family of neurotrophins, is indeed regarded for its potential involvement in physiological and pathologic angiogenesis. Binding sites for NGF have been detected on cultured ECs 5 and vascular smooth muscle cells (VSMCs), 6 and activation of NGF receptors influences vascular cell biology and fate in vitro. 6 -9 Furthermore, NGF is present in circulating monocytes, 10 regarded as important players in muscularization of nascent capillaries.…”