Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice

Lee, Edward W.; Grant, Derrick S.; Movafagh, Sharareh; Żukowska, Zofia

doi:10.1016/s0196-9781(02)00281-4

Cited by 84 publications

(58 citation statements)

References 38 publications

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“…Also our previous findings of the ability of Y1 receptor antagonist to reduce already markedly impaired aortic sprouting in Y2 -/-mice (38) suggest that Y1 receptors play a compensatory role in the absence of the major angiogenic Y2 receptor.…”

Section: Figurementioning

confidence: 68%

Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles

Lee¹,

Michalkiewicz²,

Kitlińska³

et al. 2003

J. Clin. Invest.

Self Cite

122

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Previously we showed that neuropeptide Y (NPY), a sympathetic vasoconstrictor neurotransmitter, stimulates endothelial cell migration, proliferation, and differentiation in vitro. Here, we report on NPY’s actions, receptors, and mediators in ischemic angiogenesis. In rats, hindlimb ischemia stimulates sympathetic NPY release (attenuated by lumbar sympathectomy) and upregulates NPY-Y2 (Y2) receptor and a peptidase forming Y2/Y5-selective agonist. Exogenous NPY at physiological concentrations also induces Y5 receptor, stimulates neovascularization, and restores ischemic muscle blood flow and performance. NPY-mediated ischemic angiogenesis is not prevented by a selective Y1 receptor antagonist but is reduced in Y2–/– mice. Nonischemic muscle vascularity is also lower in Y2–/– mice, whereas it is increased in NPY-overexpressing rats compared with their WT controls. Ex vivo, NPY-induced aortic sprouting is markedly reduced in Y2–/– aortas and spontaneous sprouting is severely impaired in NPY–/– mice. NPY-mediated aortic sprouting, but not cell migration/proliferation, is blocked by an antifetal liver kinase 1 antibody and abolished in mice null for eNOS. Thus, NPY mediates neurogenic ischemic angiogenesis at physiological concentrations by activating Y2/Y5 receptors and eNOS, in part due to release of VEGF. NPY’s effectiveness in revascularization and restoring function of ischemic tissue suggests its therapeutic potential in ischemic conditions

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Section: Figurementioning

confidence: 68%

Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles

Lee¹,

Michalkiewicz²,

Kitlińska³

et al. 2003

J. Clin. Invest.

Self Cite

122

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show abstract

“…The peptide stimulates proliferation of neuronal precursors via Y1R (20), vascular smooth muscle cells via both Y1 and Y5 (21), whereas its mitogenic effect in endothelial cells and angiogenic actions are Y2 and Y5R mediated (22,24,27,28). In many cell types, both Y1-and Y2R-dependent proliferative effects of NPY are associated with activation of p44/42 MAPK (20,31).…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutic strategies targeting both angiogenesis and tumor cell growth by using low doses of cytostatics combined with angiostatic agents have been already proven to be effective in neuroblastomas (39). Targeting NPYmediated angiogenesis in childhood malignancies is further supported by the fact that the peptide does not seem to be involved in developmental angiogenesis because both Y2 and NPY knockout mice have no defects in organogenesis, despite severely impaired NPY-induced angiogenesis in ischemia and retinopathy (22,27,28).…”

Section: Discussionmentioning

confidence: 99%

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Differential Effects of Neuropeptide Y on the Growth and Vascularization of Neural Crest–Derived Tumors

Kitlińska¹,

Abe²,

Kuo³

et al. 2005

Cancer Research

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127

212

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Neuropeptide Y (NPY) is a sympathetic neurotransmitter recently found to be potently angiogenic and growth promoting for endothelial, vascular smooth muscle and neuronal cells. NPY and its cognate receptors, Y1, Y2 and Y5, are expressed in neural crest-derived tumors; however, their role in regulation of growth is unknown. The effect of NPY on the growth and vascularization of neuroendocrine tumors was tested using three types of cells: neuroblastoma, pheochromocytoma, and Ewing's sarcoma family of tumors (ESFT). The tumors varied in expression of NPY receptors, which was linked to differential functions of the peptide. NPY stimulated proliferation of neuroblastoma cells via Y2/Y5Rs and inhibited ESFT cell growth by Y1/Y5-mediated apoptosis. In both tumor types, NPY receptor antagonists altered basal growth levels, indicating a regulatory role of autocrine NPY. In addition, the peptide released from the tumor cells stimulated endothelial cell proliferation, which suggests its paracrine angiogenic effects. In nude mice xenografts, exogenous NPY stimulated growth of neuroblastoma tumors, whereas it increased apoptosis and reduced growth of ESFT. However, in both tumors, NPY treatment led to an increase in tumor vascularization. Taken together, this is the first report of NPY being a growth-regulatory factor for neuroendocrine tumors, acting both by autocrine activation of tumor cell proliferation or apoptosis and by angiogenesis. NPY and its receptors may become targets for novel approaches in the treatment of these diseases, directed against both tumor cell proliferation and angiogenesis. (Cancer Res 2005; 65(5): 1719-28)

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“…Altogether, these observations suggest that the NPY/Y2R autocrine loop is essential to maintain neuroblastoma in their proliferative state Aside from being a mitogenic factor for neuroblastomas, NPY is also known to stimulate angiogenesis via its direct proliferative and pro-migratory effect on endothelial cells (Lee et al, 2003b;Movafagh et al, 2006;Zukowska-Grojec et al, 1998). Strikingly, the angiogenic effect of NPY is also mediated by Y2Rs, which are expressed in activated endothelial cells (Lee et al, 2003a;Movafagh et al, 2006). Therefore, in vivo, NPY stimulates neuroblastoma tumor growth via two independent mechanisms -a direct proliferative effect on nuroblastoma cells and indirectly, via increasing tumor vascularization (Fig.…”

Section: Neuropeptide Y -Neuronal Marker or Growth Factor?mentioning

confidence: 90%

Sympathetic Neurotransmitters in Neuroblastoma – Between Physiology and Pathology

Czarnecka¹,

Tilan²,

Kitlińska³

2012

Neuroblastoma - Present and Future

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Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice

Cited by 84 publications

References 38 publications

Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles

Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles

Differential Effects of Neuropeptide Y on the Growth and Vascularization of Neural Crest–Derived Tumors

Sympathetic Neurotransmitters in Neuroblastoma – Between Physiology and Pathology

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