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

Abstract

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

Analysis of microarray experiments of gene expression profiling

“…[154][155][156][157] It is important to note that the degree of agreement among different platforms improves substantially when the results are examined from the perspective of the biological process or molecular functions involved (functional profiling), rather than from the expression levels of individual genes. The reader is encouraged to examine the issues described in this paragraph when assessing studies comparing different microarray platforms.…”

Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve

“…In many laboratories, endothelial-derived nitric oxide synthase (eNOS) is required for postischemic blood flow recovery, because mice deficient in eNOS show a severe form of critical limb ischemia in mouse hindlimb models (10,11). Moreover, the ability of, statin-based drugs, angiotensin II, neuropeptide Y, and stromal cell-derived factor-1␣ to improve limb angiogenesis are absent in mice deficient in eNOS (12)(13)(14)(15). The molecular mechanisms for how eNOS regulates ischemia-triggered arteriogenesis and angiogenesis is related, in part, to the inability of eNOS (Ϫ͞Ϫ) mice to respond to vascular endothelial growth factor (VEGF).…”

Sympathetic Neurotransmitters in Neuroblastoma – Between Physiology and Pathology

“…This effect is associated with an increase in neuroblastoma cell apoptosis mediated by the Bim pathway, known to be activated upon growth factor withdrawal (Lu et al, 2010). 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).…”

“…They are also known to express their receptors, which creates functional autocrine loops (Baumgartner et al, 1993;Bawa-Khalfe et al, 2007;Kitlinska et al, 2005;Parsley et al, 1999). Sympathetic neurotransmitters, in turn, are known to be potent regulators of many processes involved in the regulation of tumor growth, such as cell proliferation, survival, migration and angiogenesis (Greenwood & Dragunow, 2010;Kitlinska et al, 2005;Laifenfeld et al, 2002;Lee et al, 2003b;Yaniv et al, 2008). Their involvement in the pathogenesis of neurological disorders and stress-induced exacerbation of various diseases has been well characterized (Thaker & Sood, 2008).…”