Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles.
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.
Lee
Edward W
EW
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC 20007, USA. leeew@georgetown.edu
Michalkiewicz
Mieczyslaw
M
Kitlinska
Joanna
J
Kalezic
Ivana
I
Switalska
Hanna
H
Yoo
Peter
P
Sangkharat
Amarin
A
Ji
Hong
H
Li
Lijun
L
Michalkiewicz
Teresa
T
Ljubisavljevic
Milos
M
Johansson
Hakan
H
Grant
Derrick S
DS
Zukowska
Zofia
Z
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D016228:Endothelial Growth Factors / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008222:Lymphokines / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D009478:Neuropeptide Y / Q000494:pharmacology* / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C095889:neuropeptide Y2 receptor; C100568:neuropeptide Y5 receptor; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D018819:Dipeptidyl Peptidase 4