Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing.
Neuropeptide Y (NPY), a 36-aa peptide, is widely distributed in the brain and peripheral tissues. Whereas physiological roles of NPY as a hormoneneurotransmitter have been well studied, little is known about its other peripheral functions. Here, we report that NPY acts as a potent angiogenic factor in vivo using the mouse corneal micropocket and the chick chorioallantoic membrane (CAM) assays. Unlike vascular endothelial growth factor (VEGF), microvessels induced by NPY had distinct vascular tree-like structures showing vasodilation. This angiogenic pattern was similar to that induced by fibroblast growth factor-2, and the angiogenic response was dose-dependent. In the developing chick embryo, NPY stimulated vascular sprouting from preexisting blood vessels. When [Leu(31)Pro(34)]NPY, a NPY-based analogue lacking high affinity for the NPY Y(2) receptor but capable of stimulating both Y(1) and Y(5) receptors, was used in the corneal model, no angiogenic response could be detected. In addition, NPY failed to induce angiogenesis in Y(2) receptor-null mice, suggesting that this NPY receptor subtype was mediating the angiogenic signal. In support of this finding, the Y(2) receptor, but not Y(1), Y(4), or Y(5) receptors, was found to be widely expressed in newly formed blood vessels. Further, a delay of skin wound healing with reduced neovascularization was found in Y(2) receptor-null mice. These data demonstrate that NPY may play an important role in the regulation of angiogenesis and angiogenesis-dependent tissue repair.
Ekstrand
A Jonas
AJ
AstraZeneca Research and Development, Discovery, S-431 83 Mölndal, Sweden.
Cao
Renhai
R
Bjorndahl
Meit
M
Nystrom
Susanne
S
Jonsson-Rylander
Ann-Cathrine
AC
Hassani
Hessameh
H
Hallberg
Bengt
B
Nordlander
Margareta
M
Cao
Yihai
Y
D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000502:physiology; D002642:Chick Embryo; D003315:Cornea / Q000502:physiology; D016039:Corneal Transplantation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009478:Neuropeptide Y / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry; D017476:Receptors, Neuropeptide Y / Q000172:deficiency* / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics*
D009478:Neuropeptide Y; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor