Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors

Abstract

Previously we discovered that NPY induces ischemic angiogenesis by activating Y2 and Y5 receptors. The receptors that mediate specific steps of the complex process of angiogenesis are unknown. Here, we studied in vitro NPY receptors subtypes involved in migration, proliferation, and differentiation of human endothelial cells. In cells that expressed Y1, Y2, and Y5 receptors, NPY bimodally stimulated migration and proliferation with a 2-fold increase at 10(-12) M and 10(-8) M (high- and low-affinity peaks, respectively). Preincubation of cells with NPY up-regulated the Y5 receptor and markedly enhanced endothelial cell migration and proliferation. NPY-induced endothelial cell migration was mimicked by agonists and fully blocked by antagonists for any specific NPY receptors (Y1, Y2, or Y5), while proliferation was blocked by any two antagonists (Y1+Y2, Y1+Y5, or Y2+Y5), and capillary tube formation on Matrigel was blocked by all three (Y1+Y2+Y5). Thus, NPY-induced angiogenesis requires participation of Y1, Y2, and Y5 receptor subtypes, with the Y5 receptor acting as an enhancer. We propose that these receptors form heteromeric complexes, and the Y1/Y2/Y5 receptor oligomer may be the uncloned Y3 receptor.

Peptidergic influences on proliferation, migration, and placement of neural progenitors in the adult mouse forebrain

“…The mechanism involved is unclear but may occur through modulation of phosphotyrosine-containing proteins (23) or via a PKC dependent pathway (24), both of which have links to Y2R-mediated effects. Involvement of other Y Rs in precursor proliferation in the adult brain warrants further investigation, considering observations of Y3R-mediated proliferative effects on rat aortic endothelial cells (25), and Y5R-mediated proliferation, migration, and differentiation of cultured human endothelial cells (26).…”

Extracellular molecules in hematopoietic stem cell mobilisation

“…Mice lacking neuropeptide Y have impaired mobilization in response to various mediators, including G-CSF, plerixafor and the chemotherapeutic agent 5 fluoro-uracil. Receptors for neuropeptide Y are expressed by a number of bone marrow micro-environmental cells, including stromal cells, osteoblasts, and endothelial cells [104,105]. Intravenous injection of neuropeptide Y in mice rapidly (less than 1 h) mobilized HSC and was associated with a small but significant reduction in CXCL12 concentrations in the bone marrow and reciprocal increase in the peripheral blood.…”

Neuropeptide Y Y1 receptor antagonism increases bone mass in mice

“…NPY is a neurotransmitter widely expressed through the peripheral and central nervous system, and its actions are mediated through the activation of G-protein coupled receptors, namely Y1, Y2, Y4, Y5 and y6 receptors [9]. Through specific activation of the Y1 receptor, NPY has been shown to play a critical role in a number of centrally-regulated physiological functions, such as energy homeostasis [10], anxiety [11], cardiovascular function [12] and neurogenesis [13]. More recently, NPY has been shown to regulate bone homeostasis via actions in peripheral tissues.…”