Atherosclerosis and angiogenesis: what do nerves have to do with it?
Journal Title: Pharmacological Reports - Year 2005, Vol 57, Issue
Abstract
Neuropeptide Y (NPY) is a sympathetic neurotransmitter and a stress mediator with pleiotropic activities mediated by multiple receptors, Y1-Y5. Originally known as an appetite stimulant and a vasoconstrictor, NPY has recently emerged as a growth factor for a variety of cells from vascular smooth muscle to neural precursors - implicating the peptide in atherosclerosis and tissue remodeling. NPY is also potently angiogenic, and was hailed as a potential candidate for a nerve-driven ischemic revascularization. To determine if the latter, beneficial activity of the peptide can be separated from its deleterious pro-atherosclerotic action - receptor specificity and mechanisms of this "Janus phenomenon" were studied. Expression of Y2 receptors on the endothelium, and Y1 receptors on vascular smooth muscle, were required for angiogenic and pro-atherosclerotic activities, respectively. Amplification of both activities was provided by co-expression of Y5 receptors. In rodent models, limb ischemia up-regulated the NPY-Y2 system, which contributed to post-ischemic revascularization; exogenous NPY further augmented it and nearly normalized blood flow and function of ischemic tissues. NPY-induced angiogenesis was also dependent on nitric oxide and endothelial dipeptidyl peptidase IV (DPPIV, which converts NPY to Y2/Y5-selective agonist), but resistant to Y1 receptor blockade. Conversely, vascular angioplasty up-regulated the NPY-Y1 system and promoted atherosclerosis and hyperplastic remodeling, and these activities were blocked by Y1 receptor antagonist and augmented by DPPIV inhibitors. Thus, drugs targeting specific NPY receptors may become new therapeutics against atherosclerosis/restenosis (Y1-selective antagonists) or for ischemic revascularization (Y2-selective agonists). Such drugs may be particularly beneficial for patients with elevated circulating NPY levels e.g. by chronic stress.
Authors and Affiliations
Zofia Zukowska
Buspirone improves the anti-cataleptic effect of levodopa in 6-hydroxydopamine-lesioned rats.
In Parkinson's disease (PD), prolonged exposure to L-3,4-dihydroxyphenylalanine (L-DOPA) results in motor fluctuations, such as the on-off phenomenon, and L-DOPA-induced dyskinesia. Previously, we found that activation o...
Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats: a possible role of P-glycoprotein and CYP3A4 inhibition by baicalein.
The reduced bioavailability of nimodipine after oral administration might not only be due to the metabolizing enzyme cytochrome P450 3A4(CYP3A4) but also to the P-glycoprotein efflux transporter in the small intestine. T...
Verapamil-induced autophagy-like process in colon adenocarcinoma COLO 205 cells; the ultrastructural studies.
Background: Verapamil (Ver) is a well known, worldwide used drug to correct cardiac arrhythmias. The main Ver target is the L-type calcium channel. Modulation of calcium homeostasis vaulted Ver into use in medical applic...
Effects of androsterone on convulsions in various seizure models in mice.
It is believed that a deficiency of androgens, including free testosterone, may promote the development of convulsions. The present study revealed differences in the action of androsterone (AND), a major excreted metabol...
The activity of cytochrome P450 CYP2B in rat liver during neuroleptic treatment.
The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2B measured as a rate of 16beta-hydroxylation of testosterone. The reaction was studied in cont...