RESEARCH INTERESTS

We focus on Neuropeptide Y (NPY), a major neurotransmitter in the central and peripheral nervous system, hormone and immunomodulator. NPY has pleiotropic activities ranging from stimulating appetite, obesity and anxiolysis, modulation of endocrine functions such as secretion of insulin and pituitary-adrenal hormones, to cardiovascular regulation such as vasoconstriction and vascular remodeling. These activities are mediated by activation of multiple Gi/o-coupled receptors, designated Y1-Y5.

Since the discovery of NPY in 1982 (Tatemoto and Mutt), our lab has pioneered many of the studies dealing primarily with peptide?s role in cardiovascular physiology and pathophysiology. We have found that NPY is a mediator of severe and/or prolonged stress and is responsible for slow-onset but long-lasting vasoconstriction via Y1 receptors. Males release more NPY during stress and are more sensitive to its hypertensive effects due to testosterone-dependent regulation of the NPY gene. In the last couple of years, the focus of the lab has moved towards more chronic effects of NPY on the cardiovascular system since we discovered its ability to stimulate vascular smooth muscle growth.

Using combination of integrative physiology, cellular and molecular biology, we have established that NPY is extremely potent (active at sub-picomolar concentrations) and powerful (similarly to many known growth factors) vascular mitogenic and angiogenic factor. More recent studies indicate that NPY is a sympathetic trophic factor regulating vascular remodeling in hypertension, atherosclerosis and re-stenosis, and a mediator of neurogenic angiogenesis in ischemic cardiovascular diseases, cancer, aging and obesity. A major part of the current studies is aimed at establishing which of the multiple NPY receptors are responsible for specific functions and what cellular mechanisms mediate NPY?s growth promoting effects. Another part of this research is to determine the interaction of NPY with the adrenergic system, for which it serves as a co-transmitter, and other vascular mitogenic and angiogenesis factors, such as VEGF.

Finally, we try to link animal findings with the human data. Recently, several epidemiological studies carried out in Europe supported our experimental results implicating NPY as a risk factor for atherosclerosis. A common single nucleotide polymorphism was found in the NPY signal peptide gene (Karvonen et al, 2000), which apparently makes the peptide more releasable in response to stressors (Kallio et al, 2001), and is highly correlated with increased plasma lipid levels and accelerated atherosclerosis (Karvonen et al. 2001). Whether or not NPY indeed exerts deleterious effects on the cardiovascular system - as a risk factor for atherosclerosis and stress-induced vasoconstrictor - or is beneficial - by augmenting ischemic angiogenesis - appear to depend on the type of receptors expressed in the tissues? And what are the factors which regulate NPY receptors?is the next question, which we are addressing?