Neuropeptide Y Stimulates Proliferation and Migration of Vascular Smooth Muscle Cells from Pregnancy Hypertensive Rats via Y1 and Y5 Receptors

Abstract

The increased proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in pathophysiological remodeling of arteries during hypertension in pregnancy. However, the mechanisms involved in this process remain unclear. We hypothesized that Neuropeptide Y (NPY), which is a potent mitogenic peptide, participates in modulating proliferation and migration of VSMCs during hypertension in pregnancy. Using pregnant hypertensive rats, induced by intraperitoneal injection of L-nitro-arginine methylester (L-NAME), the plasma concentration of NPY was detected. Open angle, which reflects the non-uniform remodeling with high sensitivity, was used to detect the pathophysiological vascular remodeling in vivo. The results revealed that NPY concentration and artery open angle were both significantly increased in rats with hypertension in pregnant. The underlying mechanism of elevated NPY on vascular remodeling were further analyzed by using cultured VSMCs in vitro. In cultured VSMCs, NPY most effectively stimulated the migration and proliferation of VSMCs at 10-6 mol/L, similar to the plasma concentration in L-NAME hypertension in pregnant rats. NPY up-regulated the expressions of both Y1 and Y5 receptors, increased the phosphorylations of STAT3 on Tyr705 and Ser727 residues, and induced the expression of c-Fos. The NPY-induced VSMCs proliferation was reduced by Y5 receptor antagonist, and fully blocked by combinations with other antagonist, such as Y2+Y5, Y1+Y5, and Y1+Y2+Y5. In contrast, the NPY-induced VSMC migration was blocked by either Y receptor antagonist or any combination of Y receptor antagonists. These results suggest that the elevated plasma concentration of NPY during hypertension in pregnancy may induce VSMC proliferation mainly via Y5 receptor, which subsequently modulate STAT3 and c-Fos signaling pathways to result in the vascular remodeling. These results also suggest that NPY mainly acts on VSMCs in vitro via Y1, Y5 receptors and in vascular tissues in vivo via Y5 receptor.

Comparative effects of Alpha Tocopherol and Ascorbic Acid on Chronic Stress Induced Neuropeptide Y Derangements

“…These results are consistent with Grisé et al 12 who showed increased plasma NPY levels in control group compared to restraint group, while Hassan et al 13 showed same results in a study conducted on mice. Our results are not in agreement with Zhang et al 14 who showed decreased NPY levels in control group, the difference may be due to use of rodent female rat strain and use of different kits. Eskandarzade N et al 15 showed same plasma NPY level of control group and in starved rats.…”

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

“…The proliferation and migration of vascular smooth muscle cells plays a vital role in pathophysiological remodeling of arteries during hypertension in pregnancy. NPY could promote the proliferation and migration of vascular smooth muscle cells via Y1, Y5 receptors and in vascular tissues in vivo via Y5 receptor [128]. Human hypertension is heritable [129], and exhibits pleiotropic determination with autonomic activity.…”

Development of neuropeptide Y-mediated heart innervation in rats

“…The hypertrophic effect of NPY is accompanied by increased activity of cytosolic creatine kinase, protein kinase C, and protein kinase C-dependent activation of mitogen activated protein kinase in adult and neonatal myocytes and activation of phosphoinositol 3-kinase in adults (Protas et al 2003). Via its Y1R, Y2R, and Y5R, NPY promotes angiogenesis (Kuo et al 2007;Parker and Balasubramaniam 2008;Zhang et al 2015), where the Y5R acts as an enhancer (Movafagh et al 2006). In rats, the transmural number of capillaries in the left ventricle increases 3-fold from 1 to 5 days and 5-fold from 1 to 11 day of life.…”

“…Via its Y1R, Y2R, and Y5R, NPY promotes angiogenesis and preadipocyte differentiation (Kuo et al 2007;Parker and Balasubramaniam 2008;Zhang et al 2015). NPY has been shown to be a potent, multifunctional angiogenic factor, which stimulates proliferation, migration, and capillary tube formation in endothelial cells.…”