Vascular remodeling in response to injury and in atherosclerosis is believed to be mediated by different mechanisms. Although platelet-monocyte-vascular cell interactions and neointima formation occur in both;inflammatory and thrombotic lesions after injury are not seen in animals. Surprisingly, we found such inflammatory atherosclerotic-like lesions post-angioplasty in rats treated perivascularly with neuropeptide Y (NPY), a sympathetic co-transmitter and vascular mitogen. While studying NPY and its receptors (Rs) in restenosis /atherosclerosis, we discovered that C57/BL mice, also used for pro- atherosclerotic ApoE-/- - do not express NPY in megakaryocytes (MK)/platelets and form mild or no lesions in response to angioplasty (neointima) and atherosclerosis (intimal xanthomas), whereas strains that do (all rats, Sv129, FVB) - develop significant lesions. Stress amplified post-angioplasty lesions and in platelet NPY-expressing rats advanced them into macrophage-rich, thrombotic atherosclerotic-like lesions. This was paralleled by a stress-induced increase in MK turnover and up-regulation of NPY expression in MK/platelets, mediated by sympathetic, NPY-ergic activation of MKs. The hypothesis that platelet NPY, at certain threshold concentrations, triggers the inflammatory cascade was formed when transfer of NPY-/- platelets into NPY+/+ mice, or Y1R antagonist completely prevented post-angioplasty macrophage transmigration and neointima formation. These intriguing data led us to propose that stress, via platelet NPY, amplifies vascular atherosclerotic remodeling by stimulating proinflammatory platelet-immune- endothelial-vascular interactions (Aim 1-3) and upregulating MK/platelet NPY expression (Aim 4). This is mediated by vascular and monocytic Y1R (Aim 1/3A), and antagonized by endothelial and macrophage-derived DPPIV/cd26 (Aim 1/3B), which inactivates NPY- Y1R-mediated and monocytic chemoattractant activities of RANTES and SDF-1 (Aim 1B). In vitro, platelet-monocyte-endothelial interactions will be studied in human and murine cells derived from mice with or without NPY, Y1R, DPPIV/cd26, or P-selectin, and in vivo, in the same mice after angioplasty with or without stress and platelet transfer (Aim 5). The critical role of monocytic Y1Rs in the platelet NPY-triggered inflammatory cascade will be tested with a conditional, monocyte-specific Y1R deletion (Y1R lox/lox crossed with Cre-Lyzs ).This will be the first time that mechanisms of actions of chronic stress on atherosclerotic remodeling will be studied at the cellular-molecular level.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-CVS-D (03))
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Tolunay, Eser
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University of Minnesota Twin Cities
Schools of Medicine
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Paiva, Sara P C; Veloso, Clara A; Campos, Fernanda F C et al. (2016) Elevated levels of neuropeptide Y in preeclampsia: A pilot study implicating a role for stress in pathogenesis of the disease. Neuropeptides 55:127-35
Tilan, Jason U; Everhart, Lindsay M; Abe, Ken et al. (2013) Platelet neuropeptide Y is critical for ischemic revascularization in mice. FASEB J 27:2244-55
Najafi, Amir H; Aghili, Nima; Tilan, Justin U et al. (2013) A new murine model of stress-induced complex atherosclerotic lesions. Dis Model Mech 6:323-31
Han, Ruijun; Li, Aiyun; Li, Lijun et al. (2012) Maternal low-protein diet up-regulates the neuropeptide Y system in visceral fat and leads to abdominal obesity and glucose intolerance in a sex- and time-specific manner. FASEB J 26:3528-36
Han, Ruijun; Kitlinska, Joanna B; Munday, William R et al. (2012) Stress hormone epinephrine enhances adipogenesis in murine embryonic stem cells by up-regulating the neuropeptide Y system. PLoS One 7:e36609
Hirsch, Dalay; Zukowska, Zofia (2012) NPY and stress 30 years later: the peripheral view. Cell Mol Neurobiol 32:645-59
Li, Lijun; Najafi, Amir H; Kitlinska, Joanna B et al. (2011) Of mice and men: neuropeptide Y and its receptors are associated with atherosclerotic lesion burden and vulnerability. J Cardiovasc Transl Res 4:351-62
Rasmusson, Ann M; Schnurr, Paula P; Zukowska, Zofia et al. (2010) Adaptation to extreme stress: post-traumatic stress disorder, neuropeptide Y and metabolic syndrome. Exp Biol Med (Maywood) 235:1150-62
Ruohonen, Suvi T; Abe, Ken; Kero, Mia et al. (2009) Sympathetic nervous system-targeted neuropeptide Y overexpression in mice enhances neointimal formation in response to vascular injury. Peptides 30:715-20
Baker, Stephen B; Cohen, Michael; Kuo, Lydia et al. (2009) The role of the neuropeptide Y2 receptor in liporemodeling: neuropeptide Y-mediated adipogenesis and adipose graft maintenance. Plast Reconstr Surg 123:486-92

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