血管外周神经肽Y调控血管炎症的机制研究

Neuropeptide Y is a major neurotransmitter released from sympathetic nerves which participates in the pathogenesis of vascular diseases. Growing evidence demonstrated that vascular inflammation contributes to vascular injury, but the relationship between NPY and vascular inflammation remains unclear. Recently, we found that inflammatory factor secreted from adventitial fibroblats facilitates macrophage infiltration into vascular adventitia participating in vascular remodeling after injury (ATVB, 2012). We further demonstrated that more NPY-positive nerves are distributed in the periphery of the renal arteries with concurrent macrophage infiltration after Ang II infusion suggesting that NPY mediates the interaction between perivascular nerve and vascular inflammation. Therefore, we hypothesized that perivascular nerves are activated and then release NPY after injury. And through acting on NPY receptors in adventitial fibroblasts, NPY up-regulates adhesion molecule and inflammatory factor which induces the recruitment of macrophage and exacerbation of vascular inflammation contributing to vascular diseases. The present study aimed to determine the mechanism of sympathetic nerves releasing NPY and the mechanism of NPY participating in vascular inflammation in adventitial fibroblasts. Finally, we examine whether blockade of NPY signaling pathway can inhibit adventitial inflammation and ameliorate vascular function and provide a new therapeutic target for early treatment of vascular diseases.

神经肽Y（NPY）作为交感神经释放的主要神经递质参与多种血管疾病的发生。近期研究证实血管炎症是血管损伤的始发因素，但NPY与血管炎症的关系鲜有研究。我们最近发现血管损伤时外膜成纤维细胞分泌的炎症因子致巨噬细胞大量浸润从而参与血管重塑（ATVB，2012）。进一步研究发现血管紧张素II（Ang II）灌注大鼠的肾动脉外周分布更多的NPY阳性神经，并伴随着巨噬细胞的浸润，提示NPY可能介导神经与血管炎症的相互作用。因此，本项目假设血管损伤时血管外周神经激活后释放的NPY通过作用于外膜成纤维细胞上的受体，上调粘附分子和炎性介质参与炎性细胞的招募而加剧血管炎症。本项目旨在此基础上研究1）Ang II诱导的交感神经激活释放NPY的机制；2）NPY作用于外膜成纤维细胞参与血管炎症的机制；3）干预NPY信号通路减轻外膜炎症反应从而改善血管功能以及疾病进程，为血管损伤等血管疾病的早期干预提供新的治疗靶点。

交感神经系统与肾素血管紧张素系统相互作用导致各种心血管疾病。本项目研究去肾交感神经手术是否改善血管紧张素II（Angiotensin II， Ang II）诱导的血压升高以及心血管病理学变化。24小时动态血压的结果显示，去肾交感神经能明显抑制Ang II诱导的血压升高，是通过改善肠系膜收缩与舒张功能。心超结果显示去肾交感神经能明显改善左心室肥厚。并且去肾交感神经明显抑制Ang II诱导的心脏及主动脉重塑及纤维化。进一步发现，去肾交感神经抑制巨噬细胞的浸润和炎症因子单核细胞趋化蛋白-1（Monocyte chemoattractant protein-1，MCP-1）的表达，特别是在心肌组织，以及主动脉血管外膜。有意思的是，我们发现去肾交感神经抑制Ang II诱导血浆，肾和心脏醛固酮表达升高伴随着CGRP（calcitonin gene-related peptide）的降低。研究报道CGRP作为一种保护性的神经递质，我们在细胞实验证实CGRP能抑制Ang II诱导的醛固酮表达升高。转化生长因子-β（Transforming growth factor-β，TGF-β）/Smad和丝裂原激活蛋白激酶（Mitogen-activated protein kinases，MAPKs）信号通路的激活也能被去肾交感神经所抑制。该研究成果证实肾血管外周神经可能通过传入神经从而影响CGRP表达参与调控心血管重塑，进一步提示了去肾交感神经可能作为一种有效治疗肾素-血管紧张素-醛固酮系统（RAAS）激活的心血管疾病。另一研究在主动脉缩窄模型上，发现激活的巨噬细胞浸润到损伤血管外膜，同时外膜表达大量iNOS (inducible nitric oxide synthase)。LPS激活巨噬细胞的条件培养液促进外膜成纤维细胞表达iNOS。炎症因子IL-1β和TNF-α能激活外膜成纤维细胞的iNOS信号。在细胞和动物模型上，均发现胶原的沉积，并且能被iNOS抑制剂1400W所抑制。该研究结果提示iNOS信号在血管炎症导致的血管纤维化过程中发挥着重要的作用。