血管内膜增生是介入手术后造成血管再狭窄的主要原因，理解血管内膜增生的病理与机制对预防血管再狭窄及治疗冠心病具有重要意义。细胞内钙信号参与血管平滑肌细胞基因表达调控与内膜增生过程，然而不同来源钙信号的作用与分子机制有所不同。到目前为止，人们对于内质网钙释放通道IP3R在内膜增生过程中的作用尚不清楚。课题组前期研究发现颈动脉结扎手术引起的内膜增生过程中三种IP3R亚型表达上调，同时在成年小鼠平滑肌细胞中敲除所有三种IP3R亚型显著降低细胞增殖与内膜增生。IP3R介导钙信号可能通过激活CaN-NFAT或CaMKII-CREB信号通路参与平滑肌细胞表型转化，也可能通过调节线粒体钙摄取激活线粒体mtCaMKII参与细胞迁移过程。基于此，课题组拟通过一系列在体与离体实验来验证上述哪些分子机制参与IP3R对内膜增生的调节，从而为内膜增生提供新机制，并进一步促进人们对术后再狭窄等血管重构性疾病的理解。

Coronary heart disease (CHD) is the most common type of cardiovascular disease and the top cause worldwide. Although changes of lifestyle and pharmaceutical therapy have been widely used for the prevention and treatment of CHD, the most powerful way to treat CHD clinically is percutaneous coronary intervention (PCI). However, the surgery usually causes injury of vascular endothelial cells, which further stimulates vascular smooth muscle cells to undergo phenotypic transformation, promotes cell proliferation, migration, and secretion of numerous extracellular matrix like collagen, and eventually results in neointimal hyperplasia and vascular restenosis. Therefore, it is very important to understand the pathological and molecular mechanisms underlying neointimal hyperplasia for preventing vascular restenosis during the treatment of CHD..Calcium ion (Ca2+) is an important and universal second messenger inside the cell, which has been shown to regulate numerous physiological functions. Ca2+ signal in the cytoplasm comes from two major sources, Ca2+ entry from extracellular solution via membrane Ca2+ channels and Ca2+ release from intracellular Ca2+ store via Ca2+ release channels including 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR). In vascular smooth muscle cells, Ca2+ signal has been supposed to play a critical role in neointimal hyperplasia after vascular injury. Ca2+ signals in smooth muscle cells may regulate cell proliferation, migration, collagen secretion, and gene expression. However, the majority of these studies focused on membrane Ca2+ channels and intracellular Ca2+ signaling proteins. It still remains unknown whether and how IP3R-mediated Ca2+ release plays a role in neointimal hyperplasia. .In mammals, IP3R has three different subtypes, IP3R1, IP3R2, and IP3R3, which are encoded by three different genes, respectively. Our previous studies have shown that all three IP3R subtypes are co-expressed in vascular smooth muscle cells (VSMCs). Furthermore, we also found that the expression of all three IP3R subtypes was increased during neointimal hyperplasia induced by carotid artery ligation in adult mice, which strongly indicates IP3R-mediated Ca2+ signals might play a role in this process. To investigate the physiological function of IP3R-mediated Ca2+ release in vascular remodeling especially neointimal hyperplasia, we generated inducible smooth muscle cell-specific IP3R triple knockout mouse models using smMHC-CreERT2. We found that deletion of all three IP3R subtypes in adult VSMCs dramatically reduced cell proliferation as well as intimal hyperplasia. .We next want to reveal the molecular mechanisms underlying how IP3R in VSMCs regulates neointimal. In VSMCs, the increase in cytosolic Ca2+ concentration may activate two classical Ca2+-dependent signaling pathways, calcineurin (CaN)-NFAT and Ca2+/CaMKII-CREB pathways. Activation of CaN dephosphorylates NFAT, causing the latter translocated into the nucleus. On the other hand, activation of CaMKII phosphorylates CREB, also causing the latter translocated into the nucleus. In the nucleus, NFAT and CREB can activate different gene expression patterns and affect VSMC phenotypic transformation. In addition, several recent studies revealed that mitochondrial Ca2+ signal and mitochondrial CaMKII (mtCaMKII) also play a role in VSMC migration and thus neointimal hyperplasia. Based on these three different hypotheses, we are planning to perform a series of in vivo and in vitro experiments to identify which mechanisms individually or in combination could account for the regulation of neointimal hyperplasia by IP3R-mediated Ca2+ signals. We hope our study could potentially provide new theoretical basis and method for the treatment of vascular diseases such as atherosclerosis and vascular restenosis.