Caveolin-1介导多能血管干细胞向增殖型血管平滑肌细胞分化的调节作用及机制

Proliferative SMCs play critical roles in the blood vessel formation during the development, vascular repairing or neointima formation. It is therefore important to maintain certain levels of proliferative SMCs within the vessel wall. It was previously proposed that proliferative SMCs result from dedifferentiation of contractile SMCs. However, this concept has recently been challenged by Tang et al ( Nature Communications 2012, 3:875). These studies have provided convincing data showing that MVSCs actually contribute to previously described "proliferative" SMCs, but also brings us a serious challenge. Considering this novel MVSC hypothesis and our early research findings, we propose that caveolin-1 promotes MVSCs to differentiate into proliferative SMCs, and the notch/myocardin pathway will likely induce MVSCs to differentiate into contractile SMCs. Several approaches will be used in our proposal, including caveolin-1 gene knockout and siRNA knockdown of notch and myocardin. Our research goal is to establish the roles of caveolin-1, notch and/or myocardin in the regulation of MVSC differentiation so as to develop approaches to avoid depletion of proliferative SMCs for vascular repairing.

增殖型血管平滑肌细胞（pSMC）在血管新生、损伤修复或内膜增厚中发挥关键作用。关于pSMC的来源，"平滑肌细胞（SMC）去分化"理论长期占主导地位。最近，Tang报道pSMC并非来自血管SMC去分化，而是由多能血管干细胞（MVSC）分化而来《Nature Communication 2012， 3:875》；并提出"MVSC→MSC-like细胞（pSMC）→cSMC（收缩型血管SMC）"分化路径和"MVSC分化"假说。这一发现给血管SMC研究带来重大挑战。我们结合前期工作，提出caveolin-1既介导MVSC向pSMC分化、又抑制pSMC向cSMC分化而维持pSMC数量的思路。并拟采用caveolin-1敲除、notch/myocardin沉默等策略，证实caveolin-1、notch或/和myocardin在调节MVSC分化和防止pSMC消耗、促进pSMC形成和蓄积中起重要作用。

增殖型血管平滑肌细胞（pSMC）在血管新生、损伤修复和内膜增厚中发挥关键作用。关于pSMC的来源，主要存在两种观点：即收缩型平滑肌细胞（cSMC）逆分化机制和多能血管干细胞分化机制《Nature Communication 2012，3:875》。本项目主要探讨增殖型血管平滑肌细胞（VSMC）和收缩型VSMC之间功能转化（表型转换）特性、诱导因素（如炎症应激、脂代谢紊乱）及其信号转导机制（包括caveolin-1、notch1、myocardin在p/cVSMC的时空表达变化；caveolin-1对notch1及notch1/myocardin通路的调节机制；AKT/p38/MCPIP-1与VSMC增殖等），阐明VSMC分化、增殖、舒缩与血管重构及动脉硬化的关系，并探讨其作为药物靶标的可能性。本项目研究内容包括：1）观察了间充质干细胞（BMSC）→VSMCs分化过程中相关蛋白（caveolin-1、myocardin）的表达,并构建了Caveolin-1过表达载体；2）研究了VSMC的收缩特性的调节机制；3）MCPIP-1（单核细胞趋化蛋白诱导蛋白-1）及其上游信号通路（AKT/p38）在诱导VSMC增殖（凋亡）中的作用；4）探讨了caveolin-1在炎症应激与脂代谢紊乱介导单核细胞/血管平滑肌细胞向泡沫化表型转变（形成动脉粥样硬化）过程中的作用；5）探讨了竹节参皂苷IVa甲酯对血管紧张素Ⅱ诱导的血管平滑肌细胞增殖的影响及机制；6）观察了自噬与心血管功能的关系。本项目获得如下成果（以科研论文和科研总结形式提供）：1）建立了BMSC分化模型并初步证实了caveolin-1、notch1、myocardin的时空表达规律；2)发现caveolin-1是SMC表型的重要调节因子并研究了姜黄素对小鼠血管收缩力的调节作用及机制；3）发现炎症相关蛋白MCPIP1在SMC增殖能力的调节方面发挥重要作用；4）发现自噬在调节VSMC和单核细胞向泡沫化表型转变过程中发挥重要作用；5）此外，还完成了相关文献综述。分别在《J Cell Physiol》、《Acta Pharmacol Sin》以及《中国动脉硬化杂志》等国内外核心期刊发表论文12篇、SCI 收录8篇、待发表1篇。申请相关专利1项；新申请获批国家自然基金面上项目3项，其他项目2项；培养硕士研究生1名、博士研究生2名、博士后1