血管平滑肌细胞能否维持收缩表型是决定血管稳态和重构的关键环节。胞外基质广泛参与调控细胞行为和疾病发生，但其对于血管平滑肌表型、血管稳态和重构的调控作用，目前知之甚少。我们前期揭示了维持血管平滑肌细胞收缩表型的基质蛋白—COMP，并以此找到血管重构干预靶点—金属蛋白酶ADAMTS-7。进一步通过高通量分泌组学和生物信息学分析，又发现基质相关蛋白GDF-6和Nidogen可能参与维持平滑肌收缩表型。我们提出假说：胞外基质及其结合的生长因子和蛋白酶等，构成复杂的基质蛋白网络，对于调控血管平滑肌细胞表型转化、血管稳态及重构至关重要。我们将重点验证新筛出的GDF-6和Nidogen维持平滑肌收缩表型的作用；阐明其通过何种相互作用蛋白、受体及信号通路发挥效应；利用基因敲除鼠，阐明其在血管稳态和重构中的作用；并进一步从基质蛋白网络中筛选新的基质分子或其结合蛋白；以期找到血管稳态调控的内源性关键保护物质。

Maintaining of contractile phenotype of vascular smooth muscle cells (VSMCs) is essential for vascular homostasis. Extracellular matrix (ECM) is exclusively involved in regulation of cellular behavior and disease states. However, how ECM regulates VSMCs phenotype transition, as well as vascular homostasis and remodeling remains largely unknown. Previously we have identified that matrix protein COMP is necessary and sufficient to maintain VSMCs contractile phenotype. We subsequently characterized COMP-degrading metalloproteinase ADAMTS-7 in mediating vascular remodeling. Through prelimitary high-throughput proteomics screening and bioinformatics analsysis, we recently uncovered that ECM-associated GDF-6 and Nidogen may play important role in maintaining the contractile phenotype of VSMCs. We therefore hypothesize that ECM proteins, as well as the associated growth factors and proteinases etc, interact with each other to form a comprehensive network and regulates VSMCs phenotype, vascular homostasis and remodeling. In the current study, we aim to specifically verify the effect of GDF-6 and Nidogen on keeping the contractile phenotype of VSMCs. Secondly, we will explore the underlying mechanism of GDF-6 and Nidogen on VSMCs differentiation, including interacting binding partner, receptors and signal pathway etc. Thirdly, we will characterize the in vivo effect of GDF-6 and Nidogen on vascular homostasis and remodeling. Finally, via high-throughput strategy, we will uncover more ECM and associated proteins in regulation of VSMCs contractile phenotype. The long-term goal of our study is to illustrate the key endogenous vascular protective ECM factors and to calrify their regulatory mechanism during vascular remodeling in vivo.