血管内压力增加产生的病理性机械牵张力是导致血管重构与动脉粥样硬化（AS）的重要原因。Dickkopf1（DKK1）是一种多功能分泌型糖蛋白，已作为新的肿瘤干预靶点进入临床试验，其与AS关系密切，但分子作用机制尚需明了。我们首次发现病理牵张力干预血管平滑肌细胞DKK1表达上调，促进平滑肌细胞增殖、迁移，转录因子FOXC1受牵张力调控，但上述机制及对AS的作用仍需探讨。为此，我们提出假说：病理牵张力可促进FOXC1转录活性上调DKK1表达，进而介导平滑肌细胞功能异常，促进AS发生发展。本课题将通过构建特异性平滑肌细胞DKK1基因敲除小鼠，利用分子生物学、蛋白质组学等方法，明确病理牵张力经FOXC1对平滑肌细胞DKK1的调控及其介导的平滑肌细胞功能异常在AS中的作用与机制。本研究将拓展对DKK1生物学功能的认识，为AS的防治提供新思路；同时为明确肿瘤治疗潜在的心血管作用提供理论依据。

The pathological mechanical stretch induced by increased intravascular pressure is an important cause of vascular remodeling and atherosclerosis (AS). Dickkopf1(DKK1) is a multifunctional secretory glycoprotein which has entered clinical trials as a new target for tumor intervention. Studies have shown that it is closely related to AS, but the specific mechanism is still poorly understood. Our previous study firstly found that the expression of DKK1 in smooth muscle cells was increased under pathological stretch stimulus and promoted proliferation and migration of smooth muscle cells. We also found that the expression of transcription factor FOXC1 was regulated by mechanical stretch. But the mechanisms of them and the role of DKK1 in AS still need to be further explored. Therefore, we hypothesize that pathological stretch can up-regulate DKK1 expression via promoting the transcriptional activity of FOXC1 and then promote the dysfunction of smooth muscle cells and accelerate the development of AS plaques. This study intends to construct specific smooth muscle cell DKK1 knockout mice and use molecular biology, proteomics and other methods to clarify the regulation of pathological stretch on the expression of DKK1 via FOXC1 in smooth muscle cells and its underlying mechanisms in the development of AS. This study will expand our understanding of the biological function of DKK1, and provide new ideas for the prevention and treatment of AS. And it will also provide theoretical basis for clarifying the potential cardiovascular effects of cancer treatment.