斑块内血管新生促进动脉粥样硬化（AS）的发展及斑块易损性，增加斑块破裂、出血、出现临床心血管事件的风险。前期我们首次发现DKK1促进内皮细胞功能失调并增加AS斑块易损性，同时促进新生血管增多。但DKK1在易损斑块血管新生中的作用与调控机制尚不明确。为此，我们提出如下假说：ox-LDL刺激下，经辅因子CBP协同Ets-1、c-jun促进内皮细胞DKK1的转录表达；上调MALAT1，竞争miR208b-3p活性，缓解对靶mRNA Ets-1的抑制，形成正反馈环路，调节内皮细胞的增殖迁移及小管形成，参与易损斑块内的血管新生。本课题将应用内皮细胞条件性敲除DKK1小鼠(DKK1fl/fl/Tek Cre+)，通过全转录组测序、分子生物学、组织病理学等技术，从体内外视角论证该假说，为进一步阐明DKK1在易损斑块中的作用机制并寻求合适的干预靶点提供新的理论基础。

Angiogenesis in atherosclerotic lesions plays a major role in plaque growth and instability, which is closely related with plaque rupture, hemorrhage and cardiovascular events. DKK1 is a secretory glycoprotein of the DKK family, plays many roles in both tumors and atherosclerosis. While neovascularization plays an important role in both tumors and atherosclerosis, we focused our investigation on how DKK1 affects angiogenesis. We have known DKK1 induces endothelial dysfunction, increases plaque vulnerability and raises angiogenesis in vulnerable plaque. However, the role and regulatory mechanism of DKK1 in angiogenesis of vulnerable plaque remains unclear. We propose the following hypothesis: Under ox-LDL stimulation, endothelial cells promote the transcriptional expression of DKK1 via CBP in collaboration with Ets-1 and c-jun, then raise the expression of MALAT1 to compete with miR208b-3p activity, relieve the inhibition of target mRNA Ets-1, which form a positive feedback loop to regulate the proliferation, migration, angiogenesis in endothelial cells and vulnerable plaques. Our study will use endothelial DKK1 gene knockout mice model (DKK1fl/fl/Tek Cre+) and take advantage of cellular biology and whole transcriptome sequencing to fully test our hypothesis both in vitro and in vivo and verify the mechanism of DKK1 upregulate the MALAT1/miR208b-3p/Ets-1 pathway as a positive feedback loop to participates in the angiogenesis of vulnerable plaque. Our findings illustrate that a new mechanism of DKK1 in the angiogenesis of vulnerable plaque and provide a new theoretical basis for seeking appropriate intervention targets for atherosclerosis therapy.