PGF2α-FP受体信号转导通路在血管平滑肌细胞衰老和糖尿病动脉硬化中的作用

Arterial stiffness is the most essential manifestation of vascular aging, meanwhile, it is also a major pathological change of type 2 diabetes macrovascular complications. Vascular smooth muscle cells (VSMCs) are major component cells of blood vessels, and the senescence of VSMCs can influence the arterial stiffness in diabetes, which mechanism remains incompletely understood. By studying the researches about cellular senescence and arterial stiffness in diabetes, we hypothesize that PGF2α-FP receptor signaling pathway may take part in formation and development of arterial stiffness in diabetes via regulating the senescence of VSMCs. We intend to use a senescent insulin-resistant VSMCs model to investigate the signaling mechanism of FP receptor in regulating cellular senescence by FP receptor gene overexpressing or silencing. Then we establish senescent type 2 diabetes FP-/- mice model to explore the role of PGF2α-FP receptor/Src/PAI-1 signal pathway in regulating arterial stiffness in diabetes. By investigating the common pathway of cellular senescence and arterial stiffness in diabetes, the present study is expected to provide potoential therapeutic targets for early prevention of diabetes cardiovascular complications.

动脉硬化是血管衰老的最重要表现，同时也是2型糖尿病大血管病变的主要病理改变。血管平滑肌细胞（VSMCs）是血管壁的主要构成细胞，VSMCs衰老与糖尿病动脉硬化形成关系密切，但其调控机制尚未完全阐明。本课题综合分析糖尿病动脉硬化和血管衰老国内外研究现状，提出了PGF2α-FP受体信号通路可能通过调控血管平滑肌细胞衰老，参与糖尿病动脉硬化发生发展的假说。本课题拟建立衰老的胰岛素抵抗的VSMCs模型，研究FP受体过表达及基因沉默对VSMCs衰老的调节作用及信号转导机制；以2型糖尿病衰老FP-/-小鼠为模型，探讨PGF2α-FP受体/Src/PAI-1信号转导通路在糖尿病动脉硬化中的作用。该研究可望通过深入研究血管细胞衰老与糖尿病动脉硬化的共同途径，为糖尿病心血管并发症的早期防治提供新的治疗靶点。

动脉硬化是血管衰老的最重要表现，同时也是2型糖尿病大血管病变的主要病理改变。血管平滑肌细胞（VSMCs）是血管壁的主要构成细胞，VSMCs衰老与糖尿病动脉硬化形成关系密切，但其调控机制尚未完全阐明。我们前期研究发现胰岛素抵抗状态下，PGF2α能够促进FP受体的表达， FP受体基因沉默后可以改善糖尿病大鼠的血管重构。本课题研究发现：（1）高糖能够促进血管平滑肌细胞衰老，PGF2α-FP受体参与高糖诱导血管平滑肌细胞衰老过程；（2）PGF2α发挥促进细胞衰老的作用主要是通过调节FP受体/Src/PAI-1信号通路而实现的；（3）在衰老动物体内存在主动脉硬化现象，给予FP受体基因干预治疗后，这一现象得到改善；（4）FP受体/Src/PAI-1信号通路参与了衰老动脉硬化的发生和发展。本研究证实了FP受体通过衰老调控参与动脉硬化，为糖尿病心血管并发症的防治及抗衰老提供新的治疗靶点。