Aims Vascular smooth muscle cell (VSMC) plasticity is a state in which VSMCs undergo phenotypic switching from a quiescent contractile phenotype into other functionally distinct phenotypes. Although emerging evidence suggests that VSMC plasticity plays critical roles in the development of vascular diseases, little is known about the key determinant for controlling VSMC plasticity and fate. Methods and results We found that smooth muscle cell-specific deletion of Lkb1 in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice spontaneously and progressively induced aortic/arterial dilation, aneurysm, rupture, and premature death. Single-cell RNA sequencing and imaging-based lineage tracing showed that Lkb1-deficient VSMCs transdifferentiated gradually from early modulated VSMCs to fibroblast-like and chondrocyte-like cells, leading to ossification and blood vessel rupture. Mechanistically, Lkb1 regulates polypyrimidine tract binding protein 1 (Ptbp1) expression and controls alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2. Lkb1 loss in VSMC results in an increased PKM2/PKM1 ratio and alters the metabolic profile by promoting aerobic glycolysis. Treatment with PKM2 activator TEPP-46 rescues VSMC transformation and aortic dilation in Lkb1flox/flox;Myh11-Cre/ERT2 mice. Furthermore, we found that Lkb1 expression decreased in human aortic aneurysm tissue compared to control tissue, along with changes in markers of VSMC fate. Conclusion Lkb1, via its regulation of Ptbp1-dependent alterative splicing of PKM, maintains VSMC in contractile states by suppressing VSMC plasticity.

中文翻译：

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肝激酶 B1 对 Ptbp1 控制的丙酮酸激酶肌肉选择性剪接的调节控制体内血管平滑肌细胞的可塑性


目的 血管平滑肌细胞 （VSMC） 可塑性是 VSMC 经历从静止收缩表型到其他功能不同的表型的表型转换的一种状态。尽管新出现的证据表明 VSMC 可塑性在血管疾病的发展中起着关键作用，但对控制 VSMC 可塑性和命运的关键决定因素知之甚少。方法和结果 我们发现他莫昔芬诱导的 Lkb1flox/flox 中 Lkb1 的平滑肌细胞特异性缺失;Myh11-Cre/ERT2 小鼠自发和进行性地诱导主动脉/动脉扩张、动脉瘤、破裂和过早死亡。单细胞 RNA 测序和基于成像的谱系追踪显示，Lkb1 缺陷的 VSMC 逐渐从早期调制的 VSMC 转分化为成纤维细胞样和软骨细胞样细胞，导致骨化和血管破裂。从机制上讲，Lkb1 调节聚嘧啶束结合蛋白 1 （Ptbp1） 表达并控制丙酮酸激酶肌 （PKM） 亚型 1 和 2 的选择性剪接。VSMC 中的 Lkb1 丢失导致 PKM2/PKM1 比率增加，并通过促进有氧糖酵解来改变代谢特征。用 PKM2 激活剂 TEPP-46 治疗可挽救 Lkb1flox/flox 中的 VSMC 转化和主动脉扩张;Myh11-Cre/ERT2 小鼠。此外，我们发现与对照组织相比，Lkb1 在人主动脉瘤组织中的表达降低，同时 VSMC 命运标志物的变化。结论 Lkb1 通过调节 PKM 的 Ptbp1 依赖性可变剪接，通过抑制 VSMC 可塑性将 VSMC 维持在收缩状态。