Lkb1 is a master regulator of VSMC fate and function in mice

Abstract

Acquisition and maintenance of vascular smooth muscle cell (VSMC) fate are important for vascular development and homeostasis; however, little is known about the key determinant for VSMC fate and vascular homeostasis. We found that VSMC-specific Lkb1 ablation in Lkb1flox/flox;Tagln-Cre mice caused severe vascular abnormalities and embryonic lethality. VSMC-specific deletion of Lkb1 in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice progressively induced aortic/arterial dilation, aneurysm, rupture, and premature death. Single-cell RNA sequencing and imaging-based lineage tracing showed that Lkb1-deficient VSMCs underwent dynamic transcriptional reprogramming and transformed gradually from early modulated VSMCs to fibroblast-like, chondrocyte-like, and even osteocyte-like cells. VSMC transformation followed by extracellular matrix remodeling and inflammatory cell infiltration contributed to the arterial aneurysm formation in tamoxifen-induced Lkb1flox/flox;Myh11-Cre/ERT2 mice. Finally, we found that VSMC-specific Lkb1 ablation resulted in decreased vascular contractility, hypotension, and impaired responses to angiotensin II and vessel injury in vivo. Lkb1 is therefore a key determinant of mouse VSMC fate that prevents VSMC reprogramming and sustains vascular homeostasis. Our findings have important implications for understanding the pathogenesis of aortic aneurysm.