Year: 2020
Type: preprint
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 Lkb1 flox/flox ; Tagln-Cre mice caused severe vascular abnormalities and embryonic lethality. VSMC-specific deletion of Lkb1 in tamoxifen-inducible Lkb1 flox/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 Lkb1 flox/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.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: SIRT1, Vascular Aging and an Aortic Aneurysm, Autophagy and diabetic vascular diseases, AMP-activated protein kinase in diabetes, MKP1, VSMC, and Vascular Remodeling, Liver kinase B1 in angiogenesis, Controlling atherosclerotic plaque stability, Inflammasome and unstable atherosclerotic plaques
OpenAlex ID: W3113124606