Lkb1 Downregulation Links PVAT Remodeling to Aortic Dilation or Aneurysm

Perivascular adipose tissue (PVAT) is a unique adipose tissue depot that surrounds the blood vessels throughout the body. PVAT regulates vascular physiological homeostasis and contributes to the pathogenesis of vascular diseases. Lkb1 (liver kinase b1) is strongly associated with the development of cancer and cardiovascular diseases.

In this study, we generated tamoxifen-inducible Lkb1^flox/flox;Pdgfrα-Cre^ERT2, Lkb1^flox/flox;Pdgfrβ-Cre^ERT2, and Lkb1^flox/flox;Myh11-Cre^ERT2 mice to investigate the role of Lkb1 in PVAT and related vessel function.

We found that Lkb1 is a PVAT-enriched gene that is strikingly downregulated during Ang II (angiotensin II)-induced aortic aneurysm formation. Lkb1 deficiency in Pdgfrα⁺ fibroblast induces PVAT dysfunction, which in turn results in gradual aortic dilation and exaggerates Ang II-induced aortic aneurysm formation in mice. In addition, Lkb1 deficiency in Myh11⁺ (smooth muscle myosin heavy chain 11) or Pdgfrβ⁺ (platelet-derived growth factor receptor beta) mural cells leads to PVAT dysfunction and spontaneous aortic dilation or aneurysm formation. Mechanistically, genetic deletion of Lkb1 activates renin-angiotensin system in PVAT, which drives vascular smooth muscle cell phenotype switching via paracrine signaling. Most importantly, treatment with either renin inhibitor aliskiren or Ang II receptor blocker valsartan rescues vascular smooth muscle cell phenotypic switching and aortic dilation in Lkb1^flox/flox;Pdgfrα-Cre^ERT2 mice.

Our work strongly suggests that Lkb1 deficiency in PVAT drives vascular smooth muscle cell phenotypic switching and aortic dilation and aneurysm formation. Lkb1, via its regulation of renin-angiotensin system in PVAT, maintains vessel homeostasis.