Abstract 661: Wnt16 Promotes Smooth Muscle Mitochondrial Function And Contractile Phenotype Via Taz (Wwtr1) Relays, Limiting Aneurysmal Dilatation Of Ascending Aorta

Abstract

Wnt16 is selectively expressed in arterial vascular smooth muscle (VSM) as well as in bone and skin. Non-synonymous WNT16 cSNPs that increase risk for low bone mass also convey risk for composite cardiovascular events (stroke, MI, heart failure, CV death) in the Dallas Heart Study after adjustment for age, sex, ancestry, systolic blood pressure, and body mass index (OR = 1.25, p = 0.02) . To better understand Wnt16’s role in cardiovascular biology, we generated Wnt16-/-;LDLR-/- mice. Blood pressure and pulse wave velocity were reduced in Wnt16-/-;LDLR-/- mice vs. LDLR-/- controls. Ascending aorta (AscAo) dilatation following angiotensin-II (AngII) infusion was worsened with Wnt16 deficiency, while no differences existed at baseline. Contractile markers such as Acta2 - known to convey AscAo aneurysm risk and reduce pressure with genetic deficiency - were down-regulated in Wnt16-/- VSM, with reduction in TGFbeta-induced contraction. De-differentiation markers (C3, Sca1) were upregulated, and mitochondrial respiration (Seahorse oximetry) was significantly impaired with Wnt16 deficiency. Acta2 protein was reduced with Wnt16 deficiency as was aortic Ankrd1, a target of Yap and Taz(Wwtr1) activation via nuclear TEAD-directed transcription. Wnt16-/- VSM exhibited reduced nuclear Yap+Taz. RNAi targeting Wnt16 or Taz (not Yap1 ) phenocopied Wnt16 deficiency, inhibited Wnt16 up-regulation of contractile markers and reversed C3 suppression. Wnt16 deficiency increased the Yap-Taz inhibitory protein Ccm2 in VSM. Moreover, RNAi targeting Yap-Taz inhibitory kinases Lats1/2 or Ccm2 -- but not Ccm3 or Stk3/Stk4 -- elicited responses reciprocal to Wnt16 deficiency. Biotin proximity labeling following expression of Taz-BioID2 fusion protein identified TEAD1, IQGAP3 and specific MAP4K components of the STRIPAK complex as functionally important Wnt16-Taz signaling mediators. TEAD cognates in Acta2 and C3 promoters convey responses to Wnt16 and Taz+Tead1, and Wnt16 treatment increased Taz association with the Acta2 promoter in aortic VSM. Thus, Wnt16 promotes the contractile phenotype and mitochondrial function in VSM and limits AngII aneurysmal remodeling in AscAo. Strategies that augment the VSM Wnt16-Taz relay may mitigate aneurysmal remodeling.