Abstract 450: Vascular Smooth Muscle Cell-expressed Tie2 Controls Atherosclerosis Progression

Angiopoietin (Angpt)/Tie signaling in microvascular endothelial cells (EC) controls vascular development, remodeling and maturation. Biomarker studies also imply a role of macrovascular Angpt/Tie signaling. The model of Angpt1/stimulation versus Angpt2/destabilization would imply an anti-atherosclerotic function of Angpt1 and a pro-atherosclerotic function of Angpt2. Yet, experimental studies on the role of the Angpt ligands and the Tie receptors in atherosclerosis have yielded conflicting results suggesting spatiotemporally context-dependent pro- and anti-atherosclerotic functions in different experimental settings. The endotheliocentric view of Angpt/Tie signaling is not sufficient to mechanistically explain the divergent roles of Angpt/Tie signaling during atherosclerosis. We hypothesized that vascular smooth muscle cell (VSMC)-expressed Tie2 may contribute to the pathogenesis of atherosclerosis. Employing genetic models, the present study was aimed at elucidating the role of VSMC-expressed Tie2 during atherosclerosis. Compared to EC, VSMC express lower, but consistently detectable levels of functional Tie2. We therefore generated VSMC-specific Tie2 - deficient mice ( Tie2 SMC-KO ), using a mural cell-specific Sm22α-Cre driver line. These were crossed with atherosclerosis-prone ApoE- deficient mice ( ApoE KO Tie2 SMC-KO ). ApoE KO Tie2 SMC-KO mice, fed a Western-type diet for 14 weeks, showed significantly reduced atherosclerotic lesion progression with less VSMC content. Transcriptionally, Tie2 controlled the phenotypic switch of VSMC with increased contractile and reduced synthetic phenotype-specific gene expression in isolated Tie2-deficient VSMC. Correspondingly, migration and proliferation was significantly reduced in Tie2-deficient cultured VSMC. Serum Angpt2 as well as the Angpt2/Angpt1 ratio were significantly increased in ApoE KO Tie2 SMC-KO mice. Collectively, the data expand and revise the endotheliocentric Tie2 signaling concept to show that mural cell-expressed Tie2 is involved in regulating macrovascular functions related to atherosclerosis. VSMC-expressed Tie2 acts pro-atherosclerotic to control the phenotypic switch towards a proliferative and migratory synthetic VSMC phenotype.