Abstract 16456: Regulation of Vascular Smooth Muscle Phenotypic Switch and Suppression of Atherosclerosis by c-Kit/SCF Expression in Hyperlipidemic Mice
Introduction: This study provides our novel evidence that stem cell factor (SCF) receptor c-Kit regulates vascular smooth muscle cell (SMC) phenotype and is potently anti-atherogenic.
Methods and Results: Atherosclerotic plaque was quantified in transgenic mice deficient for c-Kit (c-KitW/Wv ApoE-/-) or SCF (c-Kitlsl/+ ApoE-/-) after 16 weeks of high fat diet (HFD). Both mutant strains displayed substantially greater atherosclerosis compared with control (ApoE-/-) littermates (p<0.01 and <0.05 respectively). Transplantation of c-Kit positive bone marrow into c-KitW/Wv ApoE-/- mice failed to rescue the atherogenic phenotype indicating that increased atherosclerosis was associated with reduced arterial c-Kit. To investigate the mechanism, SMC organization and morphology were analyzed in aorta by histopathology and electron microscopy. Remarkably, SMCs were more abundant, disorganized and vacuolated in aortas of c-Kit mutant mice compared with controls (p<0.05). Markers of the “contractile” SMC phenotype (Calponin, SM22α) were downregulated in parallel with decreased c-Kit (p<0.05). Reconstitution of c-Kit in synthetic cultured SMCs conferred increased spindle-shaped morphology, reduced proliferation and elevated levels of contractile markers Calponin and SM22α, each characteristic of a resumed contractile phenotype (p<0.05). Conversely, aortas of c-KitW/Wv ApoE-/- accumulated more pro-inflammatory cytokines (MCP-1, RANTES, MIP-1β, G-CSF, p<0.01) and elevated monocytes compared with control mice treated equivalently. Additionally, quantitative mRNA screening and western blot analysis revealed elevated levels of atherosclerotic and inflammatory biomarkers Toll Like Receptors (TLR4, 6, 9) and TNF-α in cultures of c-KitW/Wv VS c-Kit+/+ SMC.
Conclusion: c-Kit/SCF expression prevents phenotypic switching of contractile SMC to the pro-inflammatory, synthetic phenotype and markedly suppresses atherosclerosis in this murine model.
Author Disclosures: L. Song: None. A. Mesa: None. N. Fernandez: None. G. Selman: None. N. Santos: None. K.A. Webster: None. R.I. Vazquez-Padron: None.
- © 2015 by American Heart Association, Inc.