Figure 6.

Overall model. With hypercholesterolemia, contractile smooth muscle cells (cSMCs) in the medial layers of the aorta activate ER stress and Perk signaling, which leads to Klf4 activation, de-differentiation of cSMCs and migration into the intima. In the intima, the migrated cells are exposed to additional environmental insults, which lead to modulation into 2 distinct fates: the mSMC1 cells proliferate and contribute to the fibrous cap and may also give rise to mSMC2 cells by an unknown mechanism. mSMC2 cells experience further ER stress in the intima, leading to decreased transcript levels and cell death, ultimately contributing to the necrotic core.