UC San Diego

In the cardiovascular system, mechanical forces are important modulators of cell functions. Being in constant contact with blood flow, vascular endothelial cells (ECs) are sensitive to hemodynamic forces such as fluid shear stress. Cells in the straight part of the arterial tree are usually resistant to atheroma formation, while cells at vessel bifurcations are athero-prone. These differences in EC phenotype can be attributed mainly to region- specific mechanical forces, i.e., laminar high shear stress in the straight vessel versus disturbed low shear stress at bifurcation points. Among many genes and proteins that respond to fluid shear stress, KrüppelLike Factor 2 (KLF2) is a transcription factor that can be induced by laminar flow. It has been noted that KLF2 possesses several anti-thrombotic and atheroprotective characteristics similar to those of high laminar shear stress. In the current study, I focused on understanding the regulatory mechanisms of KLF2 under pulsatile laminar flow (PS), and investigated its role in the flow-mediated atheroprotective functions. AMP-activated protein kinase (AMPK) was identified as an upstream signaling molecule that regulated KLF2 induction by PS flow, and results of my collaborative studies linked AMPK to the previously known ERK5/MEF2 pathway. Our findings provided a complete mechanistic explanation of KLF2 regulation under PS flow via the AMPK/ERK5/MEF2 pathway. In order to further elucidate the role of KLF2 in the atheroprotective functions of PS flow, I used gene-silencing siRNA to block KLF2 expression and examined its effects on PS flow- mediated cell anti-proliferative and anti-inflammatory responses. My results suggested that KLF2 induction was essential in keeping ECs in a quiescent and non- inflammatory state under PS flow, thus demonstrating KLF2's role in maintaining vascular homeostasis. Our investigation has provided new insights on the mechanism of how KLF2 is regulated under the mechanical stimulation of PS flow. By manipulating the expression of KLF2, I also gain understanding of the critical role it plays in PS flow-mediated cell functions. These observations identify KLF2 as an important mechano-activated transcription factor that is necessary for the endothelium to remain in an athero-resistant state in the vasculature