Y.C. Fung Professor of Bioengineering and Medicine, & Director, Institute of Engineering in Medicine, University of California San Diego
Title of Keynote Lecture: Role of Fluid Mechanics and MicroRNA in Endothelial Regulation
Vascular endothelial cells (ECs) play significant roles in regulating circulatory homeostasis. The shear stress resulting from circulatory flow modulates EC functions by activating mechano-sensors, signaling pathways, and gene and protein expressions. Sustained shear stress with a clear direction (e.g., the pulsatile shear stress, PS, in the straight part of the arterial tree) down-regulates the molecular signaling of pro-inflammatory and proliferative pathways. In contrast, shear stress without a definitive direction (e.g., the disturbed or oscillatory flow, OS, at branch points and other regions of complex geometry) causes sustained molecular signaling of pro-inflammatory and proliferative pathways. The EC responses to directed mechanical stimuli involve the remodeling of EC structure to minimize alterations in intracellular stress/strain and elicit adaptive changes in EC signaling in the face of sustained stimuli; these cellular events constitute a feedback control mechanism to maintain vascular homeostasis and are athero-protective. Such a feedback mechanism does not operate effectively in regions of complex geometry, where the mechanical stimuli do not have clear directions, thus placing these areas at risk for atherogenesis. The differential modulation of EC functions by various flow patterns involves intricate interplays of signaling pathways and gene regulation, including the participation of microRNA (miR). We found that miR-23b mediates the PS-induced inhibition of EC proliferation and that miR-21 mediates the OS-induced monocyte adhesion to ECs. miR-92a exerts an inhibitory effect on the transcription factor KLF2, which is anti-inflammatory and anti-proliferative. The athero-protective effect of PS is mediated by the inhibition of miR-92a and the atherogenic effect of OS is mediated by the activation of miR-92a. The mechanotransduction-induced modulation of EC functions involves complex changes in molecular signaling, and a systems biology approach is required for its elucidation.
He has made seminal scientific contributions to advancing our understanding of how mechanical forces modulate signal transduction and gene expression at the molecular level in blood vessels. He is a member of all three U.S. National Academies (National Academy of Sciences, National Academy of Engineering, and Institute of Medicine), as well as the American Academy of Arts and Sciences. He was recently awarded the National Medal of Science by President Obama. He is also a Member of Academia Sinica in Taiwan and a Foreign Member of the Chinese Academy of Sciences in Beijing. Dr. Chien has been a tireless advocate of biomedical science and engineering at UCSD, having served at various times as president of the following national and international societies: American Physiological Society, Microcirculatory Society, International Society of Biorheology, Biomedical Engineering Society, Federation of Societies of Experimental Biology, and American Institute of Medical and Biological Engineering.