The focal nature of the atherosclerotic lesions indicates that hemodynamic forces are critical for the regulation of vascular homeostasis in health and disease. Responses of vascular endothelial cells (ECs) to hemodynamic forces play significant roles in such regulations. In vivo studies implicate that the ECs in branch points express pro-atherogenic phenotypes. In contrast, ECs in the straight parts of the arterial tree are exposed to high shear flow with a large net forward direction, and these regions are generally spared from atherosclerosis. The in vitro studies by others and us suggest that steady and pulsatile shear stresses (PS) with a net forward direction, which simulates the flow condition at the straight part of the arterial tree, induce genes involved in anti-proliferation, anti-oxidation anti-inflammation, and maintenance of vascular tone, with athero-protective effects such as reduction of cell turnover, prevention of white cell recruitment, promotion of wound healing, and adaptive remodeling. In contrast, oscillatory shear stress (OS) without a significant forward direction is atherogenic by activating pro-proliferative, pro-oxidative, and pro-inflammatory genes. We hypothesize that, while PS and OS may activate similar signaling events at the initial stage, the results will diverge with time. Time-dependent mapping of the signal networks will lead to temporal resolution of the gene expression profiles, hence the differential functional consequences of PS vs. OS. In this proposed project, we will examine the signaling, transcriptional regulations, and functional phenotypes of ECs under PS and OS over time. Mapping the differential pathways under these flow conditions requires the use of systems biology approaches that provides a comprehensive mechanistic and network perspective on the diferential responses to stresses. In order to systematically map the flow-regulation of EC functions, we propose the following specific aims: (1) To establish the temporal map of EC signaling events under PS vs, OS. (2) To investigate the transcriptional regulations of EC gene expression under PS vs, OS. (3) To examine the temporal resolution of phenotypic responses of ECs under PS vs, OS. (4) To integrate molecular events and EC functions by reconstruction of signaling models. (5) To validate the defined EC signaling events and gene expressions in mouse arterial tree. Under these Specific Aims, we will conduct experiments systematically to obtain the data necessary for the systems biology analyses to construct the molecular and pathway models for the physiological and pathological regulations of EC molecular events and functional consequences. This integrative and collaborative systems biology approach will generate new insights into the intricate process of mechanotransduction by which different flow patterns modulate homeostasis in the arterial wall. These findings will greatly enhance our understanding of the molecular and mechanical bases of atherosclerosis, a major pathophysiological event in cardiovascular diseases.
We propose to use the systems biology approach combining the experimental procedures and bioinformatics analyses to understand the hemodynamic regulation of vascular functions. The resultant mechanistic and pathway models will provide critical information on the mechanisms of atherosclerosis, a major vascular disease impairing cardiovascular health. The study will also provide novel knowledge for disease prevention, treatments, and management.
|Chang, Shun-Fu; Chen, Li-Jing; Lee, Pei-Ling et al. (2014) Different modes of endothelial-smooth muscle cell interaction elicit differential ?-catenin phosphorylations and endothelial functions. Proc Natl Acad Sci U S A 111:1855-60|
|Bhargava, Vipul; Head, Steven R; Ordoukhanian, Phillip et al. (2014) Technical variations in low-input RNA-seq methodologies. Sci Rep 4:3678|
|Zhou, Jing; Li, Yi-Shuan; Wang, Kuei-Chun et al. (2014) Epigenetic Mechanism in Regulation of Endothelial Function by Disturbed Flow: Induction of DNA Hypermethylation by DNMT1. Cell Mol Bioeng 7:218-224|
|Masnadi-Shirazi, Maryam; Maurya, Mano Ram; Subramaniam, Shankar (2014) Time-varying causal inference from phosphoproteomic measurements in macrophage cells. IEEE Trans Biomed Circuits Syst 8:74-86|
|Gupta, Shakti; Kim, Sung-Min; Wang, Yu et al. (2014) Statistical insights into major human muscular diseases. Hum Mol Genet 23:3772-8|
|Zhou, Jing; Li, Yi-Shuan; Chien, Shu (2014) Shear stress-initiated signaling and its regulation of endothelial function. Arterioscler Thromb Vasc Biol 34:2191-8|
|Li, Song; Sengupta, Debanti; Chien, Shu (2014) Vascular tissue engineering: from in vitro to in situ. Wiley Interdiscip Rev Syst Biol Med 6:61-76|
|Wang, Kuei-Chun; Nguyen, Phu; Weiss, Anna et al. (2014) MicroRNA-23b regulates cyclin-dependent kinase-activating kinase complex through cyclin H repression to modulate endothelial transcription and growth under flow. Arterioscler Thromb Vasc Biol 34:1437-45|
|Chen, Zhen; Martin, Marcy; Li, Zhao et al. (2014) Endothelial dysfunction: the role of sterol regulatory element-binding protein-induced NOD-like receptor family pyrin domain-containing protein 3 inflammasome in atherosclerosis. Curr Opin Lipidol 25:339-49|
|Farhangmehr, Farzaneh; Maurya, Mano Ram; Tartakovsky, Daniel M et al. (2014) Information theoretic approach to complex biological network reconstruction: application to cytokine release in RAW 264.7 macrophages. BMC Syst Biol 8:77|
Showing the most recent 10 out of 19 publications