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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
4R01HL108735-05
Application #
9111932
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Galis, Zorina S
Project Start
2012-08-24
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Biomedical Engineering
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Yeh, Yi-Ting; Serrano, Ricardo; François, Joshua et al. (2018) Three-dimensional forces exerted by leukocytes and vascular endothelial cells dynamically facilitate diapedesis. Proc Natl Acad Sci U S A 115:133-138
Diez-Cuñado, Marta; Wei, Ke; Bushway, Paul J et al. (2018) miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway. Cell Rep 23:2168-2174
Miao, Yifei; Ajami, Nassim E; Huang, Tse-Shun et al. (2018) Enhancer-associated long non-coding RNA LEENE regulates endothelial nitric oxide synthase and endothelial function. Nat Commun 9:292
Gongol, Brendan; Marin, Traci; Johnson, David A et al. (2018) Bioinformatics Approach to Identify Novel AMPK Targets. Methods Mol Biol 1732:99-109
Zhang, Jiao; Dong, Jianjie; Martin, Marcy et al. (2018) AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension. Am J Respir Crit Care Med 198:509-520
Bai, Liang; Li, Zhao; Li, Qianwei et al. (2017) Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization. Arterioscler Thromb Vasc Biol 37:1470-1481
Zhu, Juan-Juan; Liu, Yue-Feng; Zhang, Yun-Peng et al. (2017) VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia. Proc Natl Acad Sci U S A 114:8271-8276
Lee, Ding-Yu; Lin, Ting-Er; Lee, Chih-I et al. (2017) MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases. Proc Natl Acad Sci U S A 114:2072-2077
Marin, Traci L; Gongol, Brendan; Zhang, Fan et al. (2017) AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Sci Signal 10:
Mukund, Kavitha; Subramaniam, Shankar (2017) Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle. Front Physiol 8:980

Showing the most recent 10 out of 50 publications