Extracellular microRNAs (miRs) in endothelial cells (ECs) can be transported by extracellular carriers to regulate the gene expression in the recipient cells, i.e., smooth muscle cells (SMCs) and macrophages (MOs), and hence modulate vascular physiology and pathophysiology. In the current funding cycle, we demonstrated that distinct flow patterns, i.e. pulsatile shear (PS, the main feature of atheroprotective flow) and oscillatory shear (OS, the main feature of atheroprone flow) differentially regulate the miR expression profiles (miRomes) in ECs to cause up- or down-regulation of genes involved in inflammation, redox state, and proliferation. Moreover, others and we have shown that the shear stress-modulated miRs in ECs (e.g., miR-126 and miR- 143/145) are transferable via carriers such as exosomes or Ago2 to SMCs to target their gene expression and alter their phenotype. In relation to translational application, patients with cardiovascular diseases have been shown to have elevations of miR-126 and miR-92a in association with extracellular vesicles, and a decrease of their associations with lipoproteins. These findings led to the hypothesis of this new proposal that atheroprotective and atheroprone flow patterns modulate distinct miR-transportomes and regulate different miR-targetomes to result in beneficial or detrimental outcome of the vasculature. Specifically, we will expand our study to investigate the mechanisms and functional consequences of the shear stress-regulated EC miR transportomes and SMC/MO targetomes. The four Specific Aims are: (1) to investigate the EC miR transportomes regulated by PS vs. OS. (2) To elucidate the miR uptake mechanism and miR targetomes in recipient SMCs and MOs under PS and OS. (3) To determine the roles of PS- and OS-modulated miR transportomes and targetomes in regulating vascular functions. (4) To validate the flow regulation of miR expression and transmission in the vasculature in animal studies in vivo and in clinical samples from patients with cardiovascular diseases. We will perform flow channel experiments, high-throughput screening, and systems biology analysis and modeling to elucidate the diverse transportomes regulated by PS vs. OS in modulating the targetomes and functions of SMCs and MOs. We will validate and translate our in vitro and in silico results by using mouse models as well as human clinical samples. The proposed research aims at investigating the mechanisms by which miRs mediate the flow-regulation of vascular phenotypes and functions, with the ultimate goal of elucidating the interplays of miRs and shear pattern in the regulation of vascular homeostasis for translational applications.

Public Health Relevance

MicroRNAs (miRs) are small non-coding RNAs that play crucial roles in the regulation of arterial function in health and disease. We will use cell cultur, experimental animals, human specimens, and system biology approaches to elucidate the roles of miRs in mediating the vascular cell communications in normal and pathophysiological flow conditions. The result may contribute to the development of novel approaches for the diagnosis and treatment of cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106579-07
Application #
9185340
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hasan, Ahmed AK
Project Start
2011-01-01
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
7
Fiscal Year
2017
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
Torzewski, Michael; Ravandi, Amir; Yeang, Calvin et al. (2017) Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. JACC Basic Transl Sci 2:229-240
Yeang, Calvin; Gordts, Philip L S M; Tsimikas, Sotirios (2017) Novel Lipoprotein(a) Catabolism Pathway via Apolipoprotein(a) Recycling: Adding the Plasminogen Receptor PlgRKT to the List. Circ Res 120:1050-1052
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
He, Ming; Chen, Zhen; Martin, Marcy et al. (2017) miR-483 Targeting of CTGF Suppresses Endothelial-to-Mesenchymal Transition: Therapeutic Implications in Kawasaki Disease. Circ Res 120:354-365
Pechlaner, Raimund; Tsimikas, Sotirios; Yin, Xiaoke et al. (2017) Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III. J Am Coll Cardiol 69:789-800
Huang, Tse-Shun; Wang, Kuei-Chun; Quon, Sara et al. (2017) LINC00341 exerts an anti-inflammatory effect on endothelial cells by repressing VCAM1. Physiol Genomics 49:339-345
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
van Capelleveen, Julian C; Bernelot Moens, Sophie J; Yang, Xiaohong et al. (2017) Apolipoprotein C-III Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol 37:1206-1212
Shang, Fenqing; Wang, Shen-Chih; Hsu, Chien-Yi et al. (2017) MicroRNA-92a Mediates Endothelial Dysfunction in CKD. J Am Soc Nephrol 28:3251-3261
Ajami, Nassim E; Gupta, Shakti; Maurya, Mano R et al. (2017) Systems biology analysis of longitudinal functional response of endothelial cells to shear stress. Proc Natl Acad Sci U S A 114:10990-10995

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