MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression predominantly through post- transcriptional repression, implicated in the control of multiple physiological and pathological processes. Recently, we described roles for endothelial miRNAs in central aspects of vascular biology such as angiogenesis and inflammation, processes that require the coordination of numerous and complex signaling pathways in which endothelial cells (ECs) act as both active participants and regulators. Endothelial activation is essential for many vascular processes leading to inflammation, vascular remodeling and vessel growth. Cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF) mediate this activation and play fundamental roles in the control of angiogenic and inflammatory responses, respectively. miRNA function is modulated by extracellular factors affecting their biogenesis or activity, thereby fine-tuning the regulation of biological responses. However, our understanding of the mechanisms governing the regulation of microRNA in ECs is limited. We postulate that physiological levels of miRNAs are regulated under conditions, such as inflammation or angiogenic activation, to coordinate specific gene expression programs in ECs. We propose three aims:
Aim 1 : To identify the molecular mechanisms whereby VEGF and TNF regulate miRNA levels in ECs.
Aim 2 : To examine the regulation of EC targets and functions by VEGF and TNF-regulated miRNA in vitro.
Aim 3 : To define the roles of VEGF and TNF- regulated miRNAs in vivo. In summary, completion of these aims will provide critical insight into fundamental regulatory mechanisms controlling endothelial miRNA biogenesis and activity and their impact on EC biology. Understanding the complex network involving EC miRNAs and their targets, leading to a coordinate pattern of gene expression undoubtedly will contribute to a better understanding of the cellular and molecular mechanisms that control EC activation and may identify potential therapeutic strategies for the regulation of endothelial activation through modulation of miRNA activity.

Public Health Relevance

We have described roles for endothelial microRNAs in central aspects of vascular biology such as angiogenesis and inflammation. The proposal main goal is to investigate the mechanisms that regulate microRNA biogenesis and functions in endothelial cell activation. This work will provide critical insight into fundamental regulatory mechanisms and may identify potential therapeutic strategies for the regulation of endothelial activation through modulation of microRNA activity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL105945-04S1
Application #
8774858
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2015-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$369,450
Indirect Cost
$147,558
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chamorro-Jorganes, Aránzazu; Araldi, Elisa; Rotllan, Noemi et al. (2014) Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells. J Cell Sci 127:1169-78
van Solingen, Coen; Araldi, Elisa; Chamorro-Jorganes, Aranzazu et al. (2014) Improved repair of dermal wounds in mice lacking microRNA-155. J Cell Mol Med 18:1104-12
Araldi, Elisa; Chamorro-Jorganes, Aranzazu; van Solingen, Coe et al. (2013) Therapeutic Potential of Modulating microRNAs in Atherosclerotic Vascular Disease. Curr Vasc Pharmacol :
Ramírez, Cristina M; Goedeke, Leigh; Rotllan, Noemi et al. (2013) MicroRNA 33 regulates glucose metabolism. Mol Cell Biol 33:2891-902
Fernández-Hernando, Carlos; Ramírez, Cristina M; Goedeke, Leigh et al. (2013) MicroRNAs in metabolic disease. Arterioscler Thromb Vasc Biol 33:178-85
Dávalos, Alberto; Suárez, Yajaira (2013) MiRNA-based therapy: from bench to bedside. Pharmacol Res 75:1-2
Ramirez, Cristina M; Rotllan, Noemi; Vlassov, Alexander V et al. (2013) Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ Res 112:1592-601
Goedeke, Leigh; Vales-Lara, Frances M; Fenstermaker, Michael et al. (2013) A regulatory role for microRNA 33* in controlling lipid metabolism gene expression. Mol Cell Biol 33:2339-52
Chamorro-Jorganes, Aránzazu; Araldi, Elisa; Suárez, Yajaira (2013) MicroRNAs as pharmacological targets in endothelial cell function and dysfunction. Pharmacol Res 75:15-27
Suarez, Yajaira; Fernandez-Hernando, Carlos (2012) New insights into microRNA-29 regulation: a new key player in cardiovascular disease. J Mol Cell Cardiol 52:584-6

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