The concept of enhancing structural and functional integrity of mitochondria in the vasculature has emerged as a novel protective mechanism for vascular dysfunction. However, there is a key knowledge gap with respect to the precise molecular events that are responsible for the vascular mitochondrial remodeling. Our preliminary data provide compelling evidence that vasoprotective unidirectional laminar flow (h-flow) stimulates mitochondrial biogenesis, fusion/fission dynamics, mitochondrial DNA quality control mechanisms and protects the endothelium from oxidative damages, cell senescence and inflammatory activation. In this proposal, we extend this concept and propose to determine the key molecular mediator(s) of the shear sensitive mitochondrial remodeling. The tumor suppressor p53 modulates mitochondrial function by localizing to mitochondria, enhancing mtDNA transcriptional regulation of mitochondrial proteins In this application, we present data that mitochondrial localization of p53 is particularly important for shear stress response and mtDNA integrity. The long-term goal is to determine molecular mechanisms by which h-flow maintains mitochondrial homeostasis in the blood vessel wall and its functional consequence in preventing endothelial dysfunction and hypertensive vascular dysfunction. The objective of this proposed study, therefore, is to determine the molecular mechanisms whereby shear stress response and mitochondrial biogenesis modulate endothelial function and test the working hypothesis that improved resistance to mitochondrial dysfunction will ameliorate the development of hypertension. Our central hypothesis is that induction of the shear stress response and resultant mitochondrial remodeling will modulate endothelial oxidant regulation and resistance to vascular dysfunction. To test this hypothesis we propose the following specific aims:
AIM 1. Investigate the mechanism whereby shear stress-induced mitochondrial remodeling prevents endothelial dysfunction and hypertension. 1A: To test the hypothesis that p53 is required for h-flow-induced endothelial mitochondrial remodeling. 1B: To determine the role of endogenous p53 in flow-dependent mitochondrial remodeling in vivo.
AIM 2. Determine cellular mechanisms and therapeutic potential of directing p53 to mitochondrial compartments. and suppressing mtDNA mutagenesis. 2A: To determine the effect of differentially targeted mitochondrial localization of p53 on mtDNA stability and mitochondrial biogenesis. We will model mitochondrial targeted p53 directing to mitochondrial (i) outer membrane, (ii) inner membrane or (iii) matrix and quantify mitochondrial biogenesis and mtDNA integrity. 2B: To investigate the role of increased mitochondrial p53 on mtDNA integrity and resistance to endothelial dysfunction and hypertension induced by AngII. T his proposed study is innovative because the completion of this project will add an entirely new dimension to the role of hemodynamic shear stress in the endothelial mitochondrial network and provide an interface between mitochondria, oxidant stress and vascular biology.

Public Health Relevance

A basic premise of this proposal is that enhancing mitochondrial biogenesis in endothelium by hemodynamic shear stress could protect against endothelial dysfunction and hypertensive vascular dysfunction by setting events in motion that decrease oxidant stress. As there is growing evidence that oxidant stress is involved in the vascular effects of cardiovascular risk factors including hypertension and diabetes, the current application addresses a fundamental question in biology and medicine, i.e. how mitochondrial biogenesis in endothelial cells modulate oxidant stress with respect to health and disease. Completion of this project may thus add an entirely new dimension to the role of hemodynamic shear stress in mitochondrial network in the blood vessel and provide an interface between mitochondria, oxidant stress and cardiovascular biology.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Galis, Zorina S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Seki, Mitsuru; Powers, Jeffery C; Maruyama, Sonomi et al. (2018) Acute and Chronic Increases of Circulating FSTL1 Normalize Energy Substrate Metabolism in Pacing-Induced Heart Failure. Circ Heart Fail 11:e004486
Shao, Ying; Nanayakkara, Gayani; Cheng, Jiali et al. (2017) Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury. Antioxid Redox Signal :
Kim, Ji-Seok; Kim, Boa; Lee, Hojun et al. (2015) Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells. Am J Physiol Heart Circ Physiol 309:H425-33
Babbitt, Dianne M; Kim, Ji-Seok; Forrester, Steven J et al. (2015) Effect of Interleukin-10 and Laminar Shear Stress on Endothelial Nitric Oxide Synthase and Nitric Oxide in African American Human Umbilical Vein Endothelial Cells. Ethn Dis 25:413-8
Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J et al. (2015) Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II. Hypertension 65:1349-55
Kim, Boa; Lee, Hojun; Kawata, Keisuke et al. (2014) Exercise-mediated wall shear stress increases mitochondrial biogenesis in vascular endothelium. PLoS One 9:e111409