Reactive oxygen species (ROS) are broadly implicated in the pathogenesis of cardiovascular disease (CVD). ROS-mediated is well recognized to increase with aging and promote vascular dysfunction, in part, via inactivation of the vasodilator nitric oxide (NO). A major source of vascular ROS is the NADPH oxidases or Nox proteins. The matricellular protein thrombospondin-1 (TSP1) is significantly elevated in the vasculature in CVD and is associated with vascular dysfunction. We reported that TSP1, via its cognate receptor CD47, inhibits vasodilatation, however the exact mechanism remain unclear. We now find (1) that TSP1 stimulates Nox-derived ROS in arterial smooth muscle cells to inhibit arterial vasodilation, and (2) that TSP1 and CD47 are increased in tissue from aged mice. These findings inform our hypothesis that TSP1-CD47 expression and CD47-mediated ROS production is increased with age further promoting cardiovascular dysfunction. This innovative proposal investigates the role of age-associated induction of TSP1 and CD47 in promoting Nox-derived ROS and limiting vascular function and angiogenesis. The mechanisms that promote aging and age-associated vascular dysfunction remain to be defined. In this proposal we will determine the status of TSP1-CD47 signaling, vascular ROS and angiogenic capacity through longitudinal studies of aging WT mice. Concurrent longitudinal studies in aging CD47 null mice will provide genetic evidence for a causative role for the TSP1-CD47 axis in age-associated ROS and vascular and angiogenic dysfunction.

Public Health Relevance

Cardiovascular diseases (CVD) including heart attack, stroke, hypertension and peripheral vascular disease occur at very high rates in the elderly. The reasons for this are unclear. A major contributor to the development of CVD is reactive oxygen species (ROS). The culprits for age-associated increases in these harmful molecules are also not completely understood. This project aims to open an entirely new field of inquiry by unraveling completely novel agonists and signaling pathways that are turned on in aging leading to vascular oxidant production, abnormal blood vessel function and delayed healing. This proposal will also identify previously unknown therapeutic targets to mitigate age-associated ROS and vascular dysfunction

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL112914-03S1
Application #
8958848
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Charette, Marc F
Project Start
2012-04-01
Project End
2016-05-31
Budget Start
2015-09-21
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Csányi, Gábor; Feck, Douglas M; Ghoshal, Pushpankur et al. (2017) CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. Antioxid Redox Signal 26:886-901
Rogers, Natasha M; Sharifi-Sanjani, Maryam; Yao, Mingyi et al. (2017) TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction. Cardiovasc Res 113:15-29
Li, Yao; Pagano, Patrick J (2017) Microvascular NADPH oxidase in health and disease. Free Radic Biol Med 109:33-47
Zhao, Chen; Isenberg, Jeffrey S; Popel, Aleksander S (2017) Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model. PLoS Comput Biol 13:e1005272
Ghouleh, Imad Al; Sahoo, Sanghamitra; Meijles, Daniel N et al. (2017) Endothelial Nox1 oxidase assembly in human pulmonary arterial hypertension; driver of Gremlin1-mediated proliferation. Clin Sci (Lond) 131:2019-2035
Dai, Hehua; Friday, Andrew J; Abou-Daya, Khodor I et al. (2017) Donor SIRP? polymorphism modulates the innate immune response to allogeneic grafts. Sci Immunol 2:
Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:
Rogers, Natasha M; Ghimire, Kedar; Calzada, Maria J et al. (2017) Matricellular protein thrombospondin-1 in pulmonary hypertension: multiple pathways to disease. Cardiovasc Res 113:858-868
Rogers, Natasha M; Zhang, Zheng J; Wang, Jiao-Jing et al. (2016) CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion. Kidney Int 90:334-347
Al Ghouleh, Imad; Meijles, Daniel N; Mutchler, Stephanie et al. (2016) Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Proc Natl Acad Sci U S A 113:E5308-17

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