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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1)
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Charette, Marc F
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University of Pittsburgh
Schools of Medicine
United States
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