title: Physiological levels of thrombospondin-1 decrease NO-dependent vasodilation in coronary microvessels from aged rats.
abstract: Aging and cardiovascular disease are associated with the loss of nitric oxide (NO) signaling and a decline in the ability to increase coronary blood flow reserve (CFR). Thrombospondin-1 (Thbs-1), through binding of CD47, has been shown to limit NO-dependent vasodilation in peripheral vascular beds via formation of superoxide (O2 (-)). The present study tests the hypothesis that, similar to the peripheral vasculature, blocking CD47 will improve NO-mediated vasoreactivity in coronary arterioles from aged individuals, resulting in improved CFR. Isolated coronary arterioles from young (4 mo) or old (24 mo) female Fischer 344 rats were challenged with the NO donor, DEA-NONO-ate (1 × 10(-7) to 1 × 10(-4) M), and vessel relaxation and O2 (-) production was measured before and after Thbs-1, αCD47, and/or Tempol and catalase exposure. In vivo CFR was determined in anesthetized rats (1-3% isoflurane-balance O2) via injected microspheres following control IgG or αCD47 treatment (45 min). Isolated coronary arterioles from young and old rats relax similarly to exogenous NO, but addition of 2.2 nM Thbs-1 inhibited NO-mediated vasodilation by 24% in old rats, whereas young vessels were unaffected. Thbs-1 increased O2 (-) production in coronary arterioles from rats of both ages, but this was exaggerated in old rats. The addition of CD47 blocking antibody completely restored NO-dependent vasodilation in isolated arterioles from aged rats and attenuated O2 (-) production. Furthermore, αCD47 treatment increased CFR from 9.6 ± 9.3 (IgG) to 84.0 ± 23% in the left ventricle in intact, aged animals. These findings suggest that the influence of Thbs-1 and CD47 on coronary perfusion increases with aging and may be therapeutically targeted to reverse coronary microvascular dysfunction.
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky; and.
authors.forename: Chris
authors.initials: C
authors.lastname: Nevitt
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky;
authors.forename: Grant
authors.initials: G
authors.lastname: McKenzie
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky;
authors.forename: Katelyn
authors.initials: K
authors.lastname: Christian
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky;
authors.forename: Jeff
authors.initials: J
authors.lastname: Austin
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky;
authors.forename: Sarah
authors.initials: S
authors.lastname: Hencke
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky; Department of Physiology, University of Louisville, Louisville, Kentucky.
authors.forename: James
authors.initials: J
authors.lastname: Hoying
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky; Department of Physiology, University of Louisville, Louisville, Kentucky amanda.leblanc@louisville.edu.
authors.forename: Amanda
authors.initials: A
authors.lastname: LeBlanc
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006834:Hydrazines / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D019700:Thrombospondin 1 / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D006834:Hydrazines; D020030:Nitric Oxide Donors; D019700:Thrombospondin 1; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine
keywords: CD47; aging; coronary blood flow; nitric oxide; thrombospondin-1