Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation

Eileen M. Bauer, Yan Qin, Thomas W. Miller, Russell W. Bandle, Gabor Csanyi, Patrick J. Pagano, Philip M. Bauer, Jurgen Schnermann, David D. Roberts, Jeff S. Isenberg

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

AimsThrombospondin-1 (TSP1), via its necessary receptor CD47, inhibits nitric oxide (NO)-stimulated soluble guanylate cyclase activation in vascular smooth muscle cells, and TSP1-null mice have increased shear-dependent blood flow compared with wild-type mice. Yet, the endothelial basement membrane should in theory function as a barrier to diffusion of soluble TSP1 into the arterial smooth muscle cell layer. These findings suggested that endothelial-dependent differences in blood flow in TSP1-null mice may be the result of direct modulation of endothelial NO synthase (eNOS) activation by circulating TSP1. Here we tested the hypothesis that TSP1 inhibits eNOS activation and endothelial-dependent arterial relaxation.Methods and resultsAcetylcholine (ACh)-stimulated activation of eNOS and agonist-driven calcium transients in endothelial cells were inhibited by TSP1. TSP1 also inhibited eNOS phosphorylation at serine1177. TSP1 treatment of the endothelium of wild-type and TSP1-null but not CD47-null arteries inhibited ACh-stimulated relaxation. TSP1-null vessels demonstrated greater endothelial-dependent vasorelaxation compared with the wild type. Conversely, TSP1-null arteries demonstrated less vasoconstriction to phenylephrine compared with the wild type, which was corrected upon inhibition of eNOS. In TSP1-null mice, intravenous TSP1 blocked ACh-stimulated decreases in blood pressure, and both intravenous TSP1 and a CD47 agonist antibody acutely elevated blood pressure in mice.ConclusionTSP1, via CD47, inhibits eNOS activation and endothelial- dependent arterial relaxation and limits ACh-driven decreases in blood pressure. Conversely, intravenous TSP1 and a CD47 antibody increase blood pressure. These findings suggest that circulating TSP1, by limiting endogenous NO production, functions as a pressor agent supporting blood pressure.

Original languageEnglish (US)
Pages (from-to)471-481
Number of pages11
JournalCardiovascular Research
Volume88
Issue number3
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Fingerprint

Thrombospondin 1
Vasodilation
Nitric Oxide Synthase
Blood Pressure
Smooth Muscle Myocytes
Nitric Oxide
Arteries
Antibodies
Nitric Oxide Synthase Type III
Phenylephrine
Vasoconstriction
Vascular Smooth Muscle
Basement Membrane
Endothelium
Endothelial Cells
Phosphorylation
Calcium

Keywords

  • Blood pressure
  • CD47
  • Thrombospondin-1
  • Vasorelaxation
  • eNOS

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation. / Bauer, Eileen M.; Qin, Yan; Miller, Thomas W.; Bandle, Russell W.; Csanyi, Gabor; Pagano, Patrick J.; Bauer, Philip M.; Schnermann, Jurgen; Roberts, David D.; Isenberg, Jeff S.

In: Cardiovascular Research, Vol. 88, No. 3, 01.12.2010, p. 471-481.

Research output: Contribution to journalArticle

Bauer, EM, Qin, Y, Miller, TW, Bandle, RW, Csanyi, G, Pagano, PJ, Bauer, PM, Schnermann, J, Roberts, DD & Isenberg, JS 2010, 'Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation', Cardiovascular Research, vol. 88, no. 3, pp. 471-481. https://doi.org/10.1093/cvr/cvq218
Bauer, Eileen M. ; Qin, Yan ; Miller, Thomas W. ; Bandle, Russell W. ; Csanyi, Gabor ; Pagano, Patrick J. ; Bauer, Philip M. ; Schnermann, Jurgen ; Roberts, David D. ; Isenberg, Jeff S. / Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation. In: Cardiovascular Research. 2010 ; Vol. 88, No. 3. pp. 471-481.
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abstract = "AimsThrombospondin-1 (TSP1), via its necessary receptor CD47, inhibits nitric oxide (NO)-stimulated soluble guanylate cyclase activation in vascular smooth muscle cells, and TSP1-null mice have increased shear-dependent blood flow compared with wild-type mice. Yet, the endothelial basement membrane should in theory function as a barrier to diffusion of soluble TSP1 into the arterial smooth muscle cell layer. These findings suggested that endothelial-dependent differences in blood flow in TSP1-null mice may be the result of direct modulation of endothelial NO synthase (eNOS) activation by circulating TSP1. Here we tested the hypothesis that TSP1 inhibits eNOS activation and endothelial-dependent arterial relaxation.Methods and resultsAcetylcholine (ACh)-stimulated activation of eNOS and agonist-driven calcium transients in endothelial cells were inhibited by TSP1. TSP1 also inhibited eNOS phosphorylation at serine1177. TSP1 treatment of the endothelium of wild-type and TSP1-null but not CD47-null arteries inhibited ACh-stimulated relaxation. TSP1-null vessels demonstrated greater endothelial-dependent vasorelaxation compared with the wild type. Conversely, TSP1-null arteries demonstrated less vasoconstriction to phenylephrine compared with the wild type, which was corrected upon inhibition of eNOS. In TSP1-null mice, intravenous TSP1 blocked ACh-stimulated decreases in blood pressure, and both intravenous TSP1 and a CD47 agonist antibody acutely elevated blood pressure in mice.ConclusionTSP1, via CD47, inhibits eNOS activation and endothelial- dependent arterial relaxation and limits ACh-driven decreases in blood pressure. Conversely, intravenous TSP1 and a CD47 antibody increase blood pressure. These findings suggest that circulating TSP1, by limiting endogenous NO production, functions as a pressor agent supporting blood pressure.",
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AU - Bauer, Eileen M.

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AU - Miller, Thomas W.

AU - Bandle, Russell W.

AU - Csanyi, Gabor

AU - Pagano, Patrick J.

AU - Bauer, Philip M.

AU - Schnermann, Jurgen

AU - Roberts, David D.

AU - Isenberg, Jeff S.

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N2 - AimsThrombospondin-1 (TSP1), via its necessary receptor CD47, inhibits nitric oxide (NO)-stimulated soluble guanylate cyclase activation in vascular smooth muscle cells, and TSP1-null mice have increased shear-dependent blood flow compared with wild-type mice. Yet, the endothelial basement membrane should in theory function as a barrier to diffusion of soluble TSP1 into the arterial smooth muscle cell layer. These findings suggested that endothelial-dependent differences in blood flow in TSP1-null mice may be the result of direct modulation of endothelial NO synthase (eNOS) activation by circulating TSP1. Here we tested the hypothesis that TSP1 inhibits eNOS activation and endothelial-dependent arterial relaxation.Methods and resultsAcetylcholine (ACh)-stimulated activation of eNOS and agonist-driven calcium transients in endothelial cells were inhibited by TSP1. TSP1 also inhibited eNOS phosphorylation at serine1177. TSP1 treatment of the endothelium of wild-type and TSP1-null but not CD47-null arteries inhibited ACh-stimulated relaxation. TSP1-null vessels demonstrated greater endothelial-dependent vasorelaxation compared with the wild type. Conversely, TSP1-null arteries demonstrated less vasoconstriction to phenylephrine compared with the wild type, which was corrected upon inhibition of eNOS. In TSP1-null mice, intravenous TSP1 blocked ACh-stimulated decreases in blood pressure, and both intravenous TSP1 and a CD47 agonist antibody acutely elevated blood pressure in mice.ConclusionTSP1, via CD47, inhibits eNOS activation and endothelial- dependent arterial relaxation and limits ACh-driven decreases in blood pressure. Conversely, intravenous TSP1 and a CD47 antibody increase blood pressure. These findings suggest that circulating TSP1, by limiting endogenous NO production, functions as a pressor agent supporting blood pressure.

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KW - Vasorelaxation

KW - eNOS

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