Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform

Lynne H. Liu, Richard J. Paul, Roy L. Sutliff, Marian L. Miller, John N. Lorenz, Raymond Y.K. Pun, John J. Duffy, Thomas Doetschman, Yoshihiro Kimura, David H. MacLennan, James B. Hoying, Gary E. Shull

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Sarco(endo)plasmic reticulum Ca2+ ATPase isoform 3 (SERCA3) is one of two Ca2+ pumps serving intracellular Ca2+ signaling pools in non-muscle tissues; however, unlike the ubiquitous SERCA2b, it exhibits a restricted cell-type distribution. Gene targeting was used to generate a mouse with a null mutation in the SERCA3 gene. Homozygous mutant mice were viable, fertile, and did not exhibit an overt disease phenotype. Because SERCA3 is expressed in arterial endothelial cells, aortic ring preparations were analyzed to determine whether it is involved in the regulation of vascular tone. Contraction-isometric force relations in response to phenylephrine or KCl, as well as relaxation produced by exposure to a nitric oxide donor, were similar in wild-type and null mutant aortas. Acetylcholine-induced endothelium-dependent relaxation of aortas after precontraction with phenylephrine was significantly reduced in homozygous mutants (61.3 ± 5.6% in wild type, 35.4 ± 7.3% in mutants). Ca2+ imaging of cultured aortic endothelial cells demonstrated that the acetylcholine-induced intra-cellular Ca2+ signal is sharply diminished in SERCA3-deficient cells and also indicated that replenishment of the acetylcholine-responsive Ca2+ stores is severely impaired. These results indicate that SERCA3 plays a critical role in endothelial cell Ca2+ signaling events involved in nitric oxide-mediated relaxation of vascular smooth muscle.

Original languageEnglish (US)
Pages (from-to)30538-30545
Number of pages8
JournalJournal of Biological Chemistry
Volume272
Issue number48
DOIs
StatePublished - Nov 28 1997
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Liu, L. H., Paul, R. J., Sutliff, R. L., Miller, M. L., Lorenz, J. N., Pun, R. Y. K., Duffy, J. J., Doetschman, T., Kimura, Y., MacLennan, D. H., Hoying, J. B., & Shull, G. E. (1997). Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform. Journal of Biological Chemistry, 272(48), 30538-30545. https://doi.org/10.1074/jbc.272.48.30538