Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS

Qi Yuan, Jingyi Yang, Gaetano Santulli, Steven R. Reiken, Anetta Wronska, Mindy M. Kim, Brent W. Osborne, Alain Lacampagne, Yuxin Yin, Andrew R. Marks

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Endothelial cells (ECs) are critical mediators of blood pressure (BP) regulation, primarily via the generation and release of vasorelaxants, including nitric oxide (NO). NO is produced in ECs by endothelial NO synthase (eNOS),which is activated by both calcium(Ca22+)-dependent and independent pathways. Here, we report that intracellular Ca2+ release from the endoplasmic reticulum(ER) via inositol 1,4,5- Trisphosphate receptor (IP3R) is required for Ca22+-dependent eNOS activation. EC-specific type 1 1,4,5- Trisphosphate receptor knockout (IP3R1-/-) mice are hypertensive and display blunted vasodilation in response to acetylcholine (ACh). Moreover, eNOS activity is reduced in both isolated IP3R1-deficient murine ECs and human ECs following IP3R1 knockdown. IP3R1 is upstream of calcineurin, a Ca22+/calmodulinactivated serine/threonine protein phosphatase. We show here that the calcineurin/nuclear factor of activated T cells (NFAT) pathway is less active and eNOS levels are decreased in IP3R1-deficient ECs. Furthermore, the calcineurin inhibitor cyclosporin A, whose use has been associated with the development of hypertension, reduces eNOS activity and vasodilation following ACh stimulation. Our results demonstrate that IP3R1 plays a crucial role in the ECmediated vasorelaxation and the maintenance of normal BP.

Original languageEnglish (US)
Pages (from-to)8532-8537
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number30
DOIs
StatePublished - Jul 26 2016

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Keywords

  • Calcium
  • ENOS
  • Endothelium
  • Hypertension
  • IP3 receptor

ASJC Scopus subject areas

  • General

Cite this

Yuan, Q., Yang, J., Santulli, G., Reiken, S. R., Wronska, A., Kim, M. M., Osborne, B. W., Lacampagne, A., Yin, Y., & Marks, A. R. (2016). Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS. Proceedings of the National Academy of Sciences of the United States of America, 113(30), 8532-8537. https://doi.org/10.1073/pnas.1608859113