title: Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS.
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 (Ca(2+))-dependent and independent pathways. Here, we report that intracellular Ca(2+) release from the endoplasmic reticulum (ER) via inositol 1,4,5-trisphosphate receptor (IP3R) is required for Ca(2+)-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 Ca(2+)/calmodulin-activated 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 EC-mediated vasorelaxation and the maintenance of normal BP.
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032;
authors.forename: Qi
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;
authors.forename: Jingyi
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; gs2620@cumc.columbia.edu yinyuxin@hsc.pku.edu.cn arm42@columbia.edu.
authors.forename: Gaetano
authors.identifier: 0000-0001-7231-375X
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032;
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032;
authors.forename: Anetta
authors.initials: A
authors.lastname: Wronska
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032;
authors.forename: Mindy M
authors.initials: MM
authors.lastname: Kim
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032;
authors.forename: Brent W
authors.initials: BW
authors.lastname: Osborne
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; INSERM U1046, CNRS UMR-9214, Université de Montpellier, 34295 Montpellier, France;
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; gs2620@cumc.columbia.edu yinyuxin@hsc.pku.edu.cn arm42@columbia.edu.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY 10032; Department of Medicine, Columbia University, New York, NY 10032 gs2620@cumc.columbia.edu yinyuxin@hsc.pku.edu.cn arm42@columbia.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000235:genetics; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine
keywords: IP3 receptor; calcium; eNOS; endothelium; hypertension