Am. J. Respir. Cell Mol. Biol., Volume 20, Number 4, April, 1999 658-666

Estrogen Acutely Stimulates Endothelial Nitric Oxide Synthase in H441 Human Airway Epithelial Cells

Erica A. Kirsch, Ivan S. Yuhanna, Zhong Chen, Zohre German, Todd S. Sherman, and Philip W. Shaul

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas

Nitric oxide (NO) is an important mediator of physiologic processes in the airway. Levels of exhaled NO are greatest and asthma symptoms are least in menstruating women during midcycle, when estrogen levels are highest. To better understand the role of estrogen in airway function, we tested the hypothesis that estrogen stimulates endothelial NO synthase (eNOS) in NCI-H441 human bronchiolar epithelial cells. eNOS activation was assessed by measuring conversion of [³H]L-arginine to [³H]L-citrulline in intact cells. eNOS activity rose in the presence of estradiol-17 (E₂), with a maximum stimulation of 243% at 10⁸ M E₂. This response was comparable to the 201% increase elicited by the calcium (Ca²⁺) ionophore A23187 (10⁵ M), and was evident as early as 5 min after such treatment. Actinomycin D had no effect on the response to E₂, and eNOS abundance was similar in control and E₂-treated cells. E₂-stimulated eNOS activity was dependent on the influx of extracellular Ca²⁺, and was completely inhibited by the estrogen receptor (ER) antagonist ICI182,780. Messenger RNA and protein for the  isoform of ER (ER) were evident in the H441 cells, and freshly isolated ovine airway epithelial cells also coexpressed eNOS and ER. These findings indicate that estrogen acutely activates existing eNOS in H441 airway epithelial cells, through a process that involves the stimulation of epithelial ER and Ca²⁺ influx. This process may play a role in the hormonal modulation of airway function.

This article has been cited by other articles:

				F Gomez Real, C Svanes, E H Bjornsson, K Franklin, D Gislason, T Gislason, A Gulsvik, C Janson, R Jogi, T Kiserud, et al. Hormone replacement therapy, body mass index and asthma in perimenopausal women: a cross sectional survey Thorax, January 1, 2006; 61(1): 34 - 40. [Abstract] [Full Text] [PDF]

				O. K. Weinberg, D. C. Marquez-Garban, M. C. Fishbein, L. Goodglick, H. J. Garban, S. M. Dubinett, and R. J. Pietras Aromatase Inhibitors in Human Lung Cancer Therapy Cancer Res., December 15, 2005; 65(24): 11287 - 11291. [Abstract] [Full Text] [PDF]

				T. Murata, M. Hori, K. Sakamoto, H. Karaki, and H. Ozaki Dexamethasone Blocks Hypoxia-induced Endothelial Dysfunction in Organ-cultured Pulmonary Arteries Am. J. Respir. Crit. Care Med., September 15, 2004; 170(6): 647 - 655. [Abstract] [Full Text] [PDF]

				F. L. M. Ricciardolo, P. J. Sterk, B. Gaston, and G. Folkerts Nitric Oxide in Health and Disease of the Respiratory System Physiol Rev, July 1, 2004; 84(3): 731 - 765. [Abstract] [Full Text] [PDF]

				R. G. Barr, C. C. Wentowski, F. Grodstein, S. C. Somers, M. J. Stampfer, J. Schwartz, F. E. Speizer, and C. A. Camargo Jr Prospective Study of Postmenopausal Hormone Use and Newly Diagnosed Asthma and Chronic Obstructive Pulmonary Disease Arch Intern Med, February 23, 2004; 164(4): 379 - 386. [Abstract] [Full Text] [PDF]

				K. S. van's Gravesande, M. E. Wechsler, H. Grasemann, E. S. Silverman, L. Le, L. J. Palmer, and J. M. Drazen Association of a Missense Mutation in the NOS3 Gene with Exhaled Nitric Oxide Levels Am. J. Respir. Crit. Care Med., July 15, 2003; 168(2): 228 - 231. [Abstract] [Full Text] [PDF]

				H. Grasemann, K. S. van's Gravesande, R. Buscher, J. M. Drazen, and F. Ratjen Effects of Sex and of Gene Variants in Constitutive Nitric Oxide Synthases on Exhaled Nitric Oxide Am. J. Respir. Crit. Care Med., April 15, 2003; 167(8): 1113 - 1116. [Abstract] [Full Text] [PDF]

				H. Grasemann, K. S. van's Gravesande, R. Buscher, N. Knauer, E. S. Silverman, L. J. Palmer, J. M. Drazen, and F. Ratjen Endothelial Nitric Oxide Synthase Variants in Cystic Fibrosis Lung Disease Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 390 - 394. [Abstract] [Full Text] [PDF]

				M. P. Haynes, L. Li, D. Sinha, K. S. Russell, K. Hisamoto, R. Baron, M. Collinge, W. C. Sessa, and J. R. Bender Src Kinase Mediates Phosphatidylinositol 3-Kinase/Akt-dependent Rapid Endothelial Nitric-oxide Synthase Activation by Estrogen J. Biol. Chem., January 17, 2003; 278(4): 2118 - 2123. [Abstract] [Full Text] [PDF]

				K. L. Chambliss and P. W. Shaul Estrogen Modulation of Endothelial Nitric Oxide Synthase Endocr. Rev., October 1, 2002; 23(5): 665 - 686. [Abstract] [Full Text] [PDF]

				J. L. Mershon, R. S. Baker, and K. E. Clark Estrogen increases iNOS expression in the ovine coronary artery Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1169 - H1180. [Abstract] [Full Text] [PDF]

				S. Premaratne, C. Xue, J. M. McCarty, M. Zaki, R. W. McCuen, R. A. Johns, W. Schepp, B. Neu, R. Lippman, P. D. Melone, et al. Neuronal nitric oxide synthase: expression in rat parietal cells Am J Physiol Gastrointest Liver Physiol, February 1, 2001; 280(2): G308 - G313. [Abstract] [Full Text] [PDF]

				M. P. Haynes, D. Sinha, K. S. Russell, M. Collinge, D. Fulton, M. Morales-Ruiz, W. C. Sessa, and J. R. Bender Membrane Estrogen Receptor Engagement Activates Endothelial Nitric Oxide Synthase via the PI3-Kinase-Akt Pathway in Human Endothelial Cells Circ. Res., October 13, 2000; 87(8): 677 - 682. [Abstract] [Full Text] [PDF]

				J.J.D. Lucca, A.S.O. Adeagbo, and N.L. Alsip Influence of oestrous cycle and pregnancy on the reactivity of the rat mesenteric vascular bed Hum. Reprod., April 1, 2000; 15(4): 961 - 968. [Abstract] [Full Text] [PDF]

				L. B. Lutz, B. Kim, D. Jahani, and S. R. Hammes G Protein beta gamma Subunits Inhibit Nongenomic Progesterone-induced Signaling and Maturation in Xenopus laevis Oocytes. EVIDENCE FOR A RELEASE OF INHIBITION MECHANISM FOR CELL CYCLE PROGRESSION J. Biol. Chem., December 22, 2000; 275(52): 41512 - 41520. [Abstract] [Full Text] [PDF]