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J. Biol. Chem., Vol. 275, Issue 37, 28739-28749, September 15, 2000

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Autocrine Action and Its Underlying Mechanism of Nitric Oxide on Intracellular Ca²⁺ Homeostasis in Vascular Endothelial Cells^*

Jie Chen, Yuepeng Wang, Yue Wang, Toshiaki Nakajima, Kuniaki Iwasawa, Hisako Hikiji^§, Mie Sunamoto^¶, Dong-Kug Choi^**, Yutaka Yoshida, Yoshiyuki Sakaki^**, and Teruhiko Toyo-oka

From the Second Department of Internal Medicine, the ^§ Department of Oral and Maxillofacial Surgery, and the ^** Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 113-0033, Japan, the ^¶ Molecular Chemistry Laboratory, Takeda Chemical Industries, Osaka 532-0024, Japan, and the  Department of Pharmacology, Niigata University, Niigata 951-8122, Japan

The rise in cytosolic Ca²⁺ concentration (Ca²⁺_i) in vascular endothelial cells (ECs) activates the production and release of nitric oxide (NO). NO modifies Ca²⁺_i homeostasis in many types of nonendothelial cells. However, its effect on endothelial Ca²⁺_i homeostasis at basal and excited states remains unclear. In the present study, to elucidate the effect of NO on basal Ca²⁺_i, inositol 1,4,5-trisphosphate-induced Ca²⁺_i release (IICR) was blocked by expressing an antisense against type-1 inositol 1,4,5-trisphosphate receptors or by microinjecting heparin to individual ECs, and the effects of NO that was released by and diffused from adjacent IICR-intact ECs were recorded. After ATP or bradykinin stimulation, IICR-inhibited ECs showed a marked reduction of basal Ca²⁺_i, which was abolished by N^G-monomethyl-L-arginine monoacetate pretreatment. The reduction disappeared in sparsely seeded ECs. Exogenous NO gas mimicked the effect of ATP or bradykinin to reduce basal Ca²⁺_i. Blocking plasma membrane Ca²⁺-ATPase (PMCA), but not Na⁺-Ca²⁺ exchange or sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase, suppressed the reduction, indicating that the reduction resulted from a NO-dependent potentiation of PMCA. To elucidate the effect of NO on elevated Ca²⁺_i, ATP-, bradykinin-, or thapsigargin-evoked Ca²⁺_i response in the presence and absence of NO production was compared in adjacent IICR-intact ECs. NO was found to potentiate PMCA, which, in turn, greatly attenuated agonist-evoked Ca²⁺_i elevation. NO also potentiated Ca²⁺ influx, which markedly increased the sustained phase of Ca²⁺_i elevation and possibly NO production. NO did not affect other Ca²⁺_i-elevating and Ca²⁺_i-sequestrating components. Thus, NO-dependent potentiation of PMCA is crucial for Ca²⁺_i homeostasis over a wide Ca²⁺_i range.

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