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ORIGINAL ARTICLE

Differential Mechanisms of Ca²⁺ Release from Vascular Smooth Muscle Cell Microsomes

Renal Pathophysiology Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Mayo Medical School, Rochester, Minnesota 55905

The release of Ca²⁺ from intracellular stores is a fundamental element of signaling pathways involved in regulation of vascular tone, proliferation, apoptosis, and gene expression. Studies of sea urchin eggs have led to the identification of three functionally distinct Ca²⁺ signaling pathways triggered by IP₃, cADPR, and NAADP. The coexistence and functional relevance of these distinct intracellular Ca²⁺ release systems has only been described in a few mammalian cell types. The purpose of this study was to determine whether the IP₃, cADPR, and NAADP Ca²⁺ release systems coexist in smooth muscle cells (SMC) and to determine the specificity of these intracellular Ca²⁺ release pathways. Microsomes were prepared from rat aortic SMC (VSMC) and were loaded with ⁴⁵Ca²⁺. cADPR, NAADP, and IP₃ induced Ca²⁺ release from VSMC microsomes in a dose-dependent fashion. Heparin blocked only IP₃-mediated Ca²⁺ release, whereas the ryanodine channel inhibitors 8-Br-cADPR and ruthenium red blocked only cADPR-induced Ca²⁺ release. Nifedipine, an L-type Ca²⁺ channel blocker, inhibited NAADP elicited Ca²⁺ release, but had no effect on IP₃- or cADPR-mediated Ca²⁺ release. An increase in pH from 7.2 to 8.2 inhibited cADPR-mediated Ca²⁺ release, but had no effect on IP₃- or NAADP-induced Ca²⁺ release. By RT-PCR, VSMC expressed ryanodine receptor types 1, 2, and 3. Ca²⁺-dependent binding of [³H]-ryanodine to VSMC microsomes was enhanced by the ryanodine receptor agonists 4-chloro-methyl-phenol (CMP) and caffeine, but was inhibited by ruthenium red and cADPR. We conclude that VSMC possess at least three functionally distinct pathways that promote intracellular Ca²⁺ release. IP₃-, cADPR-, and NAADP-induced intracellular Ca²⁺ release may play a critical role in the maladaptive responses of VSMC to environmental stimuli that are characteristically associated with hypertension and/or atherogenesis.

Key Words: vascular smooth muscle • inositol-1,4,5-trisphosphate (IP₃) • cyclic ADP-ribose (cADPR) • nicotinic acid-adenine dinucleotide phosphate (NAADP) • calcium (Ca⁺⁺)

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