Dual Functionality of Cyclooxygenase-2 as a Regulator of Tumor Necrosis Factor–Mediated G 1 Shortening and Nitric Oxide–Mediated Inhibition of Vascular Smooth Muscle Cell Proliferation

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Abstract
Background— Cyclooxygenase (COX)-2 contributes to vascular smooth muscle cell (VSMC) proliferation induced by tumor necrosis factor (TNF) and angiotensin II. The present study demonstrates, however, that depending on prevailing conditions, COX-2–derived prostanoids may also inhibit VSMC proliferation. Methods and Results— TNF-α stimulated proliferation of VSMCs by shortening the G 1 phase of the cell cycle. This effect was abolished by NS-398, a selective COX-2 inhibitor. Addition of TNF did not affect the protein-to-DNA ratio, measured by flow cytometry, suggesting that TNF does not induce VSMC hypertrophy. Inhibition of nitric oxide synthase (NOS) activity attenuated TNF-mediated increases in prostaglandin (PG) I 2 synthesis, whereas thromboxane (TX) A 2 production and COX-2 protein expression were unaffected. Moreover, inhibition of NOS activity increased TNF-mediated proliferation by ≈23%. Thus, NO preferentially stimulates PGI 2 production, suggesting that production of NO by VSMCs challenged with TNF limits the ability of the cytokine to increase proliferation. NO donors increased COX-2 protein expression and PGI 2 synthesis, had no effect on TXA 2 production, and decreased cell numbers by 50%, indicating that expression of COX-2 per se might not be sufficient to support proliferation. The effects of NO donors were prevented when COX-2 activity was inhibited with NS-398. Conclusions— The COX-2–dependent proliferative response of VSMCs to TNF was modulated in an NO-dependent manner, and PGI 2 derived from COX-2 might contribute to the antiproliferative effect of NO donors.