Angiotensin II and serotonin potentiate endothelin-1-induced vascular smooth muscle cell proliferation

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Abstract
Vascular smooth muscle cell (VSMC) proliferation induced by various growth factors has been implicated in a wide variety of pathological processes, including hypertension, atherosclerosis and restenosis after angioplasty. To investigate the interactions among well-known potent vasoconstrictor substances, endothelin-1 (ET-1), angiotensin II (Ang II), and serotonin (5-HT), on VSMC proliferation. Growth-arrested rabbit VSMCs were incubated with different concentrations of ET-1 in the absence or presence of Ang II, 5-HT, or both. VSMC proliferation was examined by increases in incorporation of [3H]thymidine into DNA and in cell number. ET-1, Ang II and 5-HT stimulated DNA synthesis in a dose-dependent manner. ET-1 had a maximal effect at a concentration of 0.5 μmol/l (259% of control), Ang II at 1 μmol/l (173%), and 5-HT at 50 μmol/l (205%). When added together, ET-1 (0.1 μmol/l) and Ang II (1 μmol/l) synergistically induced DNA synthesis (341%). When the vasoconstrictors were tested in combination, even non-mitogenic concentrations of ET-1 (0.01 nmol/l) potentiated 5-HT (5 μmol/l)-induced DNA synthesis (404%). Co-incubation of ET-1 (0.01 μmol/l) with Ang II (1 μmol/l) and 5-HT (5 μmol/l) synergistically induced DNA synthesis (566%). These effects on DNA synthesis were paralleled by an increase in cell number. The ETA/B non-selective receptor antagonist, TAK044 (1 μmol/l) and the ETA receptor antagonist, BQ123 (1 μmol/l), but not the ETB receptor antagonist, BQ788 (1 μmol/l), inhibited the mitogenic effect of ET-1 and its interaction with Ang II or 5-HT. In addition, TAK044 (1 μmol/l) or BQ123 (1 μmol/l) along with the angiotensin II type 1 (AT1) receptor antagonist, candesartan (1 μmol/l), the 5-HT2A receptor antagonist, sarpogrelate (10 μmol/l), or both, inhibited the interactions of ET-1 with Ang II or 5-HT. Our results suggest that Ang II and 5-HT could potentiate ET-1-induced VSMC proliferation. Inhibition of ETA, AT1, and 5-HT2A may be effective in the treatment of VSMC proliferative disorders associated with hypertension, atherosclerosis and restenosis after angioplasty.