Serotonin and thromboxane A2 stimulate platelet-derived microparticle-induced smooth muscle cell proliferation

Abstract

Introduction

At the sites of vascular injury, activated and aggregating platelets release small vesiculated structures called platelet microparticles (PMPs). Apart from PMPs they also release several vasoactive mediators including serotonin and thromboxane A₂ (TXA₂). PMPs, serotonin, and TXA₂ have been shown to stimulate vascular smooth muscle cell (VSMC) proliferation. Thus, this study is designed to examine the interaction between PMPs and serotonin or TXA₂ in inducing rabbit VSMC proliferation.

Methods

Growth-arrested rabbit SMCs were incubated in serum-free medium with different concentrations of PMPs with or without serotonin or TXA₂. VSMC proliferation was examined by increase in incorporation of [³H]thymidine into DNA and by increase in cell number.

Results

PMPs stimulated DNA synthesis in a dose-dependent manner; up to an added concentration of 30 μg/ml (1489±90%) they stimulated SMC proliferation in a logarithmic fashion. Serotonin at 50 μM (345±21%) and TXA₂ at 7.5 μM (900±36%) had their maximal effect. When added together, PMPs (10 μg/ml) and serotonin (5 μM), synergistically induced DNA synthesis (581±36% and 211±11% when added alone and 1201±95% when added together), whereas PMPs (10 μg/ml) and TXA₂ (5 μM) additively induced DNA synthesis (581±36% and 781±56% when added alone and 1262±115% when added together). These increases in DNA synthesis were paralleled by increase in cell number.

Conclusion

PMPs, serotonin, and TXA₂ are mitogenic to SMC, and function as amplification factors to each other, suggesting that inhibition of neointimal proliferation after vascular injury may require the combined use of multiple growth factor inhibitors to simultaneously block several critical cellular activation pathways.