Involvement of estrogen receptor and GPER in bisphenol A induced proliferation of vascular smooth muscle cells

Aortic aneurysm (AA) is a common disease that is associated with the proliferation and apoptosis of vascular smooth muscle cells (VSMCs). VSMC cells can be directly exposed to environmental endocrine disruptors (EEDs) such as bisphenol A (BPA). However, the effects of BPA on the biological functions of VSMC are not well studied. Our present study found that nanomolar bisphenol A (BPA) can increase the proliferation of VSMC, which was further evidenced by the results that BPA can increase the expression of proliferating cell nuclear antigen (PCNA). The expression of Angiotensin II (Ang II), which is associated with the proliferation and inflammation of VSMCs, was upregulated after BPA treatment. While losartan, an Ang II receptor antagonist, can attenuate BPA induced cell proliferation, suggesting the essential role of Ang II in BPA induced cell proliferation. BPA treatment can also increase the expression of tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) via an Ang II dependent manner. Both estrogen receptor alpha (ER alpha) and G protein-coupled estrogen receptor (GPER) can be detected in VSMCs. Blocking the functions of ER alpha and GPER by their specific inhibitors can attenuate the BPA induced proliferation of VSMCs and expression of Ang II. Consistently, BPA induced expression of TNF alpha and IL-6 was also attenuated by inhibitors of ER alpha and GPER. BPA can increase the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) though GPER. The inhibitor of ERK1/2 can abolish BPA induced upregulation of Ang II. Collectively, our present study suggested that BPA can trigger the proliferation of VSMCs via both ER alpha and GPER dependent manners.