BACKGROUND: Vascular remodeling, that contributes to cardiovascular diseases such as hypertension develops by anomalous proliferation and migration of vascular smooth muscle cells (VSMCs). Cortistatin (CST), a newly discovered biological peptide, has been acknowledged for its protective effects against cardiovascular diseases. Whether CST has an inhibitory regulation role in angiotensin II (Ang II)-induced proliferation and migration of VSMCs and what molecular mechanisms may participate in the CST inhibition process are still unknown. METHODS: VSMCs were divided into control group, Ang II (10 M) group, Ang II + PD98059 (5×10 M) group, Ang II + SB203580 (10 M) group, Ang II + SP600125 (10 M) group, Ang II + XMD17-109 (10 M) group, Ang II + CST (10 M) group and Ang II + CST (10 M) group. Cell proliferation was detected by western blotting and cell counting kit-8 (CCK8) analysis. Migration of VSMCs was measured by Transwell assay. RESULTS: Compared with control group, Ang II upregulated the expression levels of proliferating cell nuclear antigen (PCNA) and osteopontin (OPN) and downregulated that of α-smooth muscle actin (α-SMA), increased the proliferation rate as shown by CCK8 and VSMC migration as shown by Transwell assay in cultured VSMCs of the Ang II group. Meanwhile, in Ang II-cultured VSMCs, we found activation of extracellular signal-regulated kinase (ERK) 1/2, p38 MAP kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and ERK5 pathways by western blotting at different time points. However, the proliferation and migration stimulated by Ang II were partly reversed by drug inhibitors of the four pathways, namely, PD98059, SB203580, SP600125 and XMD17-109. When Ang II-stimulated VSMCs were cultured with CST pretreatment, we found that proliferation and migration were greatly suppressed as well as that the ERK1/2, p38 MAPK, JNK and ERK5 pathways were deactivated by CST. CONCLUSIONS: The accumulated data suggest that CST may play a protective role in Ang II-promoted proliferation and migration of VSMCs via inhibiting the mitogen-activated protein kinase (MAPK) family pathways, providing a new orientation of CST in protecting against cardiovascular diseases.