<b>Docosahexaenoic acid suppresses angiotensin II-induced A7r5 vascular smooth muscle cell proliferation and migration under pulsatile pressure str</b><b>ess </b>

Abstract

Elevated mechanical stress applied to vascular walls is well known to modulate vascular remodeling and plays a part in the pathogenesis of atherosclerosis. On the other hand, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has been shown to protect against several types of cardiovascular diseases including atherosclerosis and hypertension. The aim of this study was to clarify the effect of pulsatile pressure stress and DHA on angiotensin II-induced proliferation and migration in A7r5 vascular smooth muscle cells (VSMCs). Pulsatile pressure of between 80 and 160 mmHg was repeatedly applied to VSMCs at a frequency of 4 cycles per min using an apparatus that we developed. Cell proliferation and migration were evaluated using a live cell movie analyzer. Application of pulsatile pressure stress for 24 h significantly increased cell proliferation. Angiotensin II also significantly increased cell proliferation in the presence or absence of pressure stress. DHA significantly inhibited angiotensin II-induced cell proliferation regardless of the pressure load. Angiotensin II significantly induced cell migration regardless of the pulsatile pressure load. Pulsatile pressure stress alone slightly, but not significantly, induced cell migration. DHA inhibited angiotensin II-induced VSMC proliferation and migration under abnormal pressure conditions. Pressure stress tended to induce extracellular signal-regulated kinase (ERK) phosphorylation in the absence of angiotensin II, whereas it significantly induced ERK phosphorylation in the presence of angiotensin II. However, the pressure-induced ERK phosphorylation was not observed in the DHA-treated VSMCs. Our findings may contribute to the understanding of the beneficial effect of DHA on various cardiovascular disorders.Although the normal mechanical stress applied to vascular walls contributes to the maintenance of vascular homeostasis, excessive stress is well known to modulate vascular remodeling and plays a role in the pathogenesis of atherosclerosis. The mechanical factors applied to vascular walls can be divided into the following three factors: stretch, shear stress, and pressure. While shear stress mainly affects vascular endothelial cells, pressure mainly acts on vascular smooth muscle cells (VSMCs). We previously demonstrated that static and pulsatile mechanical pressure stresses, which simulate systolic hypertension, promote proliferation of cultured human VSMCs (13,14). Excessive proliferation of VSMCs is also induced by various cytokines and growth factors, such as angiotensin II and platelet-derived growth factors (34). In particular, a number of studies have revealed the mechanisms of VSMC proliferation and migration induced by angiotensin II (19,26). The renin-angiotensin system is known to exist not only in the circulation but also in local tissues including