Insulin-Mediated Growth in Aortic Smooth Muscle and the Vascular Renin-Angiotensin System

Abstract

Abstract —Insulin has been shown to directly affect blood vessel tone and to promote vascular hypertrophy, but the mechanism of these actions remains uncertain. Because angiotensin I (Ang I)–converting enzyme inhibitors have been shown to improve insulin action and to impede the progression of vascular hypertrophy in hypertensive animal models, it is possible that the vascular properties of insulin may be mediated through the tissue renin-angiotensin system (RAS). To evaluate this relationship, we first investigated the effect of insulin on components of the RAS using cultured rat vascular smooth muscle cells (VSMCs). Insulin treatment (1000 μU/mL) markedly increased angiotensinogen mRNA expression and angiotensinogen production. We next investigated the role of the RAS in insulin-mediated cell proliferation, using [ 3 H]thymidine uptake. Studies were done both with insulin alone and in the presence of captopril (1×10 −7 to 10 −5 mol/L) and losartan (1×10 −9 to 10 −7 mol/L). [ 3 H]Thymidine uptake was increased significantly by 1000 μU/mL insulin, and this stimulation was reduced by 1×10 −6 mol/L captopril (−38.8%, P <0.05) and by 1×10 −8 mol/L losartan (−37.5%, P <0.05). Further studies showed that the degree of insulin-mediated [ 3 H]thymidine uptake in VSMCs could be duplicated by 4×10 −10 mol/L Ang II. Losartan reduced the effects of both Ang II and insulin on [ 3 H]thymidine uptake by about 40% to 45% of baseline ( P <0.05). Captopril reduced insulin-mediated [ 3 H]thymidine uptake but did not affect Ang II–mediated [ 3 H]thymidine uptake. In summary, insulin induced significant stimulation of angiotensinogen expression and production and stimulated growth similar to that seen with Ang II in cultured rat VSMCs. Inhibition of Ang II production or its binding to the Ang II type 1 (AT 1 ) receptor inhibited insulin-mediated growth in a fashion similar to that seen with inhibition of Ang II–mediated growth. Thus, insulin can modulate the vascular RAS, and the effect of insulin on vascular growth may be via direct effects on angiotensinogen expression and translation operative through both the AT 1 receptor and the conversion of Ang I to Ang II.