Role of the RAGE signal pathway in the synergistic effects of cyclic stretch stress and AGEs on ERK activation and proliferation in VSMCs.
Increased blood pressure can trigger rapid increases in mechanical stretching on the walls of vein grafts. Stretch stress causes deformation of the vascular cells (VSMCs) and non-specifically activates RAGE and its downstream signal molecules, such as ERK, leading to over-proliferation (Ki-67 expression) of the vascular cells. Hyperglycemia can produce numerous AGEs. These modified proteins are deposited on the vascular wall, where they directly and specifically interact with RAGE and activate intracellular signaling molecules, altering vascular structure and function. Blocking RAGE and its downstream molecules may inhibit the synergistically accelerated vascular remodeling induced by hypertension-stretch stress with and without AGEs. Further investigations may provide new targets for drug development and new strategies for the treatment and prevention of vascular diseases, such as atherosclerosis, in diabetic patients.