Stressful Signaling: A Role for Endoplasmic Reticulum Stress in Aortic Stiffening During Hypertension

Abstract

Aortic stiffening is an independent predictor of negative cardiovascular outcomes and is associated with an increased risk of hypertension. Vascular smooth muscle cell (VSMC) apoptosis, collagen synthesis and contractility contribute to aortic stiffening. A cellular signaling mechanism contributing to apoptotic and fibrotic events is endoplasmic reticulum (ER) stress. We tested the hypothesis that ER stress induction with tunicamycin (TM), in primary aortic VSMCs, would cause apoptosis and collagen synthesis; additionally, inhibition of ER stress using chemical chaperones, tauroursodeoxycholic acid (TUDCA) or 4-phenylbutyric acid (PBA) in VSMCs treated with angiotensin II (Ang II), a pro-apoptotic/fibrotic agent, will prevent VSMC apoptosis and fibrosis. We demonstrated that: ER stress induces VSMC apoptosis and collagen synthesis and pharmacological inhibition of ER stress inhibits Ang II-induced VSMC apoptosis and collagen synthesis. We next hypothesized that induction of ER stress with TM in a normotensive rat would cause pro-fibrotic and apoptotic signaling contributing to aortic stiffening. Furthermore, we hypothesized that inhibition of ER stress in an Ang II hypertensive rat would improve aortic stiffening. TM-treated Sprague Dawley rats (SD, 10 μg/kg/day, 28 days) caused an increase in systolic blood pressure compared to vehicle-treated or TM-treated rats that were co-treated with ER stress inhibitor PBA, (100 mg/kg/day, 28 days) There was an increase in aortic apoptosis, collagen content and fibrosis in the TM-treated rats compared to vehicle-treated rats. Inhibition of ER stress in male SD rats given Ang II (60 ng/min, 28 days) and treated with either TUDCA or PBA (100 mg/kg/day, 28 days) led to a 20 mmHg decrease in blood pressure with either inhibitor, compared to Ang II treatment alone. Aortic apoptosis, increased collagen content and fibrosis in Ang II-treated rats were attenuated with ER stress inhibition. The results suggest that the ER stress response in the aorta could be a new mechanism through which hypertensive stimuli, such as Ang II, mediated aortic stiffening.