VSMC Ca2+ Signaling in Diabetes Associated Vascular Dysfunction

Abstract

Ca2+ signaling plays a key role in regulating vascular smooth muscle cells (VSMC) contractility and as vascular tone. Hyperglycemia (HG)‐induced vascular dysfunction (VD) (i.e hypertension) is often manifested through alteration of VSMC function. Complex interactions affect vascular tone in diabetes, a fact that makes it difficult to dissect out the specific effect of HG on VSMC contractility. Here we use A7r5 rat aortic VSMC to test the effect of long term exposure to HG on Ca2+ signaling and VSMC contractility. We test the activity and expression levels of all the primary Ca2+ influx and release pathways in these cells, and show that culturing of A7r5 cells in 5mM (low glucose) or 25mM (high glucose, HG) for more than 4 weeks results in significant difference in Ca2+ signaling pathways. While several alterations were noted, one of the most dramatic was the inhibition of the endoplasmic reticulum Ca2+‐ATPase. This inhibition seems to be due to ROS production as evidenced by the reversal of the effect when the cells were cultured for 2 weeks in HG in the presence of the strong antioxidant N‐acetyl‐cysteine. The differential effect of glucose on Ca2+ signaling was also observed on the activity of the plasma membrane Ca2+‐ATPase, while no effect was found on the Na‐Ca2+ exchanger. In summary, this study offers a relevant model for the study of Ca2+ signaling in diabetes associated‐VD using physiological glucose concentration.