Calcium/Calmodulin‐Dependent Kinase II Inhibition in Smooth Muscle Reduces Angiotensin II–Induced Hypertension by Controlling Aortic Remodeling and Baroreceptor Function

Abstract

BackgroundMultifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by angiotensin II (Ang II) in cultured vascular smooth muscle cells (VSMCs), but its function in experimental hypertension has not been explored. The aim of this study was to determine the impact of CaMKII inhibition selectively in VSMCs on Ang II hypertension.Methods and ResultsTransgenic expression of a CaMKII peptide inhibitor in VSMCs (TG SM-CaMKIIN model) reduced the blood pressure response to chronic Ang II infusion. The aortic depressor nerve activity was reset in hypertensive versus normotensive wild-type animals but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor activity account for the blood pressure difference between genotypes. Accordingly, aortic pulse wave velocity, a measure of arterial wall stiffness and a determinant of baroreceptor activity, increased in hypertensive versus normotensive wild-type animals but did not change in TG SM-CaMKIIN mice. Moreover, examination of blood pressure and heart rate under ganglionic blockade revealed that VSMC CaMKII inhibition abolished the augmented efferent sympathetic outflow and renal and splanchnic nerve activity in Ang II hypertension. Consequently, we hypothesized that VSMC CaMKII controls baroreceptor activity by modifying arterial wall remodeling in Ang II hypertension. Gene expression analysis in aortas from normotensive and Ang II–infused mice revealed that TG SM-CaMKIIN aortas were protected from Ang II–induced upregulation of genes that control extracellular matrix production, including collagen. VSMC CaMKII inhibition also strongly altered the expression of muscle contractile genes under Ang II.ConclusionsCaMKII in VSMCs regulates blood pressure under Ang II hypertension by controlling structural gene expression, wall stiffness, and baroreceptor activity.

Role of CaMKII in Ang-II-dependent small artery remodeling

“…Here, we report that remodeling and constriction are concordantly increased with CaMKII inhibition. These data are not in agreement with the concept proposed by Folkow given that we previously reported that blood pressure is lower in TG SM-CaMKIIN mice following chronic Ang-II infusion as compared to WT mice [23]. However, other studies have emerged that that do not align with this concept [25].…”

“…Chronic subcutaneous infusion of Ang-II (1.25 μg/kg/min, Anaspec) was performed using Alzet osmotic mini-pumps (model 1002, DURECT Corporation) as we previously reported [23]. …”

“…In this model, under baseline conditions, CaMKII inhibition in VSMC decreases intracellular and sarcoplasmic reticulum Ca 2+ levels without significantly affecting vasoconstriction or vascular structure [22]. However, after chronic Ang-II infusion, CaMKII inhibition reduces blood pressure, prevents of aortic stiffening and blunts splanchnic and renal nerve activity [23]. …”

“…However, data have emerged that do not align with this concept [25]. In our previous work, we assessed aortic vasoconstriction in hypertensive mice and unexpectedly detected no decrease in constriction with CaMKII inhibition [23]. Since the vascular tone of mesenteric arteries is important for blood pressure increases under chronic Ang-II infusion [26], these previous findings prompted us to investigate how CaMKII inhibition selectively in VSMC affects remodeling of mesenteric arteries following Ang-II infusion in vivo.…”

Oxidant stress promotes disease by activating CaMKII

“…Using an elegant genetic mouse model with vascular smooth muscle targeted CaMKII inhibition, the Grumbach group found that CaMKII activity contributes to the angiotensin II mediated hypertensive response in vivo, where it influences a complex and interconnected series of central and peripheral activities [52]. CaMKII is known to promote vascular smooth muscle hypertrophy [53] but this remodeling process is also affected by vascular smooth muscle death and migration.…”