Arterial Smooth Muscle Cell AKAP150 Mediates Exercise-Induced Repression of CaV1.2 Channel Function in Cerebral Arteries of Hypertensive Rats

Abstract

Background: Hypertension is a major, prevalent risk factor for the development and progression of cerebrovascular disease. Regular exercise has been recommended as an excellent choice for the large population of individuals with mild-to-moderate elevations in blood pressure, but the mechanisms that underlie its vascular-protective and antihypertensive effects remain unknown. Here, we describe a mechanism by which myocyte AKAP150 (A-kinase anchoring protein 150) inhibition induced by exercise training alleviates voltage-dependent L-type Ca²⁺ channel (Ca_V1.2) activity and restores cerebral arterial function in hypertension.

Methods: Spontaneously hypertensive rats and newly generated smooth muscle-specific AKAP150 knockin mice were used to assess the role of myocyte AKAP150/Ca_V1.2 channel in regulating cerebral artery function after exercise intervention.

Results: Activation of the AKAP150/PKCα (protein kinase Cα) signaling increased Ca_V1.2 activity and Ca²⁺ influx of cerebral arterial myocyte, thus enhancing vascular tone in spontaneously hypertensive rats. Smooth muscle-specific AKAP150 knockin mice were hypertensive with higher Ca_V1.2 channel activity and increased vascular tone. Furthermore, treatment of Ang II (angiotensin II) resulted in a more pronounced increase in blood pressure in smooth muscle-specific AKAP150 knockin mice. Exercise training significantly reduced arterial myocyte AKAP150 expression and alleviated Ca_V1.2 channel activity, thus restoring cerebral arterial function in spontaneously hypertensive rats and smooth muscle-specific AKAP150 knockin mice. AT₁R (AT₁ receptor) and AKAP150 were interacted closely in arterial myocytes. Exercise decreased the circulating Ang II and Ang II-involved AT₁R-AKAP150 association in myocytes of hypertension.

Conclusions: The current study demonstrates that aerobic exercise ameliorates Ca_V1.2 channel function via inhibiting myocyte AKAP150, which contributes to reduced cerebral arterial tone in hypertension.

Keywords: AKAP150; aerobic; cerebral arteries; exercise; hypertension.