Abstract 14618: Cavbeta2a Overexpression in Smooth Muscle Causes Hypertension via Impairment of Acetylcholine-dependent Vascular Relaxation
Introduction: The L-type Calcium channel (Cav1.2) plays an important role in smooth muscle contraction (via providing Ca2+ for contraction and inducing Ca2+ release from the sarcoplasmic reticulum) and relaxation (via activating Ca2+-activated K+ channels). Therefore, it is unclear if enhancing Ca2+ influx through Cav1.2 into vascular smooth muscle cells will cause hypertension or hypotension and what the underlying mechanism is.
Hypothesis: Increasing Ca2+ influx influx into smooth muscle cells causes hypertension through impairing arterial relaxation.
Methods: A transgenic (TG) mouse model with smooth muscle cell specific (SM22-α promoter driven) overexpression of a splicing variant of Cavβ2 subunit, Cavβ2a, tagged with GFP was established and studied.
Results: Immunostaining showed that Cavβ2a-GFP expressed in smooth muscle cells specifically in small arteries and the L-type Ca2+ current in smooth muscle cells from mesenteric arteries of TG mice was significantly increased (5.1±0.7pA/pF in TG, n=12 vs. 2.2±0.5pA/pF in control, n=10). Smooth muscle myocytes with Cavβ2a-GFP overexpression had increased Ca2+ spark frequency. Telemetric blood pressure measurement showed that 24h-averaged systolic pressure was significantly increased (135.2±9.8mmHg, n=25) compared to that of that of control c57bl/6 mice (110.2±7.8mmHg, n=16). The diastolic pressure was also significantly elevated in TG mice than in control mice. Maximum contractility of mesenteric arteries measured with 40mM KCl was not different between control and TG groups. Sodium nitroprusside relaxed the phenylephrine-precontracted mesenteric artery in the same dose-dependent manner. However, acetylcholine induced mesenteric artery relaxation was significantly impaired in TG mesenteric arteries.
Conclusions: Increasing Ca2+ influx through Cav1.2 in smooth muscle cells causes hypertension via impairment of acetylcholine-dependent relaxation but not through enhancing myocyte contractility, suggesting an interplay between the smooth muscle cell layer and endothelium regulated by smooth muscle cell Ca2+ in blood pressure control.
Author Disclosures: X. Zhang: None. Z. Cheng: None. X. Ai: None. M. Tang: None. X. Hua: None. S.R. Houser: None. M.F. Navedo: None. L.F. Santana: None. H. Wang: None. X. Chen: None.
- © 2016 by American Heart Association, Inc.