Abstract 21022: Increasing Cav1.2 in Smooth Muscle Cells Induces Both Systemic and Pulmonary Hypertension via Inhibiting Endothelium-Dependent Relaxation

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Introduction: Local activation of the L-type Ca2+ channel (Cav1.2) in smooth muscle cells (SMCs) may activate big- and small- conductance K+ channels, leading to hyperpolarization of the cell and vascular relaxation; however, large-scale activation of Cav1.2 increases cytosolic Ca2+ to enhance muscle contraction.

Hypothesis: We are testing if and how increasing Cav1.2 in SMCs causes systemic and pulmonary hypertension.

Methods: Systemic blood pressure in conscious mice were measured with telemetric blood pressure system. Intra-ventricular hemodynamics of the LV and RV were determined in 6-month old SMC-specific Cavβ2a transgenic and control mice. Whole heart, LV and the right ventricular (RV) hypertrophy was assessed by heart weight (HW)/body weight (BW), LV weigth/BW, RV weight/BW, and RV-to-left ventricle+septum (RV/LV+S) ratio. Lung and heart sections were stained with H&E. Mesenteric arteries were isolated for evaluating small arterial contractility and relaxation.

Results: SMCs from the cerebral iddle arteries of TG mice had increased ICa (by 98.5±5.4%) vs. control. Conscious TG mice had significantly higher systemic systolic (TG vs. control: 145.4±12.1mmHg, n=45 vs. 115.2±7.4mmHg, n=16 ) and diastolic (TG vs control: 116.7±9.1mmHg, n=45 vs. 87.8±8.2mmHg, n=16) pressure (telemetry). Intra-ventricular hemodynamics (anesthestized) showed significantly increased systolic and diastolic pressure in both the LV (systolic: TG vs control: 120.2±7.3mmHg, n=17 vs. 82.3±7.2mmHg, n=16) and RV (systolic: TG vs control: 60.5±6.8mmHg, n=10 vs. 20.4±4.9mmHg, n=9). HW/BW, LV/BW, RV/BW, and RV/LV+S was higher in TG mice than in control mice. Small arteries in the lungs and the heart had increased wall thickness. Mesenteric arteries from TG mice had similar maximum contractility upon 40mM KCl stimulation. Acetylcholine induced relaxation but not NO-depedent relaxation was impaired in TG mesenteric arteries. Western blot and immunostaining showed less small- and large-conductance Ca2+-activated K+ channels in the TG endothelium.

Conclusions: Excessive calcium ion (Ca2+) influx through L-type Ca2+ channels can lead to both systemic and pulmonary arterial hypertension due to impairment of endothelium-dependent relaxation.

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