Vascular smooth muscle calcium sparks and sarcoplasmic reticulum calcium load are reduced in women with preeclampsia
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Background
Maternal microvascular dysfunction is a hallmark of the hypertensive pregnancy disorder preeclampsia, but the mechanism(s) have not been defined. Historically, attention has focused on the vascular endothelium, but microvascular function is largely determined by the downstream effector, vascular smooth muscle cells (VSMCs). Within VSMCs, the principal pressure-induced vasodilatory pathway depends upon stimulation of large-conductance Ca 2+ -activated potassium channels (BK Ca ) by localised Ca 2+ -release events from sarcoplasmic reticulum (SR) ryanodine receptors (‘Ca 2+ sparks’). Here, Ca 2+ sparks are assessed in preeclampsia for the first time.
Methods
Pressurised omental resistance arteries from normotensive pregnant women and women with preeclampsia were imaged by high-speed spinning-disk laser confocal microscopy to assess Ca 2+ sparks (20-120 mmHg) and caffeine-evoked Ca 2+ release (10 mmol/L; 80 mmHg). A liquid chromatography–selected reaction monitoring–mass spectrometry (LC-SRM-MS) assay was developed to measure SR Ca 2+ pump Sarcoplasmic/Endoplasmic Reticulum Ca 2+ ATPase 2 (SERCA2) and unphosphorylated/phosphorylated proteoforms of regulatory phospholamban. Vasoactive effects of the BK Ca –dependent vasorelaxant Human β-Defensin-2 (HBD2; 0.01-10 nmol/L) were assessed by wire myography.
Results
Ca 2+ spark frequency was decreased at all intraluminal pressures in women with preeclampsia compared to normotensive pregnancy (p=1.1×10 -10 ). In preeclampsia there was reduced SR Ca 2+ released in response to caffeine (p=5.1×10 -4 ) and the ratio of SERCA2 to inhibitory unphosphorylated phospholamban was decreased (p=0.030), indicating increased SERCA2 inhibition. In arteries from women with preeclampsia, HBD2 (0.01-10 nmol/L) caused BK Ca -dependent relaxation (p=4.6×10 -10 ) without affecting Ca 2+ spark frequency.
Conclusions
In microvascular arteries from women with preeclampsia, there is a striking reduction in Ca 2+ spark frequency, likely secondary to increased inhibition of SERCA2 by unphosphorylated phospholamban and reduced SR Ca 2+ load. These defects may contribute to vascular dysfunction in preeclampsia and present novel therapeutic targets to restore physiological control of the vasculature. Meanwhile, BK Ca -mediated relaxation by HBD2 independent of Ca 2+ sparks supports vasodilatory strategies bypassing disrupted microvascular mechanisms in preeclampsia.
