Maternal Microvascular Calcium Sparks Are Reduced in Preeclampsia

BACKGROUND: Maternal microvascular dysfunction is a hallmark of the hypertensive pregnancy disorder preeclampsia, but the mechanism(s) have not been fully defined. Within vascular smooth muscle cells, the principal pressure-induced vasodilatory pathway depends on localized Ca 2+ -release events from the sarcoplasmic reticulum ryanodine receptors (Ca 2+ sparks), which stimulate BK Ca (large-conductance Ca 2+ -activated potassium channels) to cause spontaneous transient outward currents and vasorelaxation. Here, the Ca 2+ sparks–BK Ca axis is assessed in preeclampsia for the first time. METHODS: Pressurized 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 (20–110 mm Hg) and caffeine-evoked Ca 2+ release (10 mmol/L; 80 mm Hg). Electrophysiology was used to assess spontaneous transient outward currents (−60 to 0 mV) and BK Ca currents (−100 to +100 mV) in isolated vascular smooth muscle cells. A liquid chromatography–selected reaction monitoring–tandem mass spectrometry assay measured SERCA2 (sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase-2) and unphosphorylated/phosphorylated proteoforms of regulatory PLN (phospholamban). Vasoactive effects of the BK Ca -dependent vasorelaxant HBD2 (human β-defensin-2; 0.01–10 nmol/L) were assessed by wire myography. RESULTS: In microvascular arteries from women with preeclampsia, there was reduced Ca 2+ spark frequency ( P =1.1×10 − 10 ) and spontaneous transient outward current frequency ( P =0.023). There was also reduced sarcoplasmic reticulum Ca 2+ release in response to caffeine ( P =0.0013), reduced sarcoplasmic reticulum refilling ( P =2.0×10 − 4 ), and decreased ratio of SERCA2 to inhibitory unphosphorylated PLN ( P =0.030), implicating increased SERCA2 inhibition. HBD2 (0.01–10 nmol/L) caused BK Ca -dependent relaxation ( P =4.6×10 − 10 ) of omental arteries without affecting Ca 2+ spark frequency. CONCLUSIONS: In microvascular arteries from women with preeclampsia, there is a striking reduction in Ca 2+ spark frequency and spontaneous transient outward currents, likely secondary to increased inhibition of SERCA2 by unphosphorylated PLN and reduced sarcoplasmic reticulum Ca 2+ load. These defects may provide novel therapeutic targets to restore physiological control of the vasculature. BK Ca -mediated relaxation by HBD2 was independent of Ca 2+ sparks, supporting vasodilatory strategies bypassing disrupted microvascular mechanisms in preeclampsia.