Maternal Microvascular Calcium Sparks Are Reduced in Preeclampsia
Luisa C. Parnell, Anna L. Tierney, Elizabeth C. Cottrell, Harry A.T. Pritchard, Matthew N. Smith, Karolina Krakowiak, Richard D. Unwin, Alison M. Gurney, Jenny E. Myers, Adam Greenstein, Stephanie A. WortonBACKGROUND:
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 (
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.