Maternal Microvascular Calcium Sparks Are Reduced in Preeclampsia

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 Ca²⁺-release events from the sarcoplasmic reticulum ryanodine receptors (Ca²⁺ sparks), which stimulate BK_Ca (large-conductance Ca²⁺-activated potassium channels) to cause spontaneous transient outward currents and vasorelaxation. Here, the Ca²⁺ sparks-BK_Ca axis is assessed in preeclampsia for the first time.

Pressurized omental resistance arteries from normotensive pregnant women and women with preeclampsia were imaged by high-speed spinning-disk laser confocal microscopy to assess Ca²⁺ sparks (20-110 mm Hg) and caffeine-evoked Ca²⁺ 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 Ca²⁺-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.

In microvascular arteries from women with preeclampsia, there was reduced Ca²⁺ spark frequency (P=1.1×10^-10) and spontaneous transient outward current frequency (P=0.023). There was also reduced sarcoplasmic reticulum Ca²⁺ 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 Ca²⁺ spark frequency.

In microvascular arteries from women with preeclampsia, there is a striking reduction in Ca²⁺ spark frequency and spontaneous transient outward currents, likely secondary to increased inhibition of SERCA2 by unphosphorylated PLN and reduced sarcoplasmic reticulum Ca²⁺ load. These defects may provide novel therapeutic targets to restore physiological control of the vasculature. BK_Ca-mediated relaxation by HBD2 was independent of Ca²⁺ sparks, supporting vasodilatory strategies bypassing disrupted microvascular mechanisms in preeclampsia.