Altered Ca2+ signalling underlying maternal microvascular dysfunction in pre eclampsia

The hypertensive pregnancy complication pre-eclampsia is characterised by increased systemic vascular resistance and impaired endothelium-dependent relaxation, but specific microvascular mechanisms remain undefined. Highly-regulated, Ca2+ signals in both the vascular smooth muscle cell (VSMC; ‘Ca2+ sparks’) and endothelium (‘Ca2+ pulsars’) regulate myogenic tone and endothelium-dependent relaxation, yet these Ca2+ signals have not been investigated in human pre-eclampsia. Pilot data indicate markedly reduced Ca2+ sparks and possible absence of endothelial Ca2+ pulsars in pre-eclampsia, leading to the hypothesis that dysfunctional Ca2+ signaling in both VSMCs and endothelial cells governs impaired arterial relaxation in pre-eclampsia. Using omental arteries from pregnant women with uncomplicated pregnancy and pre-eclampsia, I will combine high-speed spinning-disk laser confocal microscopy, myography, electrophysiology and mass spectrometry to systematically interrogate Ca2+-mediated vasodilatory pathways. I will determine mechanisms responsible for reduced Ca2+ sparks in VSMCs (Aim 1) and defects in ligand- and flow-mediated endothelium-dependent relaxation (Aim 2). I will establish the rodent reduced uterine perfusion pressure (RUPP) model of pre-eclampsia in Manchester and assess whether it recapitulates these human microvascular abnormalities (Aim 3). Finally, I will test novel strategies to restore microvascular pathways in arteries from women with pre-eclampsia (Aim 4), informing future development of much-needed microvascular treatments for women with pre-eclampsia.