Long-term hypoxia modulates depolarization activation of BK(Ca) currents in fetal sheep middle cerebral arterial myocytes.

INTRODUCTION: Previous evidence indicates that gestational hypoxia disrupts cerebrovascular development, increasing the risk of intracranial hemorrhage and stroke in the newborn. Due to the role of cytosolic Ca(2+) in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca(2+) signals can offer insight into the pathophysiological disruptions taking place in hypoxia-related perinatal cerebrovascular disease. This study aimed to determine the extent to which gestational hypoxia disrupts local Ca(2+) sparks and whole-cell Ca(2+) signals and coupling with BK(Ca) channel activity. METHODS: Confocal imaging of cytosolic Ca(2+) and recording BK(Ca) currents of fetal sheep middle cerebral arterial (MCA) myocytes was performed. MCAs were isolated from term fetal sheep (∼140 days of gestation) from ewes held at low- (700 m) and high-altitude (3,801 m) hypoxia (LTH) for 100+ days of gestation. Arteries were depolarized with 30 mM KCl (30K), in the presence or absence of 10 μM ryanodine (Ry), to block RyR mediated Ca(2+) release. RESULTS: Membrane depolarization increased Ry-sensitive Ca(2+) spark frequency in normoxic and LTH groups along with BK(Ca) activity. LTH reduced Ca(2+) spark and whole-cell Ca(2+) activity and induced a large leftward shift in the voltage-dependence of BK(Ca) current activation. The influence of LTH on the spatial and temporal aspects of Ca(2+) sparks and whole-cell Ca(2+) responses varied. DISCUSSION: Overall, LTH attenuates Ca(2+) signaling while increasing the coupling of Ca(2+) sparks to BK(Ca) activity; a process that potentially helps maintain oxygen delivery to the developing brain.