Long-term hypoxia modulates depolarization activation of BKCa 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 Ca²⁺ in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca²⁺ 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 Ca²⁺ sparks and whole-cell Ca²⁺ signals and coupling with BK_Ca channel activity.

Methods: Confocal imaging of cytosolic Ca²⁺ 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 Ca²⁺ release.

Results: Membrane depolarization increased Ry-sensitive Ca²⁺ spark frequency in normoxic and LTH groups along with BK_Ca activity. LTH reduced Ca²⁺ spark and whole-cell Ca²⁺ 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 Ca²⁺ sparks and whole-cell Ca²⁺ responses varied.

Discussion: Overall, LTH attenuates Ca²⁺ signaling while increasing the coupling of Ca²⁺ sparks to BK_Ca activity; a process that potentially helps maintain oxygen delivery to the developing brain.