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

METHODS

Confocal imaging of cytosolic Ca and recording BK 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 release.

RESULTS

Membrane depolarization increased Ry-sensitive Ca spark frequency in normoxic and LTH groups along with BK activity. LTH reduced Ca spark and whole-cell Ca activity and induced a large leftward shift in the voltage-dependence of BK current activation. The influence of LTH on the spatial and temporal aspects of Ca sparks and whole-cell Ca responses varied.

DISCUSSION

Overall, LTH attenuates Ca signaling while increasing the coupling of Ca sparks to BK activity; a process that potentially helps maintain oxygen delivery to the developing brain.