Chronic Hypoxia Alters the Response of Fetal Ovine Middle Cerebral Arteries to Endothelin-1 (ET-1)

This study explores the hypothesis that chronic hypoxia alters the expression and intracellular coupling of endothelin receptors to induce phenotypic transformations of smooth muscle cells within the arteries of fetal cerebrovasculature. Endothelium‐denuded middle cerebral arteries (MCAs) harvested from term fetuses of pregnant adult sheep kept at sea level or 3820m for 110 days were used in contractility experiments or cultured with ET‐1 and various kinase inhibitors. Chronic hypoxia had no effect on plasma levels of ET‐1 but altered contractile responses to ET‐1 and increased ETA receptor expression in fetal MCAs. ET‐1 treatment increased arterial thicknesses in both normoxic and hypoxic arteries. Organ culture of MCAs with ET‐1 decreased colocalization of MLCK and α‐actin and this effect was attenuated by chronic hypoxia. ET‐1 also decreased MLC20 and MLCK colocalization, but this effect was similar in normoxic and hypoxic arteries. The effects of ET‐1 on colocalization were reversed by inhibitors of either PKC (7 µM chelerythrine) or p38 (10 µM SB203580) in both normoxic and hypoxic arteries. From these results we conclude that chronic hypoxia modulates phenotypic responses of fetal cerebrovascular smooth muscle to ET‐1 through elevated expression of ET‐1 receptors, which act downstream through PKC and p38 dependent pathways on contractile protein expression.This work was supported by National Institutes of Health Grants HL‐54120, HD‐31266, HL‐64867, and NS‐076945 and the Loma Linda University School of Medicine.