Chronic Hypoxia Modulates Endothelial Influences on Smooth Muscle Phenotype in Fetal Cerebral Arteries

This study explores the hypothesis that chronic hypoxia modulates endothelial regulation of smooth muscle phenotype and function in fetal cerebral arteries. Endothelium denuded and intact middle cerebral arteries harvested from term fetuses from ewes kept at sea level (Normoxic) or 3, 820 m (Hypoxic) altitudes for the last 110 days of gestation were assessed for contractile function and smooth muscle phenotype as quantified by changes in the colocalization of Non‐Muscle (NM) and Smooth Muscle (SM) Myosin Heavy Chain (MHC) with Smooth Muscle alpha‐actin (SM‐αA). Chronic hypoxia reduced maximum myogenic stress, but increased maximum K + ‐induced stress. Organ culture of arteries from normoxic animals with VEGF reproduced this increase in K + ‐induced stress but only in the presence of an intact endothelium. For NM‐MHC/AA colocalization, an index of synthetic smooth muscle, organ culture for normoxic arteries with VEGF had little effect in the absence of endothelium but in the presence of endothelium enhanced colocalization. This effect of the endothelium on NM‐MHC/AA colocalization was enhanced in hypoxic arteries. For SM‐MHC/AA colocalization, a marker for contractile smooth muscle, organ culture of normoxic arteries with VEGF had little effect in the presence or the absence of endothelium, but in hypoxic arteries endothelium dramatically amplified VEGF‐induced increases in colocalization. These results demonstrate that chronic hypoxia modulates VEGF‐dependent endothelial regulation of smooth muscle phenotype in fetal cerebral arteries. 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.