Chronic Hypoxia Diminishes the Proliferative Response of Guinea Pig Uterine Artery Vascular Smooth Muscle Cells in Vitro

Abstract

The pregnancy-related size enlargement of the guinea pig uterine artery is partially accomplished by hyperplasia in all layers of the vessel wall. We sought to determine the separate and combined effects of chronic hypoxia and pregnancy on the proliferative capacity of uterine artery vascular smooth muscle cells (UA VSMCs). We established primary UA VSMC cultures from a total of 13 guinea pigs using an enzymatic digestion technique. Animals were bred and kept in normoxia or hypoxia (P(B) = 463 mmHg, simulated elevation = 3962 m) for 45 days, a duration equivalent to midpregnancy in the guinea pig 63-day gestation. Nonpregnant matched controls were included. The proliferative response of UA VSMCs to 1, 3, 5 or 7 days of serum stimulation in vitro was compared. Exposure to hypoxia reduced UA VSMC proliferative response to serum stimulation relative to that seen in cells harvested from normoxic females. The inhibitory effect was present both in cells harvested from nonpregnant and pregnant animals and resulted in a lower UA VSMC proliferative response in the cells harvested from hypoxic compared with normoxic pregnant animals. Our data were consistent with our hypothesis that chronic maternal hypoxia compromises the capacity for growth and remodeling of the uterine artery during pregnancy, perhaps by interfering with the ability of vascular smooth muscle cells to de-differentiate to a proliferative phenotype. Noteworthy was that such effects of chronic hypoxia were retained in cultured cells.