Hypoxia inhibits proliferation of fetal pulmonary arterial smooth muscle cells in vitro

Normal pulmonary arterial development in the relatively hypoxic intrauterine environment and pulmonary arterial remodeling in hypoxic infants include extension of the smooth muscle layer into normally nonmuscular arteries and thickening of the arterial media in the muscular arteries. These changes require proliferation of immature smooth muscle cells or differentiation of smooth muscle cell precursors. Because the mechanisms that regulate these processes have not been clearly defined, we asked whether decreased oxygen tensions could promote either hyperplasia or hypertrophy of smooth muscle cell precursors in vitro. We have studied cells that proliferate and migrate out of explants from the media of the pulmonary arteries of near-term bovine fetuses, because these cells are representative of those that are involved in normal arterial development and possibly also in arterial remodeling. Decreases in oxygen tension within and below the physiologic range do not cause hyperplasia or hypertrophy of these cells. Instead, cell proliferation decreased at oxygen tensions below 60 mm Hg. The effects of hypoxia on proliferation of aortic and pulmonary arterial smooth muscle cells were identical, but effects on proliferation of dermal fibroblasts and endothelial cells were smaller in magnitude and evident only at lower oxygen tensions. These findings suggest that hypoxia does not act directly on smooth muscle cells to produce increased quantities of these cells in the pulmonary arteries during normal prenatal development or during remodeling of the pulmonary arteries of the hypoxic neonate, implying that other factors mediate these phenomena.