DEVELOPMENTALLY TIMED EXPRESSION OF AN EMBRYONIC GROWTH PHENOTYPE IN VASCULAR SMOOTH-MUSCLE CELLS

Little is known about the phenotypic changes that occur in vascular smooth muscle cells (SMCs) as the developing aorta undergoes the transition from a loosely organized, highly replicative tissue to a morphologically mature, quiescent tissue. In the present study, we have characterized the in vivo pattern of SMC replication during intrauterine and neonatal aortic development in the rat and have cultured and assessed the in vitro growth properties of embryonic, fetal, and neonatal vascular SMCs. Embryonic SMCs, which exhibited a very high in vivo replication rate (75% to 80% per day), demonstrated a significant potential for self-driven replication, as assessed by the ability to proliferate under serum-deprived conditions. Several lines of evidence suggest that the autonomous growth of SMCs in the ''embryonic growth phenotype'' may be driven by a unique mechanism independent of known adult SMC mitogens: embryonic SMC replication was not associated with the detectable secretion of mitogenic activity capable of stimulating adult SMCs, and embryonic SMCs were mitogenically unresponsive to a variety of known adult SMC growth factors. The capacity for self-driven growth was lost by embryonic day 20, suggesting that important changes in gene expression and phenotype occur in developing SMCs between embryonic days 18 and 20. Taken together, the data describe a unique embryonic growth phenotype of vascular SMCs and suggest that the replication of aortic SMCs during intrauterine development is self driven, self regulated, and controlled by a developmental timing mechanism. The conversion of SMCs from the embryonic to the late fetal/adult growth phenotype will likely be found to be an important component of a developmental system controlling vascular morphogenesis.