Developmentally timed expression of an embryonic growth phenotype in vascular smooth muscle cells.

Abstract

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.

miR-145 directs intestinal maturation in zebrafish

“…During late embryogenesis and postnatal development, SMCs have an extremely high rate of proliferation with subsequent rapid induction of multiple SMC differentiation marker genes (28,29). In zebrafish, the high proliferation rate of gut epithelial cells and SMC progenitors between 36 hpf and 74 hpf decreases significantly between 74 and 120 hpf, at a time when miR-145 begins to be expressed (12,30).…”

Perlecan regulates Oct-1 gene expression in vascular smooth muscle cells.

“…replication in the absence of matrix injury, and that one primary function of this growth-suppressive matrix may be to negatively regulate the expression of transcription factors, such as Oct-1, required for cell replication. In a separate study (Weiser et al, 1996), we have shown that expression of the perlecan gene is developmentally regulated in rat aortic SMCs and is first detectable in SMCs at embryonic day 18, a point in development when SMC replication begins to dramatically decrease (Cook et al, 1994 (Figure 12). In this context, vascular injury may involve physical, proteolytic, or compositional changes in the SMC basal lamina.…”

Arterial Smooth Muscle Cell Heterogeneity

“…30 -32 SMC populations with either spindle-shaped or epithelioid phenotypes were isolated from the healthy rat aorta at different ages. 18,19,21,22 In particular, spindle-shaped SMCs were predominant in fetuses at different developmental stages, 22 as well as in newborn (4 to 5 days) 19,21,33 and adult (6 weeks to 3 months) rats, 13,21,34,35 whereas epithelioid SMCs were prevalent in old rats (Ͼ18 months). 18,21 This suggests that the population of SMCs that exhibit an epithelioid phenotype in vitro increases in rat aortic NM with age.…”

“…13,14,16,18,20,23,[53][54][55] In addition, albeit spindle-shaped, SMCs isolated from rat embryos exhibit serum-independent growth capacity. 22 Epithelioid SMCs produce platelet-derived growth factor (PDGF)-BB, which is a potent SMC mitogen, 16,20,23 and fail to respond to the growth-inhibitory effect of transforming growth factor (TGF)-␤. 55 However, the factor(s) responsible for serum independence has never been clearly identified.…”

“…Interestingly, the subtractive hybridization approach with RNA isolated from rat embryo SMCs with an autonomous growth property and rat adult SMCs with a nonautonomous growth property 22 allowed identification of several embryonic genes; one of them, ie, embryonic growth-associated protein, is involved in the serum-independent growth of embryonic SMCs and is reexpressed in experimentally induced IT. 101 Recent studies performed in species other than the rat are providing novel insight into the understanding of IT formation.…”