**2.3.3 Jag1**

90 Congenital Heart Disease – Selected Aspects

The expression of IL-15 mRNA is significantly higher in rat DA than in the aorta. IL-15 immunoreactivity is detected predominantly in the internal elastic laminae, and to a lesser extent in SMCs, in the rat DA. IL-15 attenuates PDGF-BB-mediated SMC proliferation and PGE1-induced hyaluronan production in a dose-dependent manner. Accordingly, IL-15 might have an inhibitory effect on the physiological vascular remodelling processes

Moreover, growth hormones promote the migration of DA SMCs, thus enhancing intimal cushion formation in the DA. Growth hormones also regulate the expression of cytoskeletal, genes in DA SMCs, which may retain a synthetic phenotype in the smooth muscle-specific

SMCs retain the ability to reversibly alter their phenotype in response to various environmental and physiological changes (McDonald and Owens 2007). This property has been termed phenotypic switching or SMC plasticity. Contractile SMCs express high levels of contractile proteins involved in establishing and maintaining myofilament structure and function, including SM22α, SMA and SMMHC. In contrast, synthetic SMCs express lower levels of contractile muscle proteins and have higher rates of proliferation, migration and production of extracellular matrix components. The DA is a very specialized blood vessel, with a vascular wall composed of highly differentiated and contractile smooth muscle (Slomp, 1997). A unique transcriptional program is probably responsible for generating this particular artery during fetal development (Ivey, 2008). A growing body of evidence has demonstrated that maturation and differentiation of DA SMCs is essential for postnatal DA closure. Deletion of several factors that are required for DA SMCs to adopt a contractile phenotype results in PDA. It should be noted, however, that neointimal thickening is induced by migrating and proliferating vascular SMCs, which are characterized as a dedifferentiated (synthetic) phenotype. Therefore, the DA must consist of SMCs exhibiting

Myocardin is a remarkably potent transcriptional coactivator that regulates SMC contractile proteins. Myocardin-null mouse embryos exhibit a block in vascular SMC differentiation as well as defects in the yolk sac vasculature (Li, 2003). Importantly, mice generated after selective myocardin ablation of cardiac neural crest-derived vascular SMCs exhibit PDA and die at postnatal day 3 (Huang, 2008). In these mutant mice, the *myocardin-*deficient vascular SMCs populating the DA exhibit ultrastructural features generally associated with the synthetic, rather than the contractile, SMC phenotype. In addition, the architecture of the neointima and tunica media of the DA is markedly disturbed in association with a dramatic increase in extracellular matrix and a relative decrease in vascular SMC volume. These data demonstrate that myocardin regulates the expression of genes required to induce the contractile phenotype in neural crest–derived SMCs and provide new insights into the

Identifying gene mutations in TFAP2B, a neural crest cell-specific transcription factor involved in Char syndrome, is one of the most important discoveries regarding the

molecular and genetic systems that underlie the vascular remodeling of the DA.

involved in closing the DA (Iwasaki, 2007).

**2.3 Vascular smooth muscle differentiation** 

cytoskeletal genes (Jin, 2011).

phenotypic heterogeneity.

**2.3.1 Myocardin** 

**2.3.2 TFAP2B** 

The evolutionarily conserved Notch signaling pathway plays a major role in vascular development in mammals and other vertebrates (Kurpinski, 2010; High, 2008). Mice with SMC-specific deletion of Jag1, which encodes a Notch ligand, die postnatally from PDA (Feng, 2010). These mice exhibit defects in contractile SMC differentiation in the medial vascular wall of the DA, which therefore fails to express contractile SMC proteins. However, the differentiation of contractile vascular SMCs is confined to the region adjacent to the endothelial cell layer in the DA. Therefore, propagation of the Jag1-Notch signal throughout the width of the vascular wall is required for contractile SMC differentiation of the DA.
