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Neural crest cells (NCCs) are a unique stem cell population, which originate from the border between the neural plate and surface ectoderm and migrate throughout the body to give rise to multiple cell lineages during vertebrate embryonic development. The NCCs that contribute to heart development, referred to as the cardiac NCCs, have been assigned to the neural crest at the level of the postotic hindbrain. Recently, we found that the NCCs from the preotic region migrate into the heart and partially differentiate into coronary artery smooth muscle cells. This finding indicates that the origin of the cardiac NCCs appears more widely extended to the anterior direction than Kirby et al. first designated.

Various cellular signaling pathways play essential roles in regulating embryonic vascular development. Among them, Notch signaling is implicated in arterial endothelium differentiation and vascular morphogenesis. Mice that lack Notch receptors or other signaling components die in utero due to severe vascular abnormalities. We previously identified the Hairy-related transcription (Hrt) factor family, also called Hey, Hesr, CHF, Herp, and Gridlock, as downstream mediators of Notch signaling in the developing vasculature [1]. The Hrt family proteins, Hrt1/Hey1, Hrt2/Hey2, and Hrt3/HeyL, mainly act as transcriptional repressors, by binding to consensus DNA elements or by associating with other DNA-binding transcription factors. The mice deficient for showed perinatal lethality due to ventricular septal defects and mitral valve insufficiency, and cardiomyocyte-specific deletion of caused abnormal expression of atrial-specific genes in the ventricle and cardiac dysfunction in adulthood [2].

The placental circulation is crucial for the development of mammalian embryos [1]. The labyrinth layer in the placenta is created by extensive villous branching of the trophoblast and vascularization arising from the embryonic mesoderm. In the labyrinth, materials are exchanged between the maternal and embryonic circulation. Recently, we have found that inositol 1,4,5-trisphosphate (IP) receptors (IPRs) may be required for the placental vascularization.

Kawasaki disease is the most common acute systemic vasculitis of unknown etiology in children [1] and can cause inflammation of the coronary arteries leading to aneurysms. Tenascin-C, an extracellular matrix protein, and c-Jun N-terminal kinase (JNK), an intracellular signaling protein, are known to be associated with inflammation and tissue remodeling [2, 3]. The purpose of this study was to demonstrate tenascin-C and JNK might be involved in tissue remodeling in a -induced murine model of aneurysm.

The ductus arteriosus (DA) is a fetal vessel bypassing the still nonfunctional lungs. Closure of the DA at birth is essential for the transition from a fetal to a neonatal circulation. This closing process begins with a physiological contraction followed by definitive anatomical closure. The latter process starts already before birth by development of intimal thickening followed after birth by degeneration of the inner media, including cytolytic necrosis and apoptosis. The DA will remain patent when there is insufficient maturation in prematurely born babies or when there is a structural abnormality as seen in persistent DA (PDA). The histological changes during normal DA closure resemble the features seen in the premature ageing vessels in children with the Hutchinson progeria syndrome. The latter syndrome is caused by a mutation in the lamin A/C gene resulting in accumulation of the progerin splice variant. We studied human DA biopsies from the fetal to the neonatal period to investigate whether lamin A/C and progerin might be involved in the DA closure process. The results show an increase in the intima and inner media of progerin in the normal neonatal DA, while expression of lamin A/C is diminished. In the non-closing aorta, the fetal DA and the PDA, no or hardly any progerin expression was found. We postulate that the lamin A/C to progerin balance is important during normal anatomical closure of the DA presenting a unique case of physiological premature vascular ageing.

The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during the fetal period. It is well recognized that prostaglandin E (PGE) dilates the DA through activation of its receptor EP4 and subsequent cyclic AMP (cAMP) production during the fetal period and that oxygen constricts the DA by inhibiting potassium channels immediately after birth. In addition to the regulation of vascular tone, morphological remodeling of the DA throughout the perinatal period, such as prominent intimal thickening and poor elastogenesis, has been demonstrated.

We recently identified the molecular mechanisms of the acquisition of unique morphological remodeling in the DA during development. During the fetal period, PGE-EP4 signaling decreases elastic fiber formation through degradation of the cross-linking enzyme lysyl oxidase (LOX) and increases hyaluronan-mediated intimal thickening in the DA. This remodeling is mediated by activation of the EP4 receptor via diverse downstream intracellular signaling pathways. Hyaluronan-mediated intimal thickening was induced by the EP4-Gs protein-cyclic AMP-protein kinase A pathway. The attenuation of elastogenesis is mediated through a non-cyclic AMP signaling pathway, such as c-src-phospholipase C (PLC). These data suggest that placental PGE-mediated vascular remodeling via different signaling pathways orchestrates the subsequent luminal DA reorganization, leading to complete obliteration of the DA.

Developmental changes in the contractile system of blood vessels such as the ductus arteriosus (DA), pulmonary artery (PA), and aorta (Ao) have not been investigated extensively. We assessed the developmental changes in the expression of genes that regulate vasoconstriction of fetal blood vessels.

The fetal patency and neonatal closure of the ductus arteriosus (DA) are regulated with oxygen and prostaglandins. The proposed oxygen sensors of fetal and neonatal DA include P450-endothelin and the Kv channel [1]. We hypothesized that the ATP-sensitive potassium channel (K channel) is another oxygen sensor [2].

The cardiac conduction system (CCS) consists of distinctive components that initiate and conduct the electrical impulse required for the coordinated contraction of the cardiac chambers. The development of the CCS involves complex regulatory networks of transcription factors that act in stage, tissue and dose-dependent manners. As disrupted function or expression of these factors may lead to disorders in the development or function of components of the CCS associated with heart failure and sudden death, it is crucial to understand the molecular and cellular mechanisms underlying their complex regulation. Here, we discuss the regulation of genes driving CCS-specific gene expression and demonstrate the complexity of the mechanisms governing their regulatory networks. The three-dimensional conformation of chromatin has recently been recognized as an important regulatory layer, shaping the genome in regulatory domains and physically wiring gene promoters to their regulatory sequences. Knowledge of the mechanisms by which distal-acting regulatory sequences exert their function to drive tissue-specific gene expression and understanding how the three-dimensional chromatin landscape is involved in this regulation will increase our understanding of how disease-associated genomic variation affects the function of such sequences.

Rhythmic heartbeats are paced by electrical impulses that are autonomously generated by cardiac pacemaker cells. This chapter briefly summarizes our recent findings regarding the embryonic origin of and molecular mechanism delineating cardiac pacemaker cells, showing that pacemaker cells are physically segregated and molecularly programmed, in a tertiary heart field, prior to the onset of cardiac morphogenesis.