**4. Acknowledgments**

This work was supported by grants from the Grant-in-Aid for Scientific Research (KAKENHI) (U.Y.), the Ministry of Health, Labor and Welfare of Japan (S.M. U.Y.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.M.), the Yokohama Foundation for Advanced Medical Science (S.M., U.Y.), the Kanae Foundation for the Promotion for Medical Science (U.Y.), the Miyata Cardiology Research Promotion Funds (S.M., U.Y.), the Takeda Science Foundation (S.M., U.Y.), the Sumitomo Foundation (U.Y.), the Japan Heart Foundation Research Grant (U.Y.), the Kowa Life Science Foundation (U.Y.), the Uehara Memorial Foundation (U.Y.), "High-Tech Research Center" Project for Private Universities: MEXT (S.M.), a Waseda University Grant for Special Research Projects (S.M.), and the Vehicle Racing Commemorative Foundation (S.M.).

### **5. References**

Akaike, T., Jin, M. H., Yokoyama, U., Izumi-Nakaseko, H., Jiao, Q., Iwasaki, S., Iwamoto, M., Nishimaki, S., Sato, M., Yokota, S., Kamiya, Y., Adachi-Akahane, S., Ishikawa, Y. & Minamisawa, S. (2009). T-type Ca2+ channels promote oxygenation-induced closure of the rat ductus arteriosus not only by vasoconstriction but also by neointima formation.*J Biol Chem* Vol.284, No.36, Sep 4 2009.pp.24025-34, ISSN 0021-9258

aortic aneurysm syndrome that is due to mutations in the TGF β receptors 1 and 2 and is associated with PDA and ductal aneurysm (Loeys, 2005). Further investigation is required to identify the molecular mechanism underlying the impaired elastogenesis in cases of DA.

Ductal closure occurs in two phases. In full-term newborns, the first few hours after birth see acute and functional closure as a result of smooth muscle contraction of the DA, which is triggered by an increase in oxygen tension and a decline in levels of circulating PGE2. Importantly, prior to this, anatomical vascular remodelling occurs under the control of highly conserved yet complex molecular mechanisms. This remodelling requires a specific sequence of processes, which includes the differentiation of vascular SMCs and endothelial cells, the accumulation of extracellular matrix, vascular SMC migration into the subendothelial region, impaired elastogenesis, and eventually fibrotic changes due to apoptosis and necrosis. Recent advances in high-throughput genetic screening for human diseases and genetically manipulated animal models of PDA have facilitated the identification of pathways and genes involved in development and closure of the DA. As seen in the PGE2-EP4-cAMP signal pathway as well as in the oxygen and calcium channels, multiple vasoreactive stimulations can serve as an important modulator of vascular remodelling of the DA. In this regard, endothelin-1, nitric oxide, and other vasoreactive factors in the DA that we have not discussed here in detail may play a role in vascular remodelling of the DA. Thus, it is reasonable to infer that endothelial cells in the DA may also play an important role in the differentiation of vascular SMCs, which are considered to be a pivotal cellular structure in the pathogenesis of PDA. In addition to its role in controlling vascular tone in the functional closure of the DA, the vascular remodelling of the DA is now attracting considerable attention as a target for novel therapeutic strategies for

This work was supported by grants from the Grant-in-Aid for Scientific Research (KAKENHI) (U.Y.), the Ministry of Health, Labor and Welfare of Japan (S.M. U.Y.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.M.), the Yokohama Foundation for Advanced Medical Science (S.M., U.Y.), the Kanae Foundation for the Promotion for Medical Science (U.Y.), the Miyata Cardiology Research Promotion Funds (S.M., U.Y.), the Takeda Science Foundation (S.M., U.Y.), the Sumitomo Foundation (U.Y.), the Japan Heart Foundation Research Grant (U.Y.), the Kowa Life Science Foundation (U.Y.), the Uehara Memorial Foundation (U.Y.), "High-Tech Research Center" Project for Private Universities: MEXT (S.M.), a Waseda University Grant for Special Research Projects

Akaike, T., Jin, M. H., Yokoyama, U., Izumi-Nakaseko, H., Jiao, Q., Iwasaki, S., Iwamoto, M.,

formation.*J Biol Chem* Vol.284, No.36, Sep 4 2009.pp.24025-34, ISSN 0021-9258

Nishimaki, S., Sato, M., Yokota, S., Kamiya, Y., Adachi-Akahane, S., Ishikawa, Y. & Minamisawa, S. (2009). T-type Ca2+ channels promote oxygenation-induced closure of the rat ductus arteriosus not only by vasoconstriction but also by neointima

patients with PDA and DA-dependent cardiac anomalies.

(S.M.), and the Vehicle Racing Commemorative Foundation (S.M.).

**4. Acknowledgments** 

**5. References** 

**3. Conclusion** 


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**4** 

*USA* 

**Bone Morphogenetic Protein Signaling** 

Cristina Harmelink and Kai Jiao *The University of Alabama at Birmingham* 

**Pathways in Heart Development and Disease** 

The heart is the first organ to develop and its proper formation is requisite for survival of the embryo. Heart development relies on exquisitely controlled signaling cascades that together weave the temporal and spatial cardiac gene expression patterns required for normal heart morphogenesis and function. Aberrations in cardiogenic signaling pathways or in cardiac gene expression patterns can result in congenital heart defects (CHDs), the most common type of birth defect worldwide and the leading noninfectious cause of infant death in the Western world (Hoffman 1995; Hoffman and Kaplan 2002). This review provides evidence from multiple experimental models that demonstrates the conserved, critical roles of Bone Morphogenetic Protein (BMP) signaling pathways throughout heart development, from induction of the cardiac mesoderm to the formation of the fourchambered heart. BMP signaling pathways have roles in developmental processes that can

During gastrulation, cardiac progenitors within the lateral plate mesoderm migrate in bilateral sheets of cells to the anterior of the embryo. Within the cardiac mesoderm, there are two populations of cells that contribute to the developing heart called the first and second heart fields (FHF and SHF, respectively). At embryonic (E) day 7.5 in mice, cells of the FHF form the cardiac crescent. At this stage, the second population of cardiac cells, the SHF, is medial and anterior to the FHF. As the embryo folds, at mouse E8.0, the cardiac crescent fuses along the midline and forms the heart tube while the SHF moves dorsally. The heart tube consists of an outer myocardial layer and an inner endocardial layer, separated by an extracellular matrix (ECM) called the cardiac jelly. SHF cells migrate through the pharyngeal mesoderm to populate the anterior and posterior regions of the heart tube. Starting from E8.5 in the mouse, the heart undergoes rightward looping. Regional proliferation along the myocardium of the outer curvature of the heart tube demarcates the future atrial and ventricular chambers. The myocardium of the inflow tract (IFT), outflow tract (OFT), atrioventricular canal (AVC) and inner curvature of the heart tube is characteristically nonproliferative. The FHF contributes primarily to the left ventricle as well as to part of the atrium, and the SHF contributes to the atria, right ventricle, and OFT. At about E9.5 in the

contribute to CHDs, including formation of the septa, valves, and outflow tract.

**1. Introduction** 

**2. Overview** 

**2.1 Heart development** 

