**2.2.2 Prostacyclin (PGI2)**

86 Congenital Heart Disease – Selected Aspects

After birth, extensive remodelling of the DA wall occurs, leading to permanent closure of the DA. Although these rapid changes are readily apparent after birth, the structural remodelling of the DA has already begun in late gestation, under the control of the abovementioned unique differentiation system. Therefore, the DA has a distinct structural character from its neighboring arteries. For example, smooth muscle myosin isoform SM2, which is predominantly expressed in adult arteries, is highly expressed in the fetal DA (Kim,

Intimal thickening, though often observed in pathological arteries, such as injured or atherosclerotic arteries, is also a characteristic developmental structural change in the DA. The intimal thickening that occurs in the DA is physiological in nature and is required for postnatal DA closure (Rabinovitch, 1996; Yokoyama. 2006a). In rats, intimal thickening can be observed in the mature DA on the 21st day of gestation, though it is not observed in the immature DA on the 19th day of gestation. Intimal thickening starts with a lifting of the endothelial cells. Accumulations of hyaluronan and other extracellular matrices in the subendothelial region and fragmention of the inner elastic lamina provide optimal conditions for the migration of SMCs into the subendothelial region (De Reeder, 1988). These changes in DA structure have been well investigated both in rodents and in humans. Given that intimal thickening is poorly developed in patients with PDA and in animal models of PDA (Gittenberger-de Groot, 1980; Gittenberger-de Groot,1985; Tada,1985), this process must play a critical role in permanent closure of the DA after birth. Therefore, a common molecular mechanism must underlie the development of intimal thickening of the

Intimal thickening is associated with many characteristic phenomena such as the proliferation and migration of SMCs, the accumulation of extracellular matrix in the subendothelial region, and the fragmention of the inner elastic lamina. Analysis of the causal genes of this complex process in patients with PDA and animal models of PDA is resulting in significant progress

The cyclooxygenases COX1 and COX2 catalyze the synthesis of prostaglandin H, a precursor of biologically active prostaglandins including PGE2, from arachidonic acid. Therefore COX inhibitors such as indomethacin are often used for treatment of PDA to induce vasoconstriction of the DA by attenuating the synthesis of PGE2. Exposure *in utero* to indomethacin induces premature closure of the DA. Interestingly, it has been reported that infants of mothers who received indomethacin tocolysis are susceptible to symptomatic PDA. These contradictory observations suggest that a relatively complex mechanism underlies the role of COX1 and COX2 in the DA. Furthermore, genetic disruption of COX1 and COX2 results in postnatal PDA (Loftin, 2001). As seen in COX-deleted mice, COX2 plays a primary role in DA closure after birth, and its effect is attenuated in cases of preterm gestation. In addition to COX2, COX1 also contributes to DA closure in a gene dosagedependent manner (Loftin, 2001; Loftin, 2002). Although it is not apparent from the

**2. Anatomical closure of the DA** 

**2.1 Physiological intimal thickening of the DA** 

DA in humans and animals alike.

**2.2 Molecular mechanisms underlying intimal thickening** 

toward understanding the molecular mechanism underlying it.

**2.2.1 Cyclooxygenase (COX): The generator of PGE2** 

1993).

Dogs have been studied as an animal model of inherited PDA because their histological features of normal DA and PDA closely resemble those of humans. Through such studies, De Reeder et al. have demonstrated that the expression of PGI2 synthase is high in the endothelium and low in vascular SMCs in PDA and other patent neighboring arteries. In normally closing DA, in contrast, high amounts of PGI2 are found in the vascular SMCs of the intimal cushions, suggesting that PGI2 plays a role in the onset of intimal thickening (de Reeder, 1989).
