**2.1 Physiological intimal thickening of the DA**

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 DA in humans and animals alike.
