**2.4 Extracellular matrix involved in vascular remodelling of the DA**

Vascular cells are defined by the ways in which they regulate their extracellular matrix, and changes in the extracellular matrix, in turn, determine vascular cell phenotype, i.e. the ability to differentiate, proliferate, and migrate (Rabinovitch, 1996). As described in section 2.2.3, PGE-induced hyarulonan plays a critical role in the onset of intimal thickening of the DA (De Reeder, 1988; Yokoyama, 2006a). In addition, it has been reported that DA SMCs produce twice as much fibronectin as aortic SMCs do (Rabinovitch, 1996). Mason et al. have demonstrated that preventing fibronectin-dependent intimal thickening would be a feasible manipulation to cause PDA as a mode of treatment of congenital heart diseases (Mason, 1999). TGF β and nitric oxide induce extracellular matrix, including hyaluronan and fibronectin, in DA SMCs (Rabinovitch, 1996). Future studies will be needed to determine the other constituents of extracellular matrix that play a role in vascular remodelling of the DA.

#### **2.5 Disassembly of the internal elastic lamina and loss of elastic fiber in the medial layer of the DA**

The disassembly and fragmentation of the internal elastic lamina and sparse elastic fibers in the middle layer of the DA is a hallmark of vascular remodelling in the DA. In the normally closing DA, impaired elastogenesis coincides with increased SMC migration and proliferation, contributing to physiological occlusion. The reduced elasticity of the DA wall may help its structure collapse easily as a prelude to postnatal permanent closure of the DA. In PDA, in contrast, an abundance of elastin lamellae in the intima, a subendothelial elastic lamina, and a failure of intimal SMC migration are found in humans and animal models (de Reeder, 1990; Hinek, 1991; Slomp, 1992). In humans and in animal models such as canine puppies and the inbred Brown-Norway (BN) rat (Bokenkamp, 2006), the subendothelial elastic lamina is thought to limit the passage of SMCs from the media to the intima. In PDA in BN rats, the media of elastin lamellae are absent, and the intima contains many elastic fibers. The abnormal distribution of elastin in the PDA of BN rats suggests that impaired elastin metabolism is related to the persistence of the DA and implicates a genetic factor that may link the PDA with aortic fragility. In this regard, recent studies have identified a new

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