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A developmentally regulated program restricting insolubilization of elastin and formation of laminae in the fetal
1Department of Pathology, University of Toronto, Ontario, Canada.
Background:
The ductus arteriosus (DA) is a fetal vessel in which the elastic laminae fail to assemble normally in late gestation. This feature is associated with the development of intimal cushions, structures that partially occlude the DA lumen and assure that the vessel will close completely when it constricts postnatally.
Experimental Design:
We studied the fetal lamb DA at two different gestational time-points, 100 days before, and 138 days coincident with intimal cushion formation (term = 145 days) to establish the ultrastructural basis for the 'disassembly' of elastic laminae apparent on light microscopy and to determine further whether the mechanism was due to increased elastolytic activity, decreased synthesis of tropoelastin, or impaired insolubilization of tropoelastin.
Results:
Morphometric ultrastructural analyses of tissue from the 138-day gestation fetal lambs revealed that the volume density of elastin in the DA vessel wall was only 40% of that in the aorta (Ao) and 50% of that in the pulmonary artery (PA). Moreover, only 16% of the elastin present contributed to the formation of laminae when compared to 80% in the Ao and 50% in the PA. Despite the morphologic appearance of 'fragmented' elastin, there was no evidence of increased elastolytic activity in the DA at either gestational time-point as judged by solubilization of a [3H] elastin substrate. The reduced elastin apparent was morphologically accompanied by an increase in soluble (tropo) elastin in DA compared with Ao and PA, as measured by enzyme linked immunosorbent assay, in tissue from both 100- and 138-day gestation lambs. Lack of differences in tropoelastin mRNA levels when comparing the 3 vessels suggested that the enzyme linked immunosorbent assay measurements reflected increased DA tropoelastin accumulation owing to lack of insolubilization rather than an increase in synthesis. Reduced insolubilization of newly synthesized elastin was evident in the DA compared with the Ao at 100 days gestation and in the DA compared with both Ao and PA at 138 days gestation in association with reduced desmosine levels.
Conclusions:
The mechanism of the decrease in tropoelastin insolubilization was unrelated to lysyl oxidase activity in the tissue and represents a unique developmental program.