Hyaluronic acid accumulation and endothelial cell detachment in intimal thickening of the vessel wall. The normal and genetically defective ductus arteriosus.

The closing ductus arteriosus (DA) was studied as a model for the development of intimal thickening of vessel walls using ultrastructural and immunohistochemical techniques. The material consisted of DA from neonatal dogs of three types: normal beagles, DA-defective pups from a line of mixed poodles with a genetic defect in the closure of the DA leading to persistent ductus arteriosus (PDA line), and normal litter-mates of DA-defective pups in the PDA line. The DA of the normal litter-mates of DA-defective pups did not differ from those of normal beagles. In the DA of normal beagles and normal PDA-line pups, closure is preceded by intimal thickening characterized by formation of a widened subendothelial region (SR), detachment of endothelial cells, invagination of endothelial cells, and migration of smooth muscle cells into the SR. It was observed that immediately before and after endothelial cell detachment, there was an increase in hyaluronic acid (HA) in the SR and inner media. In the DA-defective pups, the increase in hyaluronic acid failed to occur and there was no intimal thickening. The SR failed to expand, endothelium remained attached to the internal elastic membrane, and there was no invagination of endothelium or migration of smooth muscle cells. It is hypothesized that the increased synthesis of HA is an important early event leading to intimal thickening in the normal DA and perhaps to abnormal intimal thickening of other vessels. By its hygroscopic properties, HA may be directly involved in the formation of a wide SR, inducing endothelial cell detachment and favoring smooth muscle cell migration. In affected pups of the PDA line, there is a genetically-determined "block" in the normal process of intimal thickening at or before the initiation of increased HA synthesis.