NOVEL ARTERIAL PATHOLOGY IN MICE AND HUMANS HEMIZYGOTIC FOR ELASTIN

Obstructive vascular disease is an important health problem in the ind ustrialized world. Through a series of molecular genetic studies, we d emonstrated that loss-of-function mutations in one elastin allele caus e an inherited obstructive arterial disease, supravalvular aortic sten osis (SVAS). To define the mechanism of elastin's effect, we generated mice hemizygous for the elastin gene (ELN +/-). Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at p hysiologic pressures was nearly normal. This discrepancy was explained by a paradoxical increase of 35% in the number of elastic lamellae an d smooth muscle in ELN +/- arteries. Examination of humans with ELN he mizygosity revealed a 2.5-fold increase in elastic lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans induces a compensat ory increase in the number of rings of elastic lamellae and smooth mus cle during arterial development. Humans are exquisitely sensitive to r educed ELN expression, developing profound arterial thickening and mar kedly increased risk of obstructive vascular disease.