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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2177.)
© 2007 American Heart Association, Inc.

Vascular Biology

Pathogenic Sequence for Dissecting Aneurysm Formation in a Hypomorphic Polycystic Kidney Disease 1 Mouse Model

Sabrine Hassane; Nanna Claij; Irma S. Lantinga-van Leeuwen; J. Conny Van Munsteren; Natascha Van Lent; Roeland Hanemaaijer; Martijn H. Breuning; Dorien J.M. Peters; Marco C. DeRuiter

From the Center for Human and Clinical Genetics (S.H., N.C., I.S.L.L., M.H.B., D.J.M.P.), the Department of Anatomy and Embryology (J.C.V.M., M.C.D.), Leiden University Medical Center, and the Gaubius Laboratory (N.V.L., R.H.), TNO BioSciences, Leiden, The Netherlands.

Correspondence to Dr D.J.M. Peters, Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Postal zone: S-04-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. E-mail d.j.m.peters{at}lumc.nl

Objective— Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a multi-system disorder characterized by progressive cyst formation in the kidneys. Serious complications of ADPKD are intracranial and aortic aneurysms. The condition is mainly caused by mutations in the PKD1 or PKD2 gene. We have carefully analyzed vascular remodeling in hypomorphic Pkd1^nl/nL mouse model with dissecting aneurysms in the aorta.

Methods and Results— Quantitative real-time polymerase chain reaction revealed that in the aorta the expression of normal Pkd1 is reduced to approximately 26%. Using (immuno)histochemistry we have characterized the pathogenetic sequence for dissecting aneurysm formation. The aorta shows regions with accumulation of matrix components between the elastin lamellae. This is followed by increased numbers of smooth muscle cells and locally weakening of the media. In the intima, accumulation of matrix components and detachment of endothelial cells from the elastin lamellae results in a tear. The combination of weak media and a tear in the intima leads to rupture of the vessel wall resulting in intramural bleeding.

Conclusions— The Pkd1^nl/nl mouse reveals that polycystin1 is implicated in maintenance of the vessel wall structural integrity, and it is a useful model for dissecting aneurysm formation studies.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disease associated with dissecting aneurysms. We characterized dissecting aneurysm formation in a Pkd1 mouse model. It reveals the importance of polycystin1 in the maintenance of the vessel wall integrity, and it is a useful model to study dissections in ADPKD.

Key Words: dissecting aneurysm • polycystic kidney disease • aorta • extracellular matrix • Pkd1

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