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(Stroke. 2003;34:783.)
© 2003 American Heart Association, Inc.

Original Contributions

Cerebral Vascular Abnormalities in a Murine Model of Hereditary Hemorrhagic Telangiectasia

Junichiro Satomi, MD; Richard J. Mount;; Mourad Toporsian, PhD; Andrew D. Paterson, MD; M. Christopher Wallace, MD; Robert V. Harrison, PhD Michelle Letarte, PhD

From the Cancer and Blood Research Program (J.S., M.T., M.L.), Department of Otolaryngology and Brain and Behavior Program (R.J.M., R.V.H.), and Genetics and Genomic Biology Program (A.D.P.), Hospital for Sick Children; Heart and Stroke Richard Lewar Center of Excellence (M.T., M.L.) and Departments of Public Health Science (A.D.P.) and Immunology (M.T., M.L.), University of Toronto; and University of Toronto Brain Vascular Malformation Study Group (J.S., C.W.), Toronto, Ontario, Canada.

Correspondence to Michelle Letarte, PhD, Cancer and Blood Program, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8 Canada. E-mail mablab{at}sickkids.ca

Background and Purpose— Hereditary hemorrhagic telangiectasia type 1 (HHT1) is an autosomal dominant vascular dysplasia caused by mutations in the endoglin gene and characterized by dilated vessels and arteriovenous malformations (AVMs). To understand the etiology of this disorder, we evaluated the cerebral vasculature of endoglin heterozygous (Eng^+/-) mice, which represent the only animal model of HHT1.

Methods— The cerebral vasculature of Eng^+/- and Eng^+/+ mice from C57BL/6 (B6) and 129/Ola (129) strains with a differential susceptibility to HHT1 was studied with corrosion casting. Casts were observed by scanning electron microscopy to detect malformations and evaluate arterial diameters and orientation of endothelial nuclei. Measurements were taken to assess relative constriction at arteriolar branching points and downstream relative dilatation.

Results— Three of 10 Eng^+/- mice demonstrated abnormal vascular findings including AVMs, while none of 15 Eng^+/+ mice did. The incidence of relative constriction at arteriolar branching points was significantly less in both Eng^+/- groups than in their Eng^+/+ counterparts. The occurrence of relative dilatation was significantly greater in B6-Eng^+/- than in B6-Eng^+/+ mice. Endothelial nuclei were significantly rounder and deviated more from the direction of blood flow in Eng^+/- than in Eng^+/+ mice.

Conclusions— Eng^+/- mice showed significant structural alterations in cerebral blood vessels, indicating that the level of endoglin on endothelium is critical for maintenance of normal vasculature. Since endoglin haploinsufficiency is associated with HHT1, such changes in arteriolar structures might occur in HHT1 patients and predispose them to AVMs and their sequelae.

Key Words: arterioles • endothelium • microscopy, electron • transforming growth factors • vascular malformations

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