Nonstandard abbreviations used: smooth muscle (SM); smooth muscle cell (SMC); stage-specific embryonic antigen-1 (SSEA-1); stem cell antigen-1 (Sca-1).

Endoglin (CD105) is expressed on the surface of endothelial and haematopoietic cells in mammals and binds TGFbeta isoforms 1 and 3 in combination with the signaling complex of TGFbeta receptors types I and II. Endoglin expression increases during angiogenesis, wound healing, and inflammation, all of which are associated with TGFbeta signaling and alterations in vascular structure. The importance of endoglin for normal vascular architecture is further indicated by the association of mutations in the endoglin gene with the inherited disorder Hereditary Haemorrhagic Telangiectasia Type 1 (HHT1), a disease characterised by bleeding from vascular malformations. In order to study the role of endoglin in vivo in more detail and to work toward developing an animal model of HHT1, we have derived mice that carry a targeted nonsense mutation in the endoglin gene. Studies on these mice have revealed that endoglin is essential for early development. Embryos homozygous for the endoglin mutation fail to progress beyond 10.5 days postcoitum and fail to form mature blood vessels in the yolk sac. This phenotype is remarkably similar to that of the TGFbeta1 and the TGFbeta receptor II knockout mice, indicating that endoglin is needed in vivo for TGFbeta1 signaling during extraembryonic vascular development. In addition, we have observed cardiac defects in homozygous endoglin-deficient embryos, suggesting endoglin also plays a role in cardiogenesis. We anticipate that heterozygous mice will ultimately serve as a useful disease model for HHT1, as some individuals have dilated and fragile blood vessels similar to vascular malformations seen in HHT patients.

Nonstandard abbreviations used: smooth muscle (SM); smooth muscle cell (SMC); stage-specific embryonic antigen-1 (SSEA-1); stem cell antigen-1 (Sca-1).

Enhanced endoglin expression is not limited to angiogenesis, it is also associated with inflammation.

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Background-Mutations in endoglin or activin like kinase-1, both involved in the endothelial transforming growth factor-␤ signaling pathway, cause the autosomal dominant bleeding disorder hereditary hemorrhagic telangiectasia. We and others have reported mouse models for this disease that share the characteristic phenotype of dilated vessels and sporadic hemorrhage. The reasons for the variable phenotype in hereditary hemorrhagic telangiectasia are not understood. Methods and Results-After a detailed immunohistochemical analysis of 129/Ola mice, which are heterozygous for a targeted deletion in the endoglin gene, we observed intrinsic abnormalities in the vascular walls throughout the cutaneous vasculature. Postcapillary venules were dilated, and up to 70% of the vascular wall had no smooth muscle cells. The supporting layers of collagens and elastin were irregular, with thin areas, adding to the fragility of these vessels. A variable hemorrhagic phenotype was observed in which local bleeding is associated not only with fragile vessels but also with regions of inflammation. Conclusions-These findings have relevance to our understanding of the molecular basis of vascular integrity in a wide range of diseases.

Background-Development and rupture of aortic aneurysms involve a combination of complex biological processes.Rosiglitazone, a peroxisome proliferator-activated receptor-␥ agonist, has been shown to have a broad spectrum of effects in vivo. The hypothesis that rosiglitazone would reduce aneurysm expansion or rupture was tested in the angiotensin II (Ang II)-induced hypercholesterolemic mouse model. Methods and Results-Apolipoprotein E-deficient mice, 12 months of age, were allocated to 4 groups. Three groups were infused with Ang II (1 g · min Ϫ1 · kg Ϫ1 ), and the fourth was infused with saline. Rosiglitazone was given 1 week before infusion and 1 week after infusion. At day 28, aortic size was measured, and tissues were collected for analyses. Both pretreatment and posttreatment with rosiglitazone inhibited the occurrence of fatal rupture (11 of 30 versus 0 of 30 versus 0 of 15; Pϭ0.0013) and reduced maximal dilatation of the aorta (4.6Ϯ0.13 versus 2.4Ϯ0.48 versus 2.15Ϯ0.46 mm 2 ; PϽ0.0001). Blood glucose, total cholesterol, body weight, and atherosclerosis did not differ between groups. Pretreatment with rosiglitazone inhibited the Ang II-induced expression of angiotensin type 1a Ang II receptor while having no effect on the angiotensin type 2 Ang II receptor, in addition to reducing Ang II-induced expression of E-selectin, tumor necrosis factor-␣, and interleukin-6. Key Words: aneurysm Ⅲ aneurysm, ruptured Ⅲ angiotensin Ⅲ inflammation Ⅲ polymerase chain reaction Ⅲ PPAR gamma R upture of an aortic aneurysm is the third-commonest cause of sudden death after myocardial infarction and stroke. Approximately 5% of men Ͼ60 years of age will develop an abdominal aortic aneurysm. Currently, the only treatment option for patients with aneurysms is surgical repair when the aneurysm expands past a critical point (usually a diameter threshold of 5.5 cm). Screening programs have begun to identify a large number of patients with small aortic aneurysms who would benefit from targeted pharmacotherapy to reduce aneurysm expansion and rupture. Conclusions-Pretreatment Clinical Perspective on p 3132Any potential pharmacological strategy to modulate the natural history of the aneurysmal process must be targeted to the biological process that mediates aneurysm expansion and rupture. Much of our understanding of the human pathogenesis of abdominal aortic aneurysm, obtained from analysis of aneurysmal biopsies during open surgery, is limited to analysis of the end-stage disease. Histological examination has identified that degeneration of the medial elastic fibers and compensatory deposition of collagens are accompanied by adventitial hypertrophy and infiltration of macrophages and T and B lymphocytes. Atherosclerosis and thrombus formation also are features of abdominal aortic aneurysm. [1][2][3][4] It is most likely that the dynamic remodeling process mediating the vascular changes observed in aneurysm development is the result of an initial inflammatory response. Involvement of inflammation as an instigating mechanism has been co...

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