Renal cystic disease in the Fbn1(C1039G/+) Marfan mouse is associated with enhanced aortic aneurysm formation.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), resulting in aortic aneurysm formation and dissections. Interestingly, variable aortopathy is observed even within MFS families with the same mutation. Thus, additional risk factors determine disease severity. Here, we describe a case of a 2-month-old Fbn1C1039G/+ MFS mouse with extreme aortic dilatation and increased vascular inflammation, when compared to MFS siblings, which coincided with unilateral renal cystic disease. In addition, this mouse presented with increased serum levels of creatinine, angiotensin-converting enzyme, corticosterone, macrophage chemoattractant protein-1, and interleukin-6, which may have contributed to the vascular pathology. Possibly, cystic kidney disease is associated with aneurysm progression in MFS patients. Therefore, we propose that close monitoring of the presence of renal cysts in MFS patients, during regular vascular imaging of the whole aorta trajectory, may provide insight in the frequency of cystic kidney disease and its potential as a novel indicator of aneurysm progression in MFS patients.

Hibender S ，Wanga S ，van der Made I ，Vos M ，Mulder BJ ，Balm R ，de Vries CJ ，de Waard V ... -  《-》

Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model.

Hibender S ，Franken R ，van Roomen C ，Ter Braake A ，van der Made I ，Schermer EE ，Gunst Q ，van den Hoff MJ ，Lutgens E ，Pinto YM ，Groenink M ，Zwinderman AH ，Mulder BJ ，de Vries CJ ，de Waard V ... -  《-》

Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm.

Pedroza AJ ，Tashima Y ，Shad R ，Cheng P ，Wirka R ，Churovich S ，Nakamura K ，Yokoyama N ，Cui JZ ，Iosef C ，Hiesinger W ，Quertermous T ，Fischbein MP ... -  《-》

miR-29b participates in early aneurysm development in Marfan syndrome.

Merk DR ，Chin JT ，Dake BA ，Maegdefessel L ，Miller MO ，Kimura N ，Tsao PS ，Iosef C ，Berry GJ ，Mohr FW ，Spin JM ，Alvira CM ，Robbins RC ，Fischbein MP ... -  《-》

Aortopathy in a Mouse Model of Marfan Syndrome Is Not Mediated by Altered Transforming Growth Factor β Signaling.

Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin-1 (FBN1); however, the mechanisms through which fibrillin-1 deficiency causes MFS-associated aortopathy are uncertain. Recently, attention was focused on the hypothesis that MFS-associated aortopathy is caused by increased transforming growth factor-β (TGF-β) signaling in aortic medial smooth muscle cells (SMC). However, there are many reasons to doubt that TGF-β signaling drives MFS-associated aortopathy. We used a mouse model to test whether SMC TGF-β signaling is perturbed by a fibrillin-1 variant that causes MFS and whether blockade of SMC TGF-β signaling prevents MFS-associated aortopathy. MFS mice (Fbn1C1039G/+ genotype) were genetically modified to allow postnatal SMC-specific deletion of the type II TGF-β receptor (TBRII; essential for physiologic TGF-β signaling). In young MFS mice with and without superimposed deletion of SMC-TBRII, we measured aortic dimensions, histopathology, activation of aortic SMC TGF-β signaling pathways, and changes in aortic SMC gene expression. Young Fbn1C1039G/+ mice had ascending aortic dilation and significant disruption of aortic medial architecture. Both aortic dilation and disrupted medial architecture were exacerbated by superimposed deletion of TBRII. TGF-β signaling was unaltered in aortic SMC of young MFS mice; however, SMC-specific deletion of TBRII in Fbn1C1039G/+ mice significantly decreased activation of SMC TGF-β signaling pathways. In young Fbn1C1039G/+ mice, aortopathy develops in the absence of detectable alterations in SMC TGF-β signaling. Loss of physiologic SMC TGF-β signaling exacerbates MFS-associated aortopathy. Our data support a protective role for SMC TGF-β signaling during early development of MFS-associated aortopathy.

Wei H ，Hu JH ，Angelov SN ，Fox K ，Yan J ，Enstrom R ，Smith A ，Dichek DA ... -  《Journal of the American Heart Association》