Fibulin-4 Deficiency Results in Ascending Aortic Aneurysms A Potential Link Between Abnormal Smooth Muscle Cell Phenotype and Aneurysm Progression

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Circulation Research (Impact Factor: 11.09). 12/2009; 106(3):583-92. DOI: 10.1161/CIRCRESAHA.109.207852
Source: PubMed

ABSTRACT Loss of fibulin-4 during embryogenesis results in perinatal lethality because of aneurysm rupture, and defective elastic fiber assembly has been proposed as an underlying cause for the aneurysm phenotype. However, aneurysms are never seen in mice deficient for elastin, or for fibulin-5, which absence also leads to compromised elastic fibers.
We sought to determine the mechanism of aneurysm development in the absence of fibulin-4 and establish the role of fibulin-4 in aortic development.
We generated germline and smooth muscle cell (SMC)-specific deletion of the fibulin-4 gene in mice (Fbln4(GKO) and Fbln4(SMKO), respectively). Fbln4(GKO) and Fbln4(SMKO) aortic walls fail to fully differentiate, exhibiting reduced expression of SM-specific contractile genes and focal proliferation of SMCs accompanied by degenerative changes of the medial wall. Marked upregulation of extracellular signal-regulated kinase 1/2 signaling pathway was observed in the aneurysmal wall of Fbln4(GKO) and Fbln4(SMKO) mice and both mutants developed aneurysm predominantly in the ascending thoracic aorta. In vitro, Fbln4(GKO) SMCs exhibit an immature SMC phenotype with a marked reduction of SM-myosin heavy chain and increased proliferative capacity.
The vascular phenotype in Fbln4 mutant mice is remarkably similar to a subset of human thoracic aortic aneurysms caused by mutations in SMC contractile genes. Our study provides a potential link between the intrinsic properties of SMCs and aneurysm progression in vivo and supports the dual role of fibulin-4 in the formation of elastic fibers as well as terminal differentiation and maturation of SMCs in the aortic wall.

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    • "Increased TGFbeta activity was demonstrated in aortic walls of both LDS and MFS patients. Subsequently, dysregulated TGFbeta signaling was found in other syndromic and non-syndromic forms of TAAD [Coucke et al., 2006; Zhu et al., 2006; Guo et al., 2007; Hanada et al., 2007; Gomez et al., 2009; Guo et al., 2009; Huang et al., 2010; Wang et al., 2010; Renard et al., 2011] and it was hypothesized that different molecular defects in TAAD may account for different pathogenetic mechanisms of enhanced TGFbeta signaling [Renard et al., 2011]. "
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    • "A similar phenotype is also shared by mice deficient in fibulin-4. These mice display ascending aortic aneurysms also thought to originate from defects in elastin assembly (Huang et al., 2010). Here deletion of β1 integrin prevents the organization ECM proteins leading to aneurysms and indicate that this molecule is also critical to the functional compliance of the ECM in the vessel wall. "
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    • "Similar lessons were derived from the study of a fibulin-4 (Fbln4) smooth muscle knockout model [Huang et al., 2010]. "
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