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: 11.02). 12/2009; 106(3):583-92. DOI: 10.1161/CIRCRESAHA.109.207852
Source: PubMed


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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    • "On the other hand, patients with fibulin-5 mutations present with cutis laxa, emphysema, and supravalvular aortic stenosis, but without aortic aneurysm and skeletal connective tissue abnormalities (Callewaert et al. 2013; Loeys et al. 2002). Previous studies of fibulin-4 global and conditional null mice have focused on the elastic fiber abnormalities in the vascular and pulmonary systems (Horiguchi et al. 2009; Huang et al. 2010; McLaughlin et al. 2006). However, in these studies, no determinations have been made as to whether the loss of fibulin-4 leads to skeletal and other systemic connective tissue anomalies resembling those seen in human patients. "
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    ABSTRACT: Fibulin-4 is an extracellular matrix glycoprotein essential for elastic fiber formation. Mice deficient in fibulin-4 die perinatally because of severe pulmonary and vascular defects associated with the lack of intact elastic fibers. Patients with fibulin-4 mutations demonstrate similar defects, and a significant number die shortly after birth or in early childhood from cardiopulmonary failure. The patients also demonstrate skeletal and other systemic connective tissue abnormalities, including joint laxity and flexion contractures of the wrist. A fibulin-4 null mouse strain was generated and used to analyze the roles of fibulin-4 in tendon fibrillogenesis. This mouse model displayed bilateral forelimb contractures, in addition to pulmonary and cardiovascular defects. The forelimb and hindlimb tendons exhibited disruption in collagen fibrillogenesis in the absence of fibulin-4 as analyzed by transmission electron microscopy. Fewer fibrils were assembled, and fibrils were disorganized compared with wild-type controls. The organization of developing tenocytes and compartmentalization of the extracellular space was also disrupted. Fibulin-4 was co-localized with fibrillin-1 and fibrillin-2 in limb tendons by using immunofluorescence microscopy. Thus, fibulin-4 seems to play a role in regulating tendon collagen fibrillogenesis, in addition to its essential function in elastogenesis.
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    • "SMCs secrete a large amount of the blood vessel ECM, consisting mainly of Laminin, Collagen IV, Nidogen, Perlecan, and Fibulins. Secretion of ECM from vSMCs is vital, as loss of the collagen Col4a1 leads to perinatal hemorrhage [19], while loss of Fibulin4 leads to aneurysms [20], [21]. "
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    • "EFEMP2 EGF containing fibulin-like extracellular matrix protein 2 11 Cutis laxa Huang et al. (2010) [92] "
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    ABSTRACT: Aortic aneurysm is a deceptively indolent disease that can cause severe complications such as aortic rupture and dissection. In the normal aorta, vascular smooth muscle cells within the medial layer produce and sustain the extracellular matrix (ECM) that provides structural support but also retains soluble growth factors and regulates their distribution. Although the ECM is an obvious target to identify molecular processes leading to structural failure within the vessel wall, an in-depth proteomics analysis of this important sub-proteome has not been performed. Most proteomics analyses of the vasculature to date used homogenized tissue devoid of spatial information. In such homogenates, quantitative proteomics comparisons are hampered by the heterogeneity of clinical samples (i.e. cellular composition) and the dynamic range limitations stemming from highly abundant cellular proteins. An unbiased proteomics discovery approach targeting the ECM instead of the cellular proteome may decipher the complex, multivalent signals that are presented to cells during aortic remodelling. A better understanding of the ECM in healthy and diseased vessels will provide important pathogenic insights and has potential to reveal novel biomarkers.
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