Fibrillins 1 and 2 Perform Partially Overlapping Functions during Aortic Development

Abstract

Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Elastogenesis is a complex biological process that involves the organized deposition and self-assembly of several macromolecules into microfibrils and elastic fibers (1). Elastic fibers are made of an amorphous core of cross-linked elastin and other molecules and microfibrils; the latter are heterogeneous in composition and can also form macroaggregates devoid of elastin (2, 3). Fibrillins 1 and 2 are the main structural components of extracellular microfibrils and the defective gene products in Marfan syndrome (MFS) 3 and congenital contractural arachnodactyly (CCA), respectively (4, 5). MFS is a pleiotropic disorder of the connective tissue with wide variation in clinical severity (6). Cardiovascular manifestations in the form of aortic dilatation, dissection, and rupture contribute significantly to morbidity and mortality in affected individuals. CCA, on the other hand, is a rare condition akin to MFS but with major manifestations confined to the musculoskeletal system (6). Fibrillins are large cysteine-rich glycoproteins (ϳ350 kDa) composed primarily of multiple repeated domains homologous to the calcium binding epidermal growth factor module and of distinct 8-cysteine modules (2, 3, 5). Fibrillins polymerize into a characteristic beadson-a-string microfibril structure, which gives rise to the microfibril lattice by lateral association of the individual microfibril polymers and probable association of other structural components. Fibrillins can form homo-or heteropolymeric microfibrils and can interact with integrins, growth factors, several other matrix components, and latent transforming growth factor ␤-binding proteins.Differential expression of elastic fiber components, dynamic cell-matrix interactions, and microfibril-mediated modulation of signaling molecules account for the diverse architectures and functions of elastic networks during the development and growth of individual organ systems (5). The process of aortic media formation is an illustrative example of the interplay between resident cells and elastic fiber components that ultimately results in the highly organized and functionally competent tissue (7,8). At about mid-gestation, vascular smooth muscle cells (VSMC) deposit fibrillins and tropoelastin molecules into the surrounding matrix and begin to organize them into elastic fibers. The latter process extends into early neonatal life accompanied by the gradual growth of elastic fibers into mature elastic lamellae that separate parallel layers of quiescent VSMC. The resulting organization of th...

New insights into elastic fiber assembly

“…Expression of these proteins remains high until P0 when they quickly drop to lower levels and oscillate around this value through adulthood. The fbn2 expression pattern supports the hypothesis that fibrillin-2 is involved in the initial assembly of microfibrils, but plays a lesser role in elastic fiber assembly (Carta et al, 2006). The relative amounts of each protein on the gene array may explain some phenotypes in the knockout mice.…”

“…The elastic fibers in the aorta are even thinner and more fragmented than fbn12/2 mice. This indicates that fibrillin-1 may compensate for the loss of fibrillin-2 and that fibrillin-2 may be involved in the initial assembly of aortic microfibrils (Carta et al, 2006).…”

“…Mice lacking the fibrillin-1 gene (fbn12/2) die within two weeks of birth from vascular and pulmonary complications, including ruptured aortic aneurysms, impaired breathing and diaphragmatic collapse. The elastic fibers in the aorta are abnormally thin and fragmented (Carta et al, 2006). Mice lacking the fibrillin-2 gene (fbn22/2) develop syndactyly, but show no defects in the vascular and pulmonary systems and have a normal lifespan.…”

“…Mice lacking the fibrillin-2 gene (fbn22/2) develop syndactyly, but show no defects in the vascular and pulmonary systems and have a normal lifespan. The elastic fibers in the aorta look normal (Arteaga-Solis et al, 2001;Chaudhry et al, 2001;Carta et al, 2006). Mice deficient in both fibrillins (fbn12/2;fbn22/2) die in utero.…”

Fibrillin-3 expression in human development

“…Microfibrils are found associated with elastic fibers or they can remain devoid of elastin and are then frequently associated with basement membranes (Low, 1962;Ross and Bornstein, 1969). They fulfill a wide range of physiological functions from providing a scaffold for elastic fiber assembly Carta et al, 2006), to acting as stress-bearing entities for example in the ciliary zonules of the eye (Raviola, 1971), to serving as reservoirs and regulators for growth factors of the TGF-β superfamily (for reviews see Hubmacher et al, 2006;Ramirez and Rifkin, 2009;Nistala et al, 2010). These functional aspects of microfibrils are critical for proper development documented by the clinical symptoms found in microfibrillopathies and the phenotypes of several mouse models (Hubmacher et al, 2006;Robinson et al, 2006).…”