Insights into elastic fiber fragmentation: Mechanisms and treatment of aortic aneurysm in Marfan syndrome

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in fibrillin 1 (FBN1) gene. These mutations result in defects in the skeletal, ocular, and cardiovascular systems. Aortic aneurysm is the leading cause of premature mortality in untreated MFS patients. Elastic fiber fragmentation in the aortic vessel wall is a hallmark of MFS-associated aortic aneurysms. FBN1 mutations result in FBN1 fragments that also contribute to elastic fiber fragmentation. Although recent research has advanced our understanding of MFS, the contribution of elastic fiber fragmentation to the pathogenesis of aneurysm formation remains poorly understood. This review provides a comprehensive overview of the molecular mechanisms of elastic fiber fragmentation and its role in the pathogenesis of aortic aneurysm progression. Increased comprehension of elastic fragmentation has significant clinical implications for developing targeted interventions to block aneurysm progression, which would benefit not only individuals with Marfan syndrome but also other patients with aneurysms. Moreover, this review highlights an overlooked connection between inhibiting aneurysm and the restoration of elastic fibers in the vessel wall with various aneurysm inhibitors, including drugs and chemicals. Investigating the underlying molecular mechanisms could uncover innovative therapeutic strategies to inhibit elastin fragmentation and prevent the progression of aneurysms.

Keywords: Angiotensin receptor blocker (ARB); Aortic aneurysm; Elastic fiber fragmentation; Elastin; Fibrillin-1; Losartan; MMP; Marfan syndrome; TGF-β.

Figure 1.. Schematic illustration of Fibrillin-1 gene and FBN1 protein.

(A) FBN1 consists of calcium binding EGF domains interspersed by TGF-B binding domains, EGF-like/not-calcium binding domains and hybrid domains. The integrin binding site RGD is indicated by the star. (B) Schematic illustration of calcium binding epidermal growth factor-like motif (cbEGF) in FBN1. The disulfide bridges (dashed lines) between cysteine residues (red circle) and the key calcium (blue circle) maintain the global structure of cbEGF and prevent

Figure 2.. Schematic representation of the elastin-integrin-contractile unit of VSMCs in the tunica media of the aorta.

(A) The tunica media is flanked by external elastic lamina (EEL) and internal elastic lamina (IEL). It contains layers of elastic fibers, vascular smooth-muscle cells (VSMCs) and interlamellar matrix including type-I collagen, type-III collagen and FBN1-rich microfibrils. (B) Elastic fibers are composed predominantly of elastin cores and FBN1-microfibrils. The FBN1 polypeptide with RGD sequence interacts with α_vβ₃ integrins on the cell surface of VSMCs and plays an important role in cell attachment and adhesion. TGF-β is sequestered as a large latent complex (LLC) composed of TGF-β, latency associated peptide (LAP), and latent TGFβ binding protein

Figure 3.. VSMC phenotypic modulation and acquired elastolysis in Marfan syndrome.

(A) Interlamellar matrix deficiency in MFS results in the loss of cellular adhesions over time, initiating VSMC phenotypic changes from the contractile state to the synthetic state, and these cells contribute to early elastolysis through the secretion of MMPs. (B) Later, elastolysis is associated with the infiltration of immune cells into the media. VSMC: vascular smooth muscle cell.

Figure 4.. Schematic diagram showing the role of FBN1 fragments in the vicious cycle of MMP expression and elastin fragmentation.

Fragmented fibrillin with RGD site binds to integrins which activates the ERK1/2, JNK1/2, P38α signaling pathways, leading to an increase in MMP expression.

Figure 5.. Chemotactic elastin/FBN1 fragments bind to EBP within ERC to activate the vicious cycle of MMP production.

The GxxPG motif in elastin and FBN1 fragments bind to EBP on neighboring cells to trigger downstream ERK1/2 and AKT pathways, leading to subsequent events such as the upregulation of MMPs and macrophage chemotaxis, resulting in further elastic fiber fragmentation. ERC (elastin receptor complex) contains EBP (Elastin-binding-protein) and PPCA (protective

Figure 6.. Microfibril fragmentation leads to the release of TGF-β in Marfan Syndrome.

Under normal conditions, LAP with TGF-β binds to microfibrils through LTBP. Microfibril fragmentation causes the dissociation of TGF-β from LTBP. LAP: latency-associated peptide; LTBP: latent transforming growth factor binding protein.

Figure 7.. TGF-β regulates gene transcription via Smad dependent and Smad independent pathways in SMCs and other cell types.

p: phosphorylation; Smad: small mothers against decapentaplegic protein.

Figure 8.. A diagram illustrating the connection between inhibiting aneurysm and restoring elastic fibers with various aneurysm inhibitors.

Elastic fiber fragmentation is prevalent in the vessel wall of a variety of aneurysms. Intriguingly, aneurysm inhibitors can restore the integrity of elastic fibers. TGF-β blocker: TGF-β Ab; ARB: Angiotensin Type I Receptor (ATI) blocker; PGG: Pentagalloyl glucose. L: lumen; A: adventitia.