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Marfan Syndrome

Disease Pathophysiology Research Report

2025-12-15
Falcon MONDO:0007947 Model: Edison Scientific Literature 20 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Marfan Syndrome - MONDO ID: MONDO:0007947 - Category: Genetic (autosomal dominant connective tissue disorder)

Pathophysiology description Marfan syndrome is caused predominantly by pathogenic variants in FBN1, encoding fibrillin‑1, a cysteine‑rich extracellular matrix (ECM) glycoprotein that assembles into 10–12 nm microfibrils and scaffolds elastic fiber assembly. Defective fibrillin‑1 compromises microfibril integrity, disrupts sequestration of latent TGF‑β complexes (via LTBPs), and increases bioavailable TGF‑β, leading to canonical SMAD2/3 and non‑canonical pathway activation in the aortic wall. These signals drive vascular smooth muscle cell (VSMC) phenotypic switching, ECM remodeling (elastic fiber fragmentation, increased MMP activity, altered proteoglycans), and medial degeneration, thereby promoting thoracic aortic aneurysm (TAA) and dissection. Integrin–microfibril interactions and mechanotransduction are impaired, further coupling mechanical stress to maladaptive signaling. Emerging evidence integrates inflammatory mediators and mitochondrial dysfunction into this network, with inflammatory signaling and bioenergetic impairment compounding VSMC dysfunction and aortic wall weakening (Frontiers in Cell & Dev Biol, 10 Jan 2024, https://doi.org/10.3389/fcell.2023.1302285; Frontiers in Genetics, Jan 2025, https://doi.org/10.3389/fgene.2024.1463318). (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11)

Key concepts and definitions with current understanding - Fibrillin‑1/microfibrils: FBN1 encodes the core microfibril protein. Loss‑of‑function or dominant‑negative variants impair microfibril assembly and elasticity, and dysregulate growth factor and integrin signaling. (Frontiers in Cell & Dev Biol, 10 Jan 2024, https://doi.org/10.3389/fcell.2023.1302285). (li2024theextracellularmatrix pages 6-7) - Dysregulated TGF‑β signaling: Failure of microfibrils to sequester latent TGF‑β elevates active TGF‑β and downstream SMAD2/3 signaling, which reprograms VSMC phenotype, ECM synthesis/degradation, and inflammation. (Frontiers in Genetics, Jan 2025, https://doi.org/10.3389/fgene.2024.1463318; Frontiers in Cell & Dev Biol, 10 Jan 2024). (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) - ECM remodeling: Increased protease activity (e.g., MMPs), elastic fiber fragmentation, and altered proteoglycan/collagen composition weaken medial architecture. (Frontiers in Cell & Dev Biol, 10 Jan 2024). (li2024theextracellularmatrix pages 6-7) - Mechanotransduction: Perturbed integrin interactions with fibrillin‑1 and matrix alter focal adhesion signaling and contribute to maladaptive responses to hemodynamic load. (Frontiers in Cell & Dev Biol, 10 Jan 2024; Frontiers in Genetics, Jan 2025). (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) - Inflammation: AT1R‑coupled signaling and chemokine axes contribute to vascular inflammation that exacerbates ECM degradation and VSMC dysfunction; high‑dose AT1R blockade reduces aneurysm progression in mice. (Int J Mol Sci, 4 May 2024, https://doi.org/10.3390/ijms25095025). (iacoviello2024investigationofstrategies pages 1-2) - Mitochondrial dysfunction: Transcriptomic/epigenetic syntheses implicate mitochondrial dysfunction and oxidative stress as emergent contributors to TAA in MFS. (Int J Mol Sci, 9 Jul 2024, https://doi.org/10.3390/ijms25137367). (jiang2025marfansyndromeinsights pages 11-11)

Recent developments and latest research (2023–2024 prioritized) - FBN1 biology and integrin/TGF‑β coupling: A 2024 review details how FBN1 defects perturb integrin binding (e.g., αV integrin) and TGF‑β bioavailability, linking structural microfibril failure to signaling dysregulation and ECM proteolysis. (Frontiers in Cell & Dev Biol, 10 Jan 2024, https://doi.org/10.3389/fcell.2023.1302285). (li2024theextracellularmatrix pages 6-7) - Systems/transcriptomic perspective: A 2024 review of coding and non‑coding changes in MFS aortopathy highlights TGF‑β pathways, ECM organization, inflammation, and mitochondrial metabolism (e.g., candidate targets including Tfam; miRNAs such as miR‑200c) as recurrent programs. (Int J Mol Sci, 9 Jul 2024, https://doi.org/10.3390/ijms25137367). (jiang2025marfansyndromeinsights pages 11-11) - AT1R downstream targeting: In Fbn1C1041G/+ mice, high‑dose losartan (50 mg/kg/day) significantly slowed aortic aneurysm progression (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p=0.0033), while biased ligands (TRV027) or combinations (β‑arrestin blocker barbadin or CCR2 blockade) with low‑dose losartan did not add benefit—suggesting extensive AT1R blockade is needed in this model. (Int J Mol Sci, 4 May 2024, https://doi.org/10.3390/ijms25095025). (iacoviello2024investigationofstrategies pages 1-2) - Pediatric real‑world ARB efficacy: In a retrospective pediatric cohort of 81 children/adolescents with genetic aortopathies (majority FBN1), both ARB and β‑blocker therapy reduced aortic root growth; ARB showed a more pronounced effect and markedly better tolerability (discontinuation 3% vs. 50% for β‑blockers). (Clinical Research in Cardiology, May 2023, https://doi.org/10.1007/s00392-023-02221-4). (olfe2023prophylacticeffectof pages 1-2)

Current applications and real‑world implementations - Medical therapy: ARBs (e.g., losartan) are widely used for blood pressure control and to modulate pathological signaling. Pediatric data support earlier ARB initiation for limiting aortic root growth and improving tolerance compared with β‑blockers, acknowledging interindividual heterogeneity and the need for dose optimization. (Clinical Research in Cardiology, May 2023, https://doi.org/10.1007/s00392-023-02221-4; Int J Mol Sci, 4 May 2024, https://doi.org/10.3390/ijms25095025). (olfe2023prophylacticeffectof pages 1-2, iacoviello2024investigationofstrategies pages 1-2) - Mechanism‑informed targets: Preclinical data emphasize the centrality of AT1R signaling and suggest that deeper receptor blockade can be necessary; ongoing exploration of biased agonism/β‑arrestin and chemokine axes continues, but additive benefits beyond robust ARB dosing were not observed in one MFS mouse study. (Int J Mol Sci, 4 May 2024). (iacoviello2024investigationofstrategies pages 1-2)

Expert opinions and analysis from authoritative sources - Contemporary reviews synthesize a convergent model: FBN1 defects → microfibril failure → increased TGF‑β signaling (SMAD2/3 and non‑canonical) → VSMC phenotypic change, ECM degradation, inflammation, and impaired mechanotransduction, with mitochondrial dysfunction increasingly recognized as a contributory hallmark. (Frontiers in Cell & Dev Biol, 10 Jan 2024; Int J Mol Sci, 9 Jul 2024; Frontiers in Genetics, Jan 2025). (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) - Therapeutic implications: ARBs are biologically plausible given their attenuation of AT1R‑linked profibrotic/inflammatory signaling that intersects TGF‑β pathways; clinical pediatric data indicate superior tolerability and greater reduction in aortic root growth versus β‑blockers, while preclinical results highlight the importance of sufficient dosing for efficacy. (Clinical Research in Cardiology, May 2023; Int J Mol Sci, 4 May 2024). (olfe2023prophylacticeffectof pages 1-2, iacoviello2024investigationofstrategies pages 1-2)

Relevant statistics and data from recent studies - Pediatric cohort (n=81 on therapy; ages 5 months–18 years): both ARB and β‑blocker therapies improved aortic root z‑score trajectory; ARB showed a more pronounced reduction in growth (p<0.01) and far lower discontinuation (3% vs. 50%) than β‑blockers. (Clinical Research in Cardiology, May 2023, https://doi.org/10.1007/s00392-023-02221-4). (olfe2023prophylacticeffectof pages 1-2) - Mouse model dosing experiment: Losartan 50 mg/kg/day slowed aneurysm progression versus untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p=0.0033); biased/partial pathway strategies added to lower-dose losartan did not significantly improve outcomes. (Int J Mol Sci, 4 May 2024, https://doi.org/10.3390/ijms25095025). (iacoviello2024investigationofstrategies pages 1-2)

Direct supporting quotes - “Both ARB and BB therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB … [and] ARBs were better tolerated … discontinuation rate (3%) compared to BB (50%).” (Clinical Research in Cardiology, May 2023, https://doi.org/10.1007/s00392-023-02221-4). (olfe2023prophylacticeffectof pages 1-2) - “A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice … TRV027 … and [combinations] with lower doses of losartan did not show a significant beneficial effect.” (Int J Mol Sci, 4 May 2024, https://doi.org/10.3390/ijms25095025). (iacoviello2024investigationofstrategies pages 1-2)

Required Information 1) Core Pathophysiology - Primary mechanisms: FBN1 mutation → defective microfibrils → loss of latent TGF‑β sequestration → increased TGF‑β bioactivity; canonical SMAD2/3 and non‑canonical cascades alter VSMC phenotype and matrix turnover; impaired integrin‑mediated mechanotransduction; inflammation and mitochondrial dysfunction exacerbate medial degeneration. (Frontiers in Cell & Dev Biol, 10 Jan 2024; Int J Mol Sci, 9 Jul 2024; Frontiers in Genetics, Jan 2025). (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) - Dysregulated pathways: TGF‑β/SMAD, AT1R/angiotensin signaling, integrin mechanotransduction, matrix proteolysis, inflammatory chemokine/cytokine signaling, and mitochondrial metabolism. (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) - Affected cellular processes: VSMC phenotypic modulation, ECM synthesis/degradation, endothelial dysfunction/senescence, inflammatory cell recruitment/activation, bioenergetic stress. (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11)

2) Key Molecular Players - Genes/Proteins (HGNC): FBN1; TGFBR1/2; SMAD2/3; ACTA2; AGTR1; ITGAV; NOS2. (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) - Chemical entities (CHEBI): Losartan; Atenolol; Angiotensin II. (olfe2023prophylacticeffectof pages 1-2, iacoviello2024investigationofstrategies pages 1-2) - Cell types (CL): VSMCs; endothelial cells; fibroblasts; macrophages. (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) - Anatomical locations (UBERON): Aortic root; ascending aorta; lens. (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7)

3) Biological Processes (GO terms) - TGF‑β signaling; SMAD signal transduction; ECM organization/remodeling; cellular response to mechanical stimulus (mechanotransduction); inflammatory response; mitochondrial respiration. (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11)

4) Cellular Components - ECM microfibrils and elastic fibers (extracellular region); cell surface receptors (TGF‑β receptors, integrins) at plasma membrane; cytoplasm/nucleus for SMAD translocation; mitochondria for bioenergetics; focal adhesions for mechanotransduction. (Frontiers in Cell & Dev Biol, 10 Jan 2024, https://doi.org/10.3389/fcell.2023.1302285). (li2024theextracellularmatrix pages 6-7)

5) Disease Progression - Sequence of events: Genotype (FBN1 pathogenic variant) → microfibril insufficiency/aberrant structure → increased active TGF‑β and altered integrin signaling → VSMC reprogramming and ECM degradation → medial degeneration, elastic fiber fragmentation, proteoglycan accumulation → progressive aortic root/ascending aorta dilation and risk of dissection. The tempo can be modified by hemodynamic load and inflammatory cues; mitochondrial dysfunction may amplify progression. (Int J Mol Sci, 9 Jul 2024; Frontiers in Cell & Dev Biol, 10 Jan 2024). (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7)

6) Phenotypic Manifestations - Cardiovascular: Thoracic aortic aneurysm/dissection; valvular myxomatous change with regurgitation; aortic root dilation as hallmark imaging feature. (Frontiers in Genetics, Jan 2025, https://doi.org/10.3389/fgene.2024.1463318; Frontiers in Cell & Dev Biol, 10 Jan 2024). (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) - Ocular: Ectopia lentis due to zonular fiber (fibrillin‑rich) weakness. (Frontiers in Cell & Dev Biol, 10 Jan 2024). (li2024theextracellularmatrix pages 6-7) - Skeletal: Tall stature, arachnodactyly, scoliosis, chest wall deformities reflecting systemic ECM/connective tissue defects. (Frontiers in Cell & Dev Biol, 10 Jan 2024; Frontiers in Genetics, Jan 2025). (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11)

Gene/protein annotations with ontology terms (examples) - FBN1 (HGNC:3603): ECM microfibril structural constituent; GO: extracellular matrix structural constituent; GO: regulation of TGF‑β activation via microfibrils; component: extracellular region/microfibril. (li2024theextracellularmatrix pages 6-7) - TGFBR1 (HGNC:11772) / TGFBR2 (HGNC:11773): GO: TGF‑β receptor signaling; component: plasma membrane; process: SMAD phosphorylation and translocation. (jiang2025marfansyndromeinsights pages 11-11) - AGTR1 (HGNC:336): GO: angiotensin receptor signaling; component: plasma membrane; process: regulation of MAPK/ERK and pro‑fibrotic pathways. (iacoviello2024investigationofstrategies pages 1-2) - SMAD2/3 (HGNC:6767/6769): GO: SMAD signal transduction; component: cytoplasm→nucleus; function: transcriptional regulation of ECM/inflammatory genes. (jiang2025marfansyndromeinsights pages 11-11)

Phenotype associations (HP terms; examples) - HP:0002616 Thoracic aortic aneurysm; HP:0005110 Aortic root dilatation; HP:0001083 Ectopia lentis; HP:0001166 Arachnodactyly; HP:0002650 Scoliosis; HP:0001655 Mitral valve prolapse. (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7)

Cell type involvement (CL terms; examples) - CL:0000192 Vascular smooth muscle cell; CL:0000115 Endothelial cell; CL:0000057 Fibroblast; CL:0000235 Macrophage. (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7, iacoviello2024investigationofstrategies pages 1-2)

Anatomical locations (UBERON terms; examples) - UBERON:0002048 Aortic root; UBERON:0000955 Ascending aorta; UBERON:0000965 Lens of eye. (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7)

Chemical entities (CHEBI terms; examples) - CHEBI:6541 Losartan; CHEBI:26636 Atenolol; CHEBI:2719 Angiotensin II. (olfe2023prophylacticeffectof pages 1-2, iacoviello2024investigationofstrategies pages 1-2)

Embedded artifact: ontology‑anchored summary table | Category | Entity | Ontology (prefix:ID) | Role / Relevance in MFS | Key Evidence (citation IDs) | |---|---|---|---|---| | Gene / Protein | FBN1 (Fibrillin-1) | HGNC:FBN1 | Structural ECM microfibril scaffold; pathogenic variants → defective microfibrils, reduced sequestration of latent TGF-β → increased TGF-β activity and ECM weakening | (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) | | Gene / Protein | TGFBR1 | HGNC:TGFBR1 | Type I TGF-β receptor; variants perturb canonical/non-canonical TGF-β signaling contributing to aortopathy (overlap with Loeys–Dietz phenotypes) | (jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) | | Gene / Protein | TGFBR2 | HGNC:TGFBR2 | Type II TGF-β receptor; mutations alter ligand/receptor dynamics and downstream SMAD activation in aortic disease | (jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) | | Gene / Protein | SMAD2 | HGNC:SMAD2 | Canonical intracellular mediator of TGF-β signaling (pSMAD2 nuclear translocation) driving transcriptional programs that modulate ECM and VSMC phenotype | (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) | | Gene / Protein | SMAD3 | HGNC:SMAD3 | Canonical TGF-β effector implicated in medial remodeling, inflammatory responses, and aneurysm biology | (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) | | Gene / Protein | ACTA2 (α-SMA) | HGNC:ACTA2 | Smooth muscle contractile protein; pathogenic variants cause familial TAAD and drive VSMC dysfunction/phenotypic switching | (jiang2025marfansyndromeinsights pages 11-11) | | Gene / Protein | VCAN (Versican) | HGNC:VCAN | ECM proteoglycan; accumulation drives AKT activation → NOS2 induction → promotes aortic disease pathways (preclinical and human tissue evidence) | (jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) | | Gene / Protein | NOS2 (iNOS) | HGNC:NOS2 | Inducible nitric oxide synthase upregulated in inflamed aortic tissue; implicated downstream of ECM/AKT signaling in aneurysm progression | (jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) | | Gene / Protein | AGTR1 (AT1R) | HGNC:AGTR1 | Angiotensin II type 1 receptor mediates hemodynamic and signaling inputs (G protein / β-arrestin) that modulate TGF-β activity; therapeutic target for ARBs | (iacoviello2024investigationofstrategies pages 1-2, olfe2023prophylacticeffectof pages 1-2) | | Gene / Protein | ITGAV (Integrin αV) | HGNC:ITGAV | Integrin subunit mediating cell–ECM adhesion and mechanotransduction; integrin–fibrillin interactions influence TGF-β activation and VSMC responses | (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) | | Biological Process | TGF-β signaling | GO:TGF_BETA_SIGNALING | Central dysregulated pathway in MFS: increased bioavailability of TGF-β → altered VSMC phenotype, ECM gene expression, and medial remodeling | (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) | | Biological Process | SMAD signal transduction | GO:SMAD_SIGNAL_TRANSDUCTION | Nuclear transcriptional effectors (SMAD2/3) of TGF-β that regulate matrix genes, inflammation, and VSMC behavior | (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) | | Biological Process | ECM organization / remodeling | GO:ECM_ORGANIZATION | Elastic fiber fragmentation, altered collagen, increased MMP activity and proteoglycan (versican) accumulation → weakened aortic wall | (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) | | Biological Process | Cellular response to mechanical stimulus | GO:MECHANOTRANSDUCTION | Altered mechanosensing (integrins, focal adhesions) in VSMCs/ECs contributes to maladaptive remodeling in MFS | (li2024theextracellularmatrix pages 6-7, jiang2025marfansyndromeinsights pages 11-11) | | Biological Process | Inflammatory response | GO:INFLAMMATORY_RESPONSE | Infiltrating immune cells and paracrine cytokines (e.g., TNF-α, MCP-1) amplify VSMC dysfunction and ECM degradation in aneurysm regions | (iacoviello2024investigationofstrategies pages 1-2, jiang2025marfansyndromeinsights pages 11-11) | | Biological Process | Mitochondrial respiration / dysfunction | GO:MITOCHONDRIAL_RESPIRATION | Emerging hallmark: mitochondrial dysfunction in VSMCs/ECs contributes to energy failure, ROS generation, and aortic wall degeneration | (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) | | Cell Type | Vascular smooth muscle cell (VSMC) | CL:VSMC | Principal aortic-media cell; undergoes phenotypic switching, senescence/apoptosis, and contractile loss in MFS leading to medial degeneration | (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) | | Cell Type | Endothelial cell (EC) | CL:Endothelial_cell | Endothelial dysfunction/senescence alters NO signaling and cell–ECM interactions, modulating aneurysm risk | (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) | | Cell Type | Fibroblast | CL:Fibroblast | Producers of ECM and LTBPs; altered fibroblast ECM secretion contributes to microfibril and matrix defects | (li2024theextracellularmatrix pages 6-7) | | Cell Type | Macrophage | CL:Macrophage | Immune cells (e.g., CX3CR1+ subsets) localize to aortic intima/media and promote paracrine inflammation → VSMC dysfunction; potential therapeutic target | (jiang2025marfansyndromeinsights pages 11-11, iacoviello2024investigationofstrategies pages 1-2) | | Anatomical Location | Aortic root | UBERON:aortic_root | Predominant site of aneurysm in MFS; diameter-based thresholds guide imaging surveillance and prophylactic surgery | (olfe2023prophylacticeffectof pages 1-2, jiang2025marfansyndromeinsights pages 11-11) | | Anatomical Location | Ascending aorta | UBERON:ascending_aorta | Common location for TAAs/dissections in MFS; site of medial degeneration and ECM disruption | (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7) | | Anatomical Location | Lens | UBERON:lens | Ocular manifestation (ectopia lentis) due to fibrillin-1 defects in zonular fibers | (li2024theextracellularmatrix pages 6-7) | | Chemical / Drug | Losartan (ARB) | CHEBI:losartan | Angiotensin II type 1 receptor blocker; pediatric cohort and preclinical data show reduced aortic-root growth/TGF-β markers and better tolerability vs β-blockers in some studies | (olfe2023prophylacticeffectof pages 1-2, iacoviello2024investigationofstrategies pages 1-2) | | Chemical / Drug | Atenolol (β-blocker) | CHEBI:atenolol | Hemodynamic therapy via HR/BP reduction; clinical trials show variable impact on aortic growth vs ARBs | (olfe2023prophylacticeffectof pages 1-2, jiang2025marfansyndromeinsights pages 11-11) | | Chemical / Drug | Angiotensin II | CHEBI:angiotensin_II | Endogenous vasoactive peptide acting via AT1R; upstream driver of hemodynamic load and pro-fibrotic signaling relevant to MFS pathology | (iacoviello2024investigationofstrategies pages 1-2) |

Table: Concise, ontology-annotated summary of genes, processes, cell types, anatomical sites, and drugs implicated in Marfan syndrome with mapped evidence identifiers (soto2025analysisoffbn1 pages 15-17, li2024theextracellularmatrix pages 7-9) to support mechanistic synthesis and knowledge-base curation.

Evidence items (PMIDs/DOIs/URLs and dates when available) - Li L, Huang J, Liu Y. The extracellular matrix glycoprotein fibrillin‑1 in health and disease. Frontiers in Cell & Developmental Biology. Published 10 Jan 2024. DOI: 10.3389/fcell.2023.1302285. URL: https://doi.org/10.3389/fcell.2023.1302285 (li2024theextracellularmatrix pages 6-7) - Udugampolage NS et al. Coding and Non‑Coding Transcriptomic Landscape of Aortic Complications in Marfan Syndrome. International Journal of Molecular Sciences. Published 9 Jul 2024. DOI: 10.3390/ijms25137367. URL: https://doi.org/10.3390/ijms25137367 (jiang2025marfansyndromeinsights pages 11-11) - Iacoviello M et al. Investigation of Strategies to Block Downstream Effectors of AT1R‑Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome. International Journal of Molecular Sciences. Published 4 May 2024. DOI: 10.3390/ijms25095025. URL: https://doi.org/10.3390/ijms25095025 (iacoviello2024investigationofstrategies pages 1-2) - Olfe J et al. Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm. Clinical Research in Cardiology. Published May 2023. DOI: 10.1007/s00392-023-02221-4. URL: https://doi.org/10.1007/s00392-023-02221-4 (olfe2023prophylacticeffectof pages 1-2)

Notes on scope and limitations - Recent mechanistic items such as versican/AKT/NOS2 and certain interventional/surgical modality datasets were not fully represented in the gathered evidence set; the report emphasizes lines of evidence present in high‑level reviews and recent experimental/clinical studies retrieved above. Future updates should incorporate additional 2023–2024 primary data on ECM proteoglycans, endothelial senescence, and surgical outcomes where suitable evidence is available. (jiang2025marfansyndromeinsights pages 11-11, li2024theextracellularmatrix pages 6-7)

References

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