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Elastin

Elastin is an extracellular matrix (ECM) protein that imparts elasticity, extensibility, and recoil to vertebrate tissues, enabling them to withstand repeated mechanical stress while returning to their original shape.^[1] Primarily synthesized during embryonic development and early postnatal periods, it forms insoluble, cross-linked fibers that constitute up to 90% of elastic structures in dynamic organs.^[1] With a remarkably long half-life of approximately 70 years, elastin degradation is limited, underscoring its role in long-term tissue resilience.^[1] Structurally, elastin derives from the precursor tropoelastin, a 60–72 kDa polypeptide encoded by the ELN gene on human chromosome 7q11, which is rich in hydrophobic amino acids such as glycine, alanine, valine, and proline (>75% non-polar content).^[1] These monomers are secreted by fibroblasts and smooth muscle cells, then enzymatically cross-linked via lysyl oxidase to form mature elastin fibers, often associated with microfibrils like fibrillin for structural support.^[2] The resulting network exhibits low stiffness (Young's modulus of 0.13–1.5 MPa) and high extensibility (up to 200% elongation), functioning as an efficient elastic energy storage mechanism through entropic elasticity driven by disordered polypeptide chains.^[2] Elastin is most abundant in load-bearing tissues, comprising 28–32% of the dry mass in the aorta, 2–4% in the skin's dermis, and significant portions in lungs, bladder, ligaments, and cartilage, where it facilitates functions like blood pressure accommodation, respiratory expansion, and skin flexibility.^[1]^[3] Its biomechanical properties—high resilience and reversible deformability—are essential for preventing tissue fatigue, though dysregulation in synthesis or degradation contributes to pathologies like aortic aneurysms and emphysema.^[2] Regulation involves matrix metalloproteinases (e.g., MMP-2, MMP-9), tissue inhibitors (TIMPs), and signaling molecules such as TGF-β, highlighting elastin's integration into broader ECM homeostasis.^[1]

Structure and Composition

Molecular Structure

Elastin is an insoluble, cross-linked polymer derived from the soluble precursor protein tropoelastin, which is encoded by the ELN gene located on the long arm of human chromosome 7q11.2.^[4] Tropoelastin has a molecular weight of approximately 72 kDa and features an unusual amino acid composition dominated by non-polar residues, including over 75% glycine, valine, alanine, and proline, while lacking tryptophan and cysteine.^[5] This composition contributes to its flexibility and hydrophobicity, enabling the protein's role in elastic tissues.^[6] The primary structure of tropoelastin consists of alternating hydrophobic and cross-linking domains, arising from the 34 exons of the ELN gene.^[6] Hydrophobic domains, rich in glycine, proline, alanine, and valine, adopt beta-turns and disordered coil conformations that provide the structural basis for elasticity.^[5] These regions feature repetitive motifs such as VPGVG (valine-proline-glycine-valine-glycine), which promote dynamic, irregular secondary structures without stable alpha-helices or beta-sheets.^[6] Cross-linking domains, in contrast, are hydrophilic and enriched with lysine residues arranged in motifs like KP (lysine-proline) or KA (lysine-alanine).^[6] These lysines undergo oxidative deamination by lysyl oxidase to form allysine aldehydes, which then react to create tetrafunctional cross-links, including desmosine and isodesmosine.^[5] Such cross-links stabilize the elastin polymer, rendering it insoluble and durable in the extracellular matrix.^[7] The elasticity of elastin arises from biophysical models emphasizing entropy-driven recoil, where random chain conformations in the relaxed state maximize disorder.^[8] Upon stretching, the hydrophobic domains align, reducing conformational entropy; relaxation then restores high-entropy randomness, enabling reversible extension up to 200% with minimal energy dissipation.^[8] This entropic mechanism, akin to rubber elasticity, is facilitated by the disordered coils in hydrophobic regions and the sparse cross-linking that maintains network integrity without rigidity.^[9]

Elastic Fibers

Elastic fibers represent a hierarchical assembly within the extracellular matrix, consisting of a central amorphous core primarily composed of crosslinked elastin, which accounts for approximately 90% of the fiber's mass, surrounded by a peripheral network of microfibrils rich in fibrillin that constitute the remaining 10%.^[1] These microfibrils, with diameters ranging from 10 to 12 nm, form a scaffold that guides the deposition and organization of the elastin core during fiber maturation.^[10] Mature elastic fibers exhibit diameters typically between 0.2 and 1.5 μm, allowing them to bundle into larger structures such as lamellae, particularly in dynamic tissues like arteries where they contribute to overall structural integrity.^[11] Interactions between elastin and fibrillin-1 occur through specific binding motifs, such as GxxPG sequences in fibrillin-1 that facilitate association with tropoelastin, the soluble precursor to elastin; additionally, these components support integrin-mediated cell adhesion, enabling cellular interactions with the fiber network via integrins like αvβ3.^[12]^[13] Visualization of elastic fibers relies on techniques such as transmission electron microscopy, which reveals the beaded appearance of microfibrils surrounding the dense elastin core, and histological staining with Verhoeff's method, which selectively highlights elastic fibers in black against a red counterstain for collagen.^[14]^[15] The structural organization of elastic fibers demonstrates evolutionary conservation across vertebrates, where they provide essential recoil properties to support physiological functions in extensible tissues.^[16]

Biosynthesis

Gene Expression and Tropoelastin

The human ELN gene, which encodes the tropoelastin precursor of elastin, is located on chromosome 7q11.23 and spans approximately 45 kb of genomic DNA.^[17] It consists of 34 in-frame exons, with exons 34 and 35 having been lost in higher primates, allowing for extensive alternative splicing that generates over 30 distinct mRNA isoforms without disrupting the open reading frame.^[17] These isoforms arise primarily from variable inclusion or exclusion of exons such as 22 (often skipped), and alternate splice sites in exons 8, 20, 24, and 26, resulting in tissue-specific variants that may subtly influence elastic fiber assembly and properties, though their precise functional roles remain under investigation.^[17] Transcription of the ELN gene is tightly regulated by the GC-rich promoter region, which lacks a TATA box and utilizes multiple transcription start sites.^[17] Key regulators include the myocardin-related transcription factor (MRTF), particularly MRTF-A, which acts as a potent coactivator of serum response factor (SRF) to drive ELN expression in vascular smooth muscle cells and fibroblasts during development and injury response.^[18] This MRTF/SRF pathway integrates cytoskeletal signals, such as actin polymerization, to enhance promoter activity, while growth factors like TGF-β1 and IGF-1 further potentiate transcription, contrasting with inhibitory effects from proinflammatory cytokines such as IL-1β and TNF-α.^[17] The resulting ELN mRNA is translated on ribosomes associated with the rough endoplasmic reticulum (RER) in elastogenic cells, yielding the ~72 kDa tropoelastin polypeptide.^[1] In the RER, tropoelastin undergoes limited post-translational modifications to ensure proper folding and stability. Proline residues are hydroxylated to hydroxyproline at approximately 20-24% of prolines, catalyzed by prolyl 4-hydroxylase, which contributes to structural rigidity; this hydroxylation occurs at specific, non-random sites.^[19]^[1] Unlike many extracellular matrix proteins, tropoelastin lacks significant glycosylation or other modifications such as disulfide bond formation, maintaining its hydrophobic character essential for subsequent self-assembly. Chaperones like BiP and FKBP65 assist in folding, while interaction with elastin-binding protein (EBP) prevents aggregation and targets the protein for export.^[1] Tropoelastin is secreted via the classical exocytic pathway, progressing from the RER through the Golgi apparatus for packaging into secretory vesicles.^[20] In the trans-Golgi network, the EBP-tropoelastin complex is concentrated into vesicles that fuse with the plasma membrane, releasing the precursor extracellularly through exocytosis; this process, observable in fibroblasts and smooth muscle cells, takes about 30 minutes under normal conditions and can be disrupted by agents like brefeldin A (which fuses ER/Golgi) or monensin (which blocks Golgi exit).^[20]^[1] ELN gene expression exhibits a distinct developmental profile, with peak tropoelastin production occurring during late gestation and the early postnatal period to support rapid elastic fiber formation in growing tissues like the vasculature and lungs.^[21] This surge aligns with organ maturation, after which expression declines sharply by adolescence, reaching low basal levels in adulthood due to the long half-life (~70 years) of mature elastin, ensuring limited turnover.^[1]

Assembly and Crosslinking

Following secretion, tropoelastin undergoes coacervation, a self-assembly process into globular aggregates driven by hydrophobic interactions between its non-polar domains, particularly those containing Val-Pro-Gly-Val-Gly motifs. This entropically favorable, endothermic event occurs at physiological pH (around 7.4) and temperature (37°C), where ordered water shells around hydrophobic residues dissipate, enabling monomer association into nanoparticles approximately 200 nm in diameter that further coalesce into 1–2 μm spherules and eventually fibrillar structures.^[22]^[23] These tropoelastin coacervates align and deposit onto preformed microfibril scaffolds composed primarily of fibrillin-1, which provides a beaded filamentous template essential for organized elastic fiber formation. Tropoelastin binds directly to fibrillin-1 via its C-terminal foot domain interacting with the N-terminal region of fibrillin-1, while fibulin-5 acts as a chaperone by bridging tropoelastin aggregates to these microfibrils, facilitating alignment and preventing premature aggregation.^[24]^[25] Crosslinking stabilizes the deposited tropoelastin into an insoluble elastin polymer through oxidative deamination of specific lysine residues, catalyzed by the copper-dependent enzyme lysyl oxidase (LOX) and its paralogs (LOXL1–4). LOX oxidizes the ε-amino group of lysine to form α-aminoadipic-δ-semialdehyde (allysine), which then undergoes spontaneous aldol condensations and Schiff base reactions to yield unique tetrafunctional crosslinks: desmosine and isodesmosine. These bridges interconnect four tropoelastin chains, typically within lysine-rich alanine-rich (KA) domains, rendering the structure highly stable. The initial oxidation reaction is:

\text{Lysine} + \text{O}_2 + \text{H}_2\text{O} \xrightarrow{\text{LOX}} \text{Allysine} + \text{NH}_3 + \text{H}_2\text{O}_2

Approximately 90% of tropoelastin lysines are modified into allysine or incorporated into crosslinks.^[22] Microfibrillar-associated proteins, such as MFAP-4, further assist in tropoelastin deposition by enhancing coacervation and colocalizing with fibrillin-1 scaffolds to promote proper fiber assembly. Post-crosslinking, the mature elastin network exhibits extreme insolubility due to its dense hydrophobic packing and extensive covalent bridges, conferring resistance to proteolytic degradation. In adults, elastin turnover is minimal, with a half-life exceeding 70 years and negligible new synthesis, ensuring long-term tissue resilience.

Function

Elastic Recoil Mechanism

Elastin's elastic recoil is fundamentally a passive process driven by biophysical forces that enable reversible deformation without significant energy storage, distinguishing it from crystalline springs. In the classical entropy elasticity model, the protein's disordered polypeptide chains exist in a highly random, high-entropy configuration at rest; upon stretching, these chains align and straighten, decreasing configurational entropy, and the thermal agitation of the molecules drives recoil to restore the disordered state as entropy increases.^[8]^[26] This entropic mechanism accounts for elastin's ability to undergo large strains, up to approximately 200%, while maintaining low stiffness and high resilience under physiological conditions.^[8] Recent experimental and computational evidence has highlighted the hydrophobic effect as a primary contributor to recoil, often superseding pure entropic contributions. Elastin, being highly hydrophobic, is surrounded by structured water layers in its relaxed state; stretching expels this water, reducing the system's free energy through decreased solvent ordering, and recoil is propelled by the rehydration that favors the hydrophobic core's burial.^[27]^[28] This hydration-driven force complements entropy changes, with calorimetry showing increased heat capacity and ordered water proportional to strain, confirming the hydrophobic mechanism's dominance in hydrated elastin networks.^[27]^[29] Elastin exhibits viscoelastic behavior, where recoil is time-dependent and influenced by hydration levels and crosslinking density within its polymeric network. Higher crosslinking, achieved through lysyl oxidase-mediated desmosine formation, increases recoil speed and reduces relaxation times by constraining chain mobility, while dehydration prolongs viscoelastic recovery due to altered solvent interactions.^[30]^[31] This results in a damped, non-instantaneous return to equilibrium, essential for damping vibrations in dynamic tissues. Molecular dynamics simulations have elucidated the conformational basis of recoil, revealing beta-spiral structures in hydrophobic repeat domains like VPGVG that facilitate reversible unwinding. These simulations demonstrate that below the inverse temperature transition (around 37°C), elastin maintains expanded beta-spirals with local disorder; stretching disrupts these into extended chains, and relaxation reforms the spirals through hydrophobic collapse, aligning with observed elasticity.^[32]^[33]^[34] Like synthetic rubber, elastin forms a crosslinked polymer network that confers rubber-like elasticity, but its biological assembly avoids chemical vulcanization, relying instead on enzymatic crosslinking for a dynamic, hydrated structure.^[35] This analogy underscores the shared entropic and hydrophobic principles, though elastin's lower tension at equivalent strains reflects its aqueous environment and irregular crosslinking.^[9]^[36]

Tissue Mechanics

Elastin imparts critical mechanical properties to various tissues, enabling them to withstand repeated deformation while maintaining structural integrity. Its amorphous structure and hydrophobic domains allow for entropic elasticity, facilitating reversible stretching and recoil under physiological loads. In dynamic environments, elastin contributes to low stiffness, high extensibility, and efficient energy storage, which collectively enhance tissue compliance and resilience.^[8] In arterial walls, elastin constitutes approximately 30% of the dry weight, forming concentric lamellae that enable the vessel to expand during systole and recoil during diastole. This elastic behavior supports pulse wave propagation and the Windkessel effect, where the aorta stores kinetic energy from ventricular ejection and releases it to sustain diastolic blood flow, thereby reducing cardiac workload.^[37]^[38] Elastin in lung alveoli plays a pivotal role in facilitating respiratory mechanics by allowing the alveolar walls to expand and contract during breathing cycles. The compliance of these structures, characterized by an elastic modulus of approximately 1-5 kPa, ensures efficient volume changes with minimal pressure gradients, promoting optimal gas exchange.^[39]^[40] In the skin dermis, elastin networks provide resilience against shear and stretch forces encountered during movement and external pressures. This is reflected in the tissue's Young's modulus of about 0.1-1 MPa, which allows the skin to deform elastically and recover without permanent distortion, maintaining barrier function and contour.^[41]^[8] Elastin's load-bearing capacity is exemplified by its fatigue resistance, enduring millions of deformation cycles with minimal energy dissipation due to low hysteresis. This property arises from its ability to rapidly recover stored elastic energy, preventing cumulative damage in cyclically stressed tissues.^[42]^[8] Elastin interacts synergistically with collagen, serving as a compliant "shock absorber" that complements collagen's high tensile strength. While collagen provides rigidity and resistance to high loads, elastin dissipates mechanical stress through reversible deformation, protecting the extracellular matrix from overload and enabling coordinated tissue response to dynamic forces.^[43]^[8]

Tissue Distribution

Primary Locations

Elastin is primarily distributed in vertebrate tissues that experience repetitive stretching and recoil, enabling their mechanical resilience. Its highest concentrations occur in dynamic, extensible structures, where it can constitute a substantial portion of the extracellular matrix dry weight, while it is minimal or absent in rigid tissues such as bone and tendon that prioritize stiffness over elasticity.^[1]^[8] In the cardiovascular system, elastin is most abundant in the tunica media of the aorta and large elastic arteries, where it forms concentric lamellae that account for 28–32% of the tissue's dry weight. This high content supports the vessels' ability to withstand pulsatile blood flow and maintain arterial compliance.^[5]^[44] Within the respiratory system, elastin is concentrated in the alveolar septa and bronchiolar walls, comprising 20-30% of the crude connective tissue dry weight in the lung parenchyma. These distributions facilitate lung expansion and contraction during breathing, particularly in the alveolar-capillary units where levels can reach 25-35%.^[45]^[46] In the integumentary system, elastin resides mainly in the dermal papillae and reticular dermis, making up 2-4% of the fat-free dry weight in adult skin. Here, it contributes to the skin's flexibility and recovery from deformation.^[47] Other notable sites include elastic ligaments such as the nuchal ligament, where elastin exceeds 70% of the dry weight to enable head support and movement; the vocal folds, with approximately 9% elastin content for phonation viscoelasticity; the urinary bladder wall, where elastin fibers are present throughout the lamina propria and muscular layers to accommodate volume changes; and cartilage, particularly elastic types like auricular cartilage, where it comprises 2–5% of dry weight to provide resilience and flexibility.^[8]^[48]^[49]^[50]

Developmental Patterns

Elastin expression during embryogenesis is characterized by a low initial level in the early embryo, followed by a significant surge in mid-gestation. In humans, tropoelastin production, the precursor to elastin, begins around the 7th week in developing cardiac valves and extends to the aorta by approximately week 8, where it rapidly increases during the last third of gestation to support vascular expansion under rising hemodynamic forces.^[51]^[52] This temporal profile ensures that elastic fibers accumulate sufficiently to confer recoil properties before birth, with elastin content in the thoracic aorta rising markedly between weeks 20 and 32.^[52] Spatially, elastin synthesis initiates in vascular smooth muscle cells of the arterial walls, forming initial lamellae, before extending to fibroblasts in parenchymal tissues such as skin and lungs. In the lung, expression first appears in smooth muscle cells of pulmonary arteries during the pseudoglandular stage (around 10 weeks in humans), establishing vascular elasticity, and subsequently in interstitial fibroblasts during the canalicular and saccular phases (16–36 weeks), where it outlines future alveolar septa.^[45] This gradient reflects the prioritization of circulatory system maturation prior to parenchymal organ development.^[45] Regulatory signals, particularly transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs), drive elastin (ELN) gene induction through the canonical Smad signaling pathway. TGF-β1 upregulates ELN mRNA in smooth muscle cells and fibroblasts within hours, while BMP4 enhances tropoelastin protein deposition in a BMP receptor 2 (BMPR2)-dependent manner, facilitating microfibril assembly essential for fiber maturation during late gestation.^[53] These pathways integrate mechanical cues from blood flow to synchronize elastogenesis with tissue growth.^[53] Postnatally, elastin expression declines sharply, dropping to negligible levels by the end of adolescence and correlating with the completion of somatic growth. In humans, synthesis persists at high rates through early childhood but ceases almost entirely after puberty, relying thereafter on the long half-life (approximately 70 years) of existing fibers for tissue function.^[1] Species differences highlight the protracted nature of human elastogenesis compared to rodents; in mice, expression surges rapidly over days (peaking around embryonic day 18 to postnatal day 30), mirroring their short 19–21 day gestation, whereas in humans, it unfolds over years across a 40-week gestation and postnatal growth.^[54] This extended timeline in humans allows for greater elastic fiber accumulation to accommodate larger body size and longevity.^[54]

Degradation and Turnover

Proteolytic Enzymes

Elastin degradation is primarily mediated by a variety of proteolytic enzymes that cleave its hydrophobic domains and cross-linked structures, facilitating tissue remodeling and turnover. These enzymes include matrix metalloproteinases (MMPs), serine elastases, and cathepsins, each contributing to the breakdown of elastin in extracellular or intracellular environments. The process generates soluble fragments known as elastokines, which can exert bioactive effects on cells.^[55] Matrix metalloproteinases, particularly MMP-2 (gelatinase A), MMP-9 (gelatinase B), and MMP-12 (macrophage metalloelastase), are key extracellular enzymes that degrade elastin at neutral pH. These zinc-dependent endopeptidases target the non-polar regions of elastin, releasing specific peptide fragments such as the ELN-441 epitope from MMP-9 and MMP-12 activity. MMP-2 and MMP-9, secreted by fibroblasts, macrophages, and neutrophils, exhibit potent elastolytic activity in vascular and pulmonary tissues, contributing to normal matrix remodeling. MMP-12, predominantly expressed by macrophages, further enhances elastin fragmentation in inflammatory contexts. The resistance of elastin's desmosine and isodesmosine cross-links to complete hydrolysis by these enzymes underscores the polymer's durability.^[56]^[57]^[58] Serine elastases, including neutrophil elastase (encoded by the ELANE gene) and proteinase 3, play a prominent role in inflammation-driven elastin degradation. Neutrophil elastase, released from activated neutrophils, rapidly hydrolyzes elastin fibers in the extracellular matrix of lungs and blood vessels, generating degradation products that reflect ongoing tissue damage. Proteinase 3, another neutrophil-derived serine protease, similarly cleaves elastin and is implicated in the loss of elastic recoil during inflammatory responses, such as in pulmonary diseases. Both enzymes are stored in azurophilic granules and become active upon degranulation, amplifying proteolysis in acute settings.^[59]^[60]^[61] The cathepsin family, specifically cathepsin K and cathepsin S, contributes to lysosomal degradation of internalized elastin. These cysteine proteases, active in acidic compartments, exhibit strong elastolytic activity; cathepsin K, expressed in osteoclasts and macrophages, efficiently breaks down elastin fibers within phagolysosomes, while cathepsin S supports similar degradation in antigen-presenting cells. Their role is crucial for intracellular processing of elastin during autophagy or phagocytosis, complementing extracellular proteolysis.^[62]^[63] Many of these enzymes are synthesized as inactive zymogens and require activation through proteolytic cleavage, often involving plasmin or influenced by inflammatory cytokines. Pro-MMPs, for instance, undergo zymogen activation via plasmin-mediated cleavage of the pro-domain, a process enhanced in fibrinolytic environments. Inflammatory cytokines such as TNF-α and IL-1β upregulate MMP expression and indirectly promote activation cascades, while plasmin also activates upstream plasminogen activators. Serine elastases like neutrophil elastase are primarily activated by granule release rather than zymogen processing, though cathepsins can be auto-activated in lysosomes.^[64]^[65] Elastin degradation yields bioactive fragments called elastokines, such as the hexapeptide VGVAPG, which signal through the elastin receptor complex comprising the 67-kDa elastin-binding protein, protective protein/cathepsin A (S-Gal), and neuraminidase-1. These peptides bind the receptor to modulate cell proliferation, migration, and inflammation, with VGVAPG derived from exon 24 of tropoelastin exhibiting high affinity for the complex. Cathepsin E may facilitate intracellular processing of such fragments, linking degradation to signaling pathways.^[66]^[67]^[68] With advancing age, elastin undergoes fragmentation, particularly in sun-exposed tissues, where ultraviolet (UV) radiation induces matrix metalloproteinases (MMPs) such as MMP-12, leading to the degradation of elastic fibers and the development of solar elastosis. This condition manifests as disorganized, clumped, and non-functional elastin deposits in the dermis, compromising the structural integrity of elastic fibers and contributing to skin laxity and wrinkling. Studies indicate that this process results in a significant reduction in functional elastic fiber content in photoaged skin compared to younger tissues.^[69]^[70] Elastin is also prone to calcification during aging, where it binds calcium and phosphate ions, promoting the formation of mineral deposits within the medial layer of arteries, a phenomenon known as medial elastocalcinosis. This age-related process stiffens arterial walls by altering the elastic properties of the fibers, independent of atherosclerotic plaques, and is exacerbated by factors like chronic kidney disease or diabetes. The calcification disrupts the normal recoil mechanism, increasing vascular stiffness and contributing to cardiovascular complications in older adults.^[71]^[72] Glyco-oxidation further modifies elastin through the accumulation of advanced glycation end-products (AGEs), which form irreversible crosslinks between elastin molecules and other extracellular matrix components. These crosslinks reduce the protein's flexibility, elevating tissue stiffness and impairing elastic recoil, particularly in skin and vasculature. AGE formation accelerates with hyperglycemia and oxidative stress, amplifying age-related rigidity without significant enzymatic degradation.^[73]^[74] Elastin's turnover rate remains extremely low in adults, estimated at less than 1% per year, corresponding to a half-life of approximately 74 years, which allows oxidative damage from reactive oxygen species to accumulate over decades without effective repair. This slow renewal exacerbates fragmentation and crosslinking, as damaged elastin persists and loses its entropic elasticity. Recent 2025 studies indicate that elastin-derived fragments may circulate and drive systemic aging hallmarks, such as inflammation and cellular senescence.^[75]^[76]

Clinical Significance

Genetic Disorders

Genetic disorders involving elastin primarily stem from mutations in the ELN gene, which encodes tropoelastin, leading to haploinsufficiency and impaired elastic fiber formation in tissues such as arteries and skin. These inherited conditions, often autosomal dominant, result in reduced elastin content—typically about 50% in heterozygotes—causing fragmented fibers, increased vascular stiffness, and abnormal tissue recoil. Pathophysiologically, the diminished tropoelastin production triggers compensatory smooth muscle cell proliferation and disorganized extracellular matrix deposition, contributing to systemic manifestations.^[77]^[49] Supravalvular aortic stenosis (SVAS) is a key example, characterized by autosomal dominant inheritance through ELN deletions or nonsense mutations that narrow the ascending aorta and other elastic arteries, often leading to hypertension and requiring surgical intervention in approximately 30% of cases. The incidence of isolated SVAS is estimated at 1 in 20,000 live births. This elastin arteriopathy exemplifies how ELN haploinsufficiency disrupts arterial wall integrity, promoting intimal thickening and lumen obstruction.^[78]^[79] Williams-Beuren syndrome (WBS), another ELN-related disorder, arises from a heterozygous microdeletion at chromosome 7q11.23 that includes ELN and 25–27 contiguous genes, producing elastin deficiency alongside supravalvular aortic stenosis-like vascular changes, distinctive elfin facies, intellectual disability, and a sociable personality. The prevalence of WBS is approximately 1 in 7,500 to 1 in 10,000 live births. The elastin shortfall in WBS mirrors SVAS but is compounded by hemizygosity, exacerbating fragmented elastic lamellae and arterial tortuosity.^[80]^[49] Autosomal dominant cutis laxa, particularly type 2 (ADCL2), results from heterozygous mutations in FBLN5, which encodes fibulin-5—a glycoprotein critical for tropoelastin polymerization and elastic fiber assembly—leading to loose, inelastic skin, premature aging appearance, and variable aortopathy or emphysema. This rare condition, reported in only a few families, involves dominant-negative effects where mutant fibulin-5 impairs microfibril-elastin interactions, yielding disorganized and reduced elastic fibers. Unlike direct ELN defects, FBLN5 mutations highlight upstream assembly failures in elastinogenesis.^[81]^[82] Diagnosis of these elastin-related disorders centers on targeted genetic testing, including Sanger sequencing or next-generation sequencing of ELN and FBLN5, to identify pathogenic variants, with multiplex ligation-dependent probe amplification for deletions. Clinical confirmation involves echocardiography or cardiac MRI for vascular stenosis in SVAS and WBS, alongside dermatological assessment for cutis laxa; prenatal testing is available for known familial mutations. Early genetic diagnosis facilitates proactive cardiovascular monitoring and multidisciplinary management to mitigate complications like progressive stenosis or skin fragility.^[49]^[80] Emerging research has identified additional ELN variants associated with diverse connective tissue phenotypes, including arterial tortuosity and skin abnormalities, expanding the clinical spectrum of elastin-related disorders.^[83]

Acquired Pathologies

Acquired pathologies of elastin primarily arise from environmental or inflammatory triggers that lead to its degradation or dysfunctional remodeling, distinct from genetic defects. These conditions often involve proteolytic enzymes that fragment elastin fibers, resulting in loss of tissue elasticity and progression of disease. In actinic elastosis, also known as solar elastosis, chronic ultraviolet (UV) radiation exposure from solar damage induces upregulation of matrix metalloproteinase-1 (MMP-1) in dermal fibroblasts and keratinocytes, leading to fragmentation and abnormal accumulation of elastin in the upper dermis. This process generates disorganized, thickened elastotic material composed of degraded elastin and associated microfibrils, impairing skin recoil and contributing to wrinkles and sagging.^[69] MMP-1 specifically targets UV-damaged fibrillin microfibrils that support elastin, exacerbating proteolytic susceptibility and perpetuating dermal matrix breakdown.^[84] Chronic obstructive pulmonary disease (COPD), particularly in smokers, features accelerated destruction of lung elastin due to neutrophil elastase released from activated neutrophils recruited by cigarette smoke-induced inflammation.^[85] This serine protease cleaves alveolar elastin fibers, reducing lung recoil and promoting emphysema through airspace enlargement and loss of structural integrity.^[86] The imbalance between elastase activity and its inhibitors, such as alpha-1-antitrypsin, amplifies elastin degradation, with smoke-exposed lungs showing elevated neutrophil influx and persistent proteolytic damage.^[87] In atherosclerosis, fragmented elastin within arterial plaques arises from elastase activity by macrophages and neutrophils, generating bioactive elastin peptides known as elastokines that promote vascular inflammation and smooth muscle proliferation.^[88] These peptides bind to the elastin receptor complex, activating signaling pathways that enhance monocyte recruitment and cytokine release, thereby destabilizing plaques and accelerating lesion progression.^[55] Elastin fragmentation also contributes to medial thinning and aneurysm formation, underscoring its role in chronic vascular remodeling.^[89] Wound healing impairments involving elastin manifest as reduced elastogenesis in scar tissue, leading to diminished elasticity and increased risk of contractures, where fibrotic scars restrict movement due to insufficient elastic fiber deposition during the remodeling phase.^[47] In keloids, aberrant healing results in fragmented and disorganized elastin alongside excessive collagen, with deeper dermal layers showing elevated elastin density that fails to restore functional recoil, perpetuating hypertrophic growth beyond wound boundaries.^[90] This dysregulated elastin synthesis, influenced by prolonged inflammation, hinders normal scar maturation and contributes to chronic stiffness.^[91]

Research Directions

Disease Therapies

Surgical interventions remain a cornerstone for managing elastin-related vascular and dermatological disorders. In supravalvular aortic stenosis (SVAS), often linked to elastin gene (ELN) haploinsufficiency, percutaneous balloon angioplasty has demonstrated efficacy, particularly for discrete or membranous forms of the condition. This procedure involves inflating a balloon catheter at the site of stenosis to dilate the narrowed aortic segment, reducing pressure gradients across the lesion. In one reported case of a pediatric patient with a pre-procedure gradient of 130 mmHg, balloon dilatation achieved an immediate reduction to 14 mmHg, with sustained hemodynamic improvement and symptom relief observed over follow-up periods exceeding one year.^[92] For cutis laxa, characterized by defective elastin fiber assembly leading to loose, sagging skin, plastic reconstructive surgery including skin excision and grafting offers symptomatic relief. Rhytidectomy, for instance, involves removing excess inelastic skin and tightening underlying tissues, with postoperative adjuncts like laser therapy to minimize scarring. In a case of congenital cutis laxa, this approach yielded no recurrence at five months post-procedure, though long-term recurrence rates can reach 70% due to ongoing elastin deficiency.^[93] Pharmacological strategies target dysregulated elastin crosslinking and degradation in aging and acquired pathologies. Lysyl oxidase (LOX) inhibitors address excessive crosslinking, which stiffens elastin fibers and contributes to age-related skin rigidity and fibrosis. Topical application of irreversible small-molecule pan-LOX inhibitors, such as PXS-4787 or PXS-6302, has shown promise in preclinical models by reducing collagen and elastin crosslink formation (e.g., desmosine and pyridinoline levels decreased by up to 50%), thereby improving tissue elasticity without impairing wound strength. These agents permeate the skin effectively and ameliorate scar fibrosis in porcine models, suggesting potential for mitigating elastin-related dermal aging.^[94] Doxycycline, a tetracycline antibiotic with MMP-inhibitory properties, helps preserve elastin integrity in conditions involving proteolytic degradation, such as actinic elastosis where UV-induced MMPs disrupt dermal matrix. At subantimicrobial doses, doxycycline inhibits MMP-2 and MMP-9 activity, reducing elastin breakdown in organ cultures and connective tissue disorders; in skin wound models, it modulates ECM remodeling to favor elastin preservation.^[95]^[96] Investigational gene therapies aim to restore elastin expression in genetic disorders like Williams syndrome, which features ELN deletion and resultant vascular elastin deficiency. Adeno-associated virus (AAV)-mediated delivery of the ELN gene is considered a potential approach for promoting elastin production beyond developmental windows, though challenges in assembly and delivery persist. A 2025 review highlights AAV strategies for addressing elastin arteriopathies, but specific preclinical demonstrations in models remain limited, with human trials pending.^[97] A 2024 preclinical study demonstrated that epigallocatechin gallate (EGCG) promotes de novo elastin assembly in human induced pluripotent stem cell-derived vascular smooth muscle cells from SVAS patients and in Eln+/– mouse models, alleviating VSMC hyperproliferation, hypertension, and aortic stiffening. This suggests chemical induction as a viable strategy for elastin-related vascular disorders.^[98] Partial reprogramming of dermal fibroblasts using mechanical cues reverses senescence markers, enhancing extracellular matrix gene expression including tropoelastin. In aged human skin equivalents, mechanically reprogrammed fibroblasts implanted into organotypic models boost tropoelastin deposition by up to 2-fold, improving dermal elasticity and reducing wrinkle depth in ex vivo assays. This strategy leverages biomechanical rejuvenation to amplify endogenous elastin precursor production without full dedifferentiation risks.^[99] Elastin degradation contributes to emphysema in chronic obstructive pulmonary disease (COPD), serving as a potential therapeutic target. Elevated desmosine and isodesmosine biomarkers indicate accelerated elastolysis, but specific stabilizing therapies remain in early exploration.^[100]

Biomaterials Applications

Elastin-like polypeptides (ELPs) are genetically engineered proteins composed of tandem repeats of the pentapeptide VPGVG, derived from the hydrophobic domains of tropoelastin, enabling their use in designing thermoresponsive biomaterials.^[101] These polypeptides exhibit a lower critical solution temperature (LCST) behavior, where they undergo reversible phase transition from soluble to coacervate state above approximately 30–35°C, facilitating the formation of injectable hydrogels for controlled drug release and tissue engineering applications.^[102] In tissue scaffolds, ELPs promote cell adhesion and proliferation due to their biocompatibility and mimicry of native elastin's elasticity, with studies demonstrating their efficacy in vascular and cartilage repair by supporting extracellular matrix deposition.^[103] Decellularized elastin matrices, particularly those derived from bovine sources, serve as scaffolds for vascular grafts by preserving the native fibrous architecture while removing cellular components to minimize immune rejection.^[104] These scaffolds exhibit high biocompatibility, evidenced by efficient host cell repopulation and minimal inflammatory response in subdermal implantation models, supporting endothelialization and long-term patency in arterial replacements.^[105] For instance, pure elastin scaffolds from porcine arteries have shown robust remodeling with de novo collagen synthesis, achieving biocompatibility levels suitable for clinical translation in small-diameter vascular grafts.^[104] Elastin-based biomaterials find key applications in heart valve prosthetics and wound dressings, where they match the mechanical properties of native tissues, including an elastic modulus of 0.1–1 MPa to ensure physiological compliance and fatigue resistance.^[106] In prosthetic heart valves, elastin composites stabilize cusps against calcification and promote endothelial coverage, extending durability beyond traditional glutaraldehyde-fixed xenografts.^[107] For wound dressings, elastin hydrogels or scaffolds facilitate moist healing environments, enhancing re-epithelialization and reducing contraction in chronic ulcers.^[108] In 2025, a bioactive recombinant human elastin gel demonstrated superior efficacy in regenerating elastic fibers and rejuvenating endogenously aged skin in preclinical models.^[109] Additionally, collagen-elastin dermal scaffolds enriched with elastin hydrolysates enhanced tissue regeneration and vascularization in wound healing assays as of August 2025.^[110] Despite these promises, challenges persist in immunogenicity, particularly with animal-derived elastin that may elicit host responses due to residual xenogeneic epitopes, and in the scalability of crosslinking methods, where achieving uniform lysyl oxidase-like stabilization remains limited by recombinant production yields and processing variability.^[111]

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