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VCAM-1
VCAM-1
VCAM-1
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"CD106" redirects here. For the radio station formerly known as "CD106 the Wolf", see WNCD.
"Cd106" redirects here. For the isotope of cadmium (Cd-106 or 106Cd), see Cadmium-106.

VCAM1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesVCAM1, CD106, INCAM-100, vascular cell adhesion molecule 1
External IDsOMIM: 192225; MGI: 98926; HomoloGene: 838; GeneCards: VCAM1; OMA:VCAM1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7412

22329

Ensembl

ENSG00000162692

ENSMUSG00000027962

UniProt

P19320

P29533

RefSeq (mRNA)

NM_080682
NM_001078
NM_001199834

NM_011693

RefSeq (protein)

NP_001069
NP_001186763
NP_542413

NP_035823

Location (UCSC)Chr 1: 100.72 – 100.74 MbChr 3: 115.9 – 115.92 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the VCAM1 gene.[5] VCAM-1 functions as a cell adhesion molecule.

Structure

[edit]

VCAM-1 is a member of the immunoglobulin superfamily, the superfamily of proteins including antibodies and T-cell receptors. The VCAM-1 gene contains six or seven immunoglobulin domains, and is expressed on both large and small blood vessels only after the endothelial cells are stimulated by cytokines. It is alternatively spliced into two known RNA transcripts that encode different isoforms in humans.[6] The gene product is a cell surface sialoglycoprotein, a type I membrane protein that is a member of the Ig superfamily.

Function

[edit]

The VCAM-1 protein mediates the adhesion of lymphocytes, monocytes, eosinophils, and basophils to vascular endothelium. It also functions in leukocyte-endothelial cell signal transduction, and it may play a role in the development of atherosclerosis and rheumatoid arthritis.

Upregulation of VCAM-1 in endothelial cells by cytokines occurs as a result of increased gene transcription (e.g., in response to tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1)) and through stabilization of messenger RNA (mRNA) (e.g., Interleukin-4 (IL-4)). The promoter region of the VCAM1 gene contains functional tandem NF-κB (nuclear factor-kappa B) sites. The sustained expression of VCAM-1 lasts over 24 hours.

Primarily, the VCAM-1 protein is an endothelial ligand for VLA-4 (Very Late Antigen-4 or integrin α4β1) of the β1 subfamily of integrins. VCAM-1 expression has also been observed in other cell types (e.g., smooth muscle cells). It has also been shown to interact with EZR[7] and Moesin.[7]

VCAM-1 is also upregulated if vWF (Von Willebrand Factor) is given in knock-out (KO) ADMATS13 mice but not on mice without KO.[8]

CD106 also exists on the surface of some subpopulations of mesenchymal stem cells (MSC).[9]

Pharmacology

[edit]

Certain melanoma cells can use VCAM-1 to adhere to the endothelium,[10] VCAM-1 may participate in monocyte recruitment to atherosclerotic sites, and it is highly overexpressed in the inflamed brain.[11] As a result, VCAM-1 is a potential drug target.

References

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Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

VCAM-1

View on Grokipedia
from Grokipedia
Vascular cell molecule 1 (VCAM-1) is a transmembrane belonging to the immunoglobulin (Ig) superfamily, encoded by the VCAM1 on 1p21.2 in humans, and serves as a key mediator of leukocyte-endothelial cell interactions during inflammatory responses. It is primarily expressed on the surface of cytokine-activated endothelial cells, where it facilitates the , rolling, and transmigration of leukocytes such as lymphocytes, monocytes, and into tissues. Discovered in as a cytokine-inducible molecule, VCAM-1 exists in multiple isoforms due to , with the predominant human form featuring seven extracellular Ig-like domains that interact with α4β1 and α4β7 on leukocytes. VCAM-1 expression is tightly regulated by pro-inflammatory cytokines such as alpha (TNF-α) and interleukin-1 (IL-1), which activate signaling pathways like to upregulate its transcription on lining post-capillary venules. Beyond , it is also found on macrophages, dendritic cells, and certain cancer cells under chronic inflammatory conditions, contributing to immune cell recruitment in various tissues including the and lymph nodes, where it shows the highest basal expression levels. Functionally, VCAM-1 not only promotes firm adhesion but also triggers intracellular signaling events, including calcium fluxes and (ROS) production, which support leukocyte activation and diapedesis across the vascular barrier. The molecule's dysregulation is implicated in numerous pathological conditions, serving as a and therapeutic target in inflammatory and immune-mediated diseases. Elevated soluble VCAM-1 levels in serum correlate with disease activity in , , and , where it drives excessive leukocyte infiltration leading to tissue damage. In cancer, VCAM-1 expression on tumor-associated and malignant cells enhances , , and immune evasion, with high levels associated with poor in various solid tumors. Therapeutic strategies targeting VCAM-1, such as blocking antibodies, have shown promise in preclinical models by reducing inflammation in , , and joint destruction in .

Genetics and Structure

Gene Organization

The VCAM1 gene, which encodes vascular cell adhesion molecule 1, is located on the short arm of human at the cytogenetic band 1p21.2. This genomic region spans approximately 19 kb, from positions 100,719,742 to 100,739,045 on the GRCh38 reference assembly. The gene comprises 9 exons, with the coding sequence distributed across exons 1 through 9, and introns separating them to form a compact structure typical of members. Exons 2 through 8 primarily encode the extracellular immunoglobulin-like (Ig-like) domains that define the protein's adhesive properties, while exon 1 contains the sequence and exon 9 encodes the transmembrane and cytoplasmic regions. events, particularly involving exons 5 and 8, generate multiple transcript variants. The predominant full-length isoform arises from the inclusion of exon 5, producing a protein with seven Ig-like domains; in contrast, the shorter isoform results from exon 5 exclusion, yielding six Ig-like domains and omitting the fourth domain. A third minor isoform involves additional splicing at exon 8, further diversifying potential protein products, though the two main forms predominate in cytokine-activated . The VCAM1 gene exhibits strong evolutionary conservation across mammals, with orthologs identified in species such as (Vcam1 on chromosome 3), rat, and non-human , reflecting shared roles in leukocyte . Key regulatory elements in the promoter region, including multiple binding sites, are conserved and mediate inducible expression in response to inflammatory cytokines like TNF-α and IL-1β.

Protein Domains and Isoforms

VCAM-1 is a type I transmembrane belonging to the (IgSF), with a predicted core molecular weight of approximately 81 kDa for the full-length polypeptide. The mature protein, following post-translational processing, exhibits an apparent molecular weight of around 110 kDa due to extensive and other modifications. Structurally, VCAM-1 features an N-terminal extracellular region, a single hydrophobic transmembrane helix spanning residues 699-720, and a short cytoplasmic C-terminal tail consisting of 19 (residues 721-739). This architecture anchors the protein in the plasma membrane, positioning the extracellular domains for interactions with circulating cells. The extracellular portion of VCAM-1 is composed of seven immunoglobulin-like domains (D1-D7), each characterized by a beta-sandwich fold stabilized by conserved disulfide bonds between cysteine residues. These domains are classified as I-set Ig-like folds, with D1-D3 and D5-D7 adopting typical topologies, while D4 shows structural homology to the others but contributes uniquely to ligand recognition. Alternative splicing of the VCAM1 gene produces two principal membrane-bound isoforms: the full-length VCAM-1A isoform retaining all seven domains, which supports maximal adhesive function, and the VCAM-1B isoform lacking D4 (resulting in six domains), which exhibits diminished binding affinity to its primary ligands. A soluble isoform can also arise from proteolytic cleavage or alternative splicing, but the membrane forms predominate in cellular contexts. Key structural motifs include multiple N-linked sites—six in VCAM-1A (e.g., at Asn28, Asn71, Asn238, Asn309, Asn476, and Asn552)—which add significant mass and influence protein stability, folding, and surface presentation. These glycans, primarily complex-type, are essential for the protein's sialoglycoprotein nature and may modulate interactions. Crystal s derived from , such as the N-terminal D1-D2 fragment (PDB: 1VSC), reveal detailed beta-sheet arrangements and loop regions critical for function, with D1 and D4 identified as primary sites for engagement through conserved acidic motifs in their C-D loops.

Expression and Regulation

Cellular and Tissue Expression

VCAM-1 is primarily expressed on , particularly in post-capillary venules, where its expression is markedly upregulated in response to inflammatory stimuli. It is also detected on cells, dendritic cells, and fibroblasts under activated conditions. This inducible expression pattern facilitates leukocyte during , with basal levels remaining low in quiescent endothelium. In terms of tissue distribution, VCAM-1 shows constitutive higher expression on vascular endothelium in lymphoid tissues such as the spleen and lymph nodes, with inducible expression in organs such as the heart, lung, and kidney, where it supports immune cell trafficking during inflammation. Basal expression is minimal in the brain but increases significantly in inflamed tissues, including atherosclerotic plaques, highlighting its role in localized inflammatory responses. Isoform-specific patterns further characterize this distribution: the full-length, membrane-bound isoform with seven immunoglobulin-like domains is anchored on endothelial cells, while a soluble form (sVCAM-1), generated via alternative splicing or proteolytic shedding, circulates in serum and elevates during systemic inflammation, serving as a marker of endothelial activation. During development, VCAM-1 exhibits transient expression in the embryonic heart, where it is essential for myocardial organization and chorioallantoic fusion, with knockout models demonstrating embryonic lethality due to cardiac defects. It is also expressed in neural crest-derived cells contributing to heart organogenesis, aiding in cell migration and tissue remodeling. Detection of VCAM-1 typically involves immunohistochemistry, which reveals its colocalization with von Willebrand factor in endothelial cells, confirming vascular specificity. Additionally, enzyme-linked immunosorbent assay (ELISA) quantifies serum sVCAM-1 levels as a non-invasive biomarker for inflammatory states. Cytokines such as TNF-α induce this expression pattern in endothelial cells.

Molecular Regulation

The promoter of the VCAM-1 , located in the 5' flanking , features consensus binding sites for key transcription factors including , AP-1, and members of the family, which render it highly responsive to proinflammatory stimuli such as cytokines. These sites facilitate the recruitment of transcription factors upon cellular activation, enabling precise control over expression in endothelial cells exposed to inflammatory cues. Major inducers of VCAM-1 expression include proinflammatory cytokines TNF-α and IL-1β, which activate the complex, leading to phosphorylation and degradation of , nuclear translocation of , and subsequent binding to the promoter for transcriptional activation. This pathway results in sustained VCAM-1 expression persisting beyond 24 hours, supporting prolonged leukocyte recruitment during inflammation. Additionally, disturbed and contribute to upregulation by enhancing activity and promoter accessibility, promoting endothelial activation in vascular environments prone to . In contrast, suppressors such as glucocorticoids inhibit VCAM-1 transcription by recruiting histone deacetylase 2 (HDAC2) to the promoter, reducing histone acetylation and blocking , AP-1, and GATA binding. Statins similarly attenuate expression through PPAR-α activation, which interferes with signaling, or via HDAC-mediated mechanisms that limit promoter accessibility. Post-transcriptionally, microRNAs like miR-126 repress VCAM-1 by directly targeting its 3' , thereby dampening mRNA stability and translation in endothelial cells. Epigenetic modifications further fine-tune VCAM-1 regulation, with increased histone (e.g., H3K18ac) at the promoter enhancing openness and transcriptional activity, particularly in settings of chronic inflammation where sustained signaling predominates. This is dynamically linked to coactivators like p300, amplifying cytokine-driven responses. The temporal dynamics of VCAM-1 expression reflect its role in adaptive immune responses, with rapid induction occurring within 4 hours of acute stimulation by TNF-α or IL-1β, peaking at 6-24 hours and maintaining elevated levels for extended periods to facilitate mononuclear . This contrasts with the more transient upregulation of , which peaks earlier (within 2-4 hours) but declines more rapidly, emphasizing VCAM-1's suitability for sustained interactions in ongoing .

Biological Functions

Cell Adhesion Mechanisms

VCAM-1 primarily facilitates leukocyte adhesion through its interaction with the α4β1 (also known as ), which is expressed on various leukocytes including lymphocytes, monocytes, and . This binding occurs via the first and fourth immunoglobulin-like domains (D1 and D4) of VCAM-1, which contain the recognition sequence Ile-Asp-Ser-Pro-Leu (IDSPL) that engages the metal ion-dependent site () on the α4β1 . The affinity of this interaction in the high-affinity state of the is high, with a (Kd) in the range of approximately 1-10 nM, enabling stable under physiological conditions. In addition to α4β1, VCAM-1 engages secondary such as α4β7 on gut-homing lymphocytes, which binds primarily to D1 of VCAM-1 and supports tissue-specific , and αDβ2 on certain myeloid cells like , which exhibits weaker binding affinity compared to α4β1. These interactions contribute to diverse roles, though α4β1 remains the dominant pathway for most leukocyte-endothelial contacts. Isoform variations in VCAM-1, such as the predominant seven-domain form versus the alternatively spliced six-domain form (lacking domain 4), both of which can undergo proteolytic shedding to produce soluble variants, can subtly influence binding efficiency to these . The process mediated by VCAM-1 involves initial and rolling of leukocytes on the endothelial surface under hydrodynamic shear flow in the vasculature, followed by firm that transitions to spreading and transmigration. This stepwise mechanism relies on the conformational of α4β1 from low- to high-affinity states, triggered by , and requires divalent cations such as Mg²⁺ to stabilize the integrin-ligand interface and support bond formation against shear forces. Soluble VCAM-1 (sVCAM-1), generated by proteolytic shedding of the membrane-bound form, circulates in plasma and can bind α4 on leukocytes, acting as a competitive inhibitor that reduces to endothelial VCAM-1 in systemic inflammatory contexts. Biophysical studies reveal that the Ig-like domains of VCAM-1 exhibit flexibility, particularly at interdomain hinges, allowing conformational adjustments that optimize ligand engagement during dynamic ; this has been visualized through techniques like showing alternative domain orientations.

Signaling Pathways

Engagement of VCAM-1 on endothelial cells by its ligand triggers intracellular signaling cascades that promote cytoskeletal reorganization and increased . Ligation of VCAM-1 activates Src family kinases, which initiate downstream of the PI3K/Akt pathway, leading to events that facilitate and formation of cup-like protrusions around adherent leukocytes. This process involves Rac1 , which coordinates cytoskeletal rearrangement essential for endothelial cell shape changes and enhanced paracellular permeability. Additionally, VCAM-1 signaling induces calcium fluxes that further support these dynamic alterations in endothelial . On the leukocyte side, the interaction between VLA-4 and VCAM-1 stimulates inside-out and outside-in signaling, promoting cell migration and survival. This binding leads to phosphorylation of focal adhesion kinase (FAK), which anchors the integrin complex and activates downstream ERK/MAPK pathways to enhance motility and cytoskeletal dynamics in leukocytes. ERK activation, in particular, supports leukocyte spreading and directed migration across the endothelium by modulating actin remodeling. VCAM-1 signaling exhibits crosstalk with , amplifying inflammatory responses through synergistic effects on leukocyte arrest and transmigration. Clustering of recruits VCAM-1 into shared microdomains, where both molecules activate common pathways such as p38 MAPK and PKC, while VCAM-1 specifically drives ROS production via (). This ROS generation, producing approximately 1 μM H₂O₂, activates matrix metalloproteinases (MMP2 and MMP9) that degrade endothelial junctions, thereby enhancing and leukocyte infiltration. The cooperative interaction strengthens overall adhesion and facilitates efficient . Negative regulation of VCAM-1 signaling is mediated by protein tyrosine phosphatases, including , which dephosphorylates key substrates to attenuate pathway duration and prevent excessive activation. acts as a counterbalance by inhibiting sustained in Src and PI3K/Akt cascades. Similarly, PTP1B is activated downstream of VCAM-1 via PKCα-mediated serine , indirectly limiting signaling by modulating transmigration without direct oxidation by ROS. Experimental evidence from models underscores these pathways' roles. VCAM-1-deficient mice exhibit impaired leukocyte , with reduced B-cell homing and diminished transmigration in inflammatory models. (CYBB) in non-hematopoietic cells blocks VCAM-1-dependent by 68% in allergen-challenged lungs, highlighting ROS's necessity. Furthermore, disruption of VCAM-1 signaling correlates with attenuated activation in , as ROS-mediated pathways that sustain are impaired, reducing pro-inflammatory gene expression.

Pathophysiological Roles

Cardiovascular Diseases

VCAM-1 plays a critical role in by facilitating the recruitment of monocytes to the , where its upregulation in early promotes leukocyte and infiltration into the arterial intima. Studies in animal models demonstrate that reduced VCAM-1 expression significantly attenuates nascent formation, highlighting its essential function in the initiation of plaque development independent of profiles or circulating leukocyte counts. Elevated levels of soluble VCAM-1 (sVCAM-1) in circulation correlate with plaque instability and predict adverse cardiovascular events, with concentrations exceeding 1000 ng/mL serving as a threshold for heightened risk in patients with . In , chronic exposure to low or disturbed on endothelial cells induces VCAM-1 expression, contributing to and vascular remodeling through enhanced inflammatory . This mechanosensitive upregulation exacerbates and promotes the progression of hypertensive vascular pathology by amplifying monocyte-endothelial interactions under hemodynamic stress. In with reduced (HFrEF), elevated sVCAM-1 levels reflect underlying immune activation and endothelial inflammation, with median concentrations around 997 ng/mL observed in affected patients. A 2025 analysis from the DAPA-HF trial linked higher sVCAM-1 tertiles (≥1126.4 ng/mL) to increased risk of worsening or cardiovascular death, with an adjusted of 1.40, mediated through distinct inflammatory pathways involving myocardial immune infiltration. Following (MI), VCAM-1 contributes to post-infarct inflammation by upregulating expression in the infarcted and remote myocardium, driving leukocyte recruitment and exacerbating tissue damage. Animal models indicate that VCAM-1 blockade, such as through targeted downregulation in mesenchymal stem cells, reduces infarct size and myocardial while improving cardiac function by limiting inflammatory infiltration. As a , sVCAM-1 serum levels above 800 ng/mL signal elevated cardiovascular risk, particularly when integrated with (CRP) for enhanced prognostic accuracy in predicting events like coronary instability or progression. This combination leverages sVCAM-1's reflection of endothelial activation alongside CRP's marker of to stratify patient outcomes more effectively.

Inflammatory and Autoimmune Diseases

VCAM-1 plays a pivotal role in (RA) by facilitating leukocyte infiltration into synovial tissues. In RA, synovial exhibits overexpression of VCAM-1, which interacts with α4β1 on T cells and B cells, promoting their firm adhesion and subsequent transmigration into the inflamed synovium. This process drives the accumulation of autoreactive lymphocytes, exacerbating joint inflammation and pannus formation. Furthermore, serum levels of soluble VCAM-1 (sVCAM-1) are elevated in RA patients and correlate positively with disease activity scores, such as the Disease Activity Score 28 (DAS28), indicating its utility as a for monitoring inflammatory severity. In (MS), VCAM-1 upregulation at the blood-brain barrier (BBB) is critical for enabling pathogenic T-cell entry into the (CNS). Endothelial cells and in MS lesions express heightened levels of VCAM-1, which binds to (α4β1 ) on encephalitogenic T cells, facilitating their adhesion and diapedesis across the BBB during active disease phases. This interaction contributes to demyelination and plaque formation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Additionally, sVCAM-1 levels are markedly elevated in the (CSF) of MS patients, particularly during relapses, reflecting ongoing endothelial activation and BBB disruption. VCAM-1 also contributes to pathogenesis in other autoimmune diseases, such as (IBD) and (SLE). In IBD, VCAM-1 on intestinal binds to α4β7 on gut-homing lymphocytes, supporting their recruitment to inflamed mucosa and perpetuating chronic colitis. This adhesion mechanism overlaps with interactions involving mucosal addressin cell adhesion molecule-1 (MAdCAM-1), amplifying leukocyte infiltration in conditions like . In SLE, VCAM-1 expression is dysregulated on endothelial cells, promoting vascular inflammation and immune complex-mediated damage; systematic reviews highlight its frequent elevation as a marker of endothelial activation in active disease. Serum VCAM-1 levels correlate with SLE disease activity, underscoring its role in systemic vascular pathology. In neuroinflammatory contexts like (AD), microglial VCAM-1 expression, induced by interleukin-33 (IL-33), directs toward (ApoE) at amyloid-beta (Aβ) plaques, enhancing Aβ clearance while contributing to plaque-associated . VCAM-1 is further implicated in , where its upregulation on drives blood-brain barrier dysfunction and post-stroke , as evidenced by recent studies showing that VCAM-1 blockade preserves cerebrovascular integrity and reduces infiltration after ischemic events. Sustained VCAM-1 expression underlies chronic inflammation in conditions such as through a loop involving signaling. In psoriatic lesions, pro-inflammatory cytokines like IL-1 and TNF-α activate in and endothelial cells, leading to persistent VCAM-1 upregulation that recruits T cells and sustains epidermal . This -mediated loop amplifies adhesion molecule expression, including VCAM-1 on dermal endothelium, contributing to the vicious cycle of plaque formation and immune cell persistence.

Oncological Involvement

VCAM-1 plays a critical role in cancer progression by facilitating tumor cell adhesion, vascular interactions, and modulation of the . In , tumor cells often express VCAM-1 or its VLA-4 (α4β1 ), enabling binding to endothelial VCAM-1 and promoting during dissemination. This mechanism is particularly prominent in , where circulating melanoma cells with upregulated α4 adhere to VCAM-1 on activated , supporting metastatic spread to distant sites such as lungs and . Similarly, in , ectopic VCAM-1 expression on metastatic cells attracts VLA-4-positive macrophages, providing survival signals and enhancing colonization of leukocyte-rich organs like the lungs. Blocking the VCAM-1/VLA-4 axis with antibodies or inhibitors has shown potential to reduce metastatic burden in preclinical models of these cancers. Beyond direct , VCAM-1 contributes to tumor by recruiting pro-angiogenic to the endothelial lining, thereby promoting neovascularization essential for tumor growth. Endothelial VCAM-1 upregulation, often induced by factors like VEGF, facilitates monocyte transmigration and differentiation into tumor-associated macrophages that secrete angiogenic cytokines. In , elevated VCAM-1 expression on tumor-associated and correlates with increased and poor patient , as it drives formation and metastatic progression. This recruitment process underscores VCAM-1's role in sustaining the hypoxic . VCAM-1 also aids immune evasion strategies employed by tumors, with soluble VCAM-1 (sVCAM-1) potentially interfering with natural killer (NK) cell adhesion and cytotoxicity by competing for binding sites on immune effectors. In the context of , a 2024 review emphasizes VCAM-1's involvement in (MSC)-tumor interactions, where VCAM-1 expression on MSCs enhances their homing to tumor sites but can foster an immunosuppressive niche that shields cancer cells from immune surveillance. Therapeutically, VCAM-1 overexpression in strengthens tumor-stroma interactions, linking to resistance via NF-κB-mediated signaling that recruits immunosuppressive and sustains cell survival under drug pressure. Targeting this pathway may sensitize tumors to agents like by disrupting infiltration. As a prognostic marker, high tissue VCAM-1 levels in strongly predict involvement and reduced overall survival, with expression upregulated in 70% of advanced cases and associated with epithelial-mesenchymal transition.

Pharmacology and Therapeutics

Inhibitors and Modulators

Direct inhibitors of VCAM-1 primarily target the interaction between VCAM-1 and its , very late antigen-4 ( or α4β1 ), to prevent leukocyte adhesion. Monoclonal specific to VCAM-1, such as the anti-VCAM-1 7H, have demonstrated efficacy in preclinical models by blocking this interaction, leading to reduced plaque formation, , and improved plaque stability in atherosclerotic mice. These bind to VCAM-1 domains critical for engagement, thereby inhibiting endothelial-leukocyte adhesion without broadly affecting other adhesion molecules. Small molecule inhibitors, exemplified by cyclic peptides derived from the C-D loop of VCAM-1 domain 1, directly mimic and block the binding site on VCAM-1, preventing α4β1 attachment in cell-based assays. Although many small molecules like BIO5192 target rather than VCAM-1 itself, they effectively disrupt the VCAM-1/ axis, achieving potent inhibition with high selectivity (IC50 ≈ 1.8 nM for α4β1) and minimal off-target effects on other . Indirect modulators of VCAM-1 expression often act through upstream inflammatory pathways. Statins, such as , downregulate VCAM-1 by inhibiting activation in endothelial cells, thereby reducing cytokine-induced expression in models of like lipopolysaccharide-stimulated coronary endothelial cells. This mechanism suppresses VCAM-1 surface levels and subsequent leukocyte recruitment without directly binding the molecule. Similarly, , a phosphodiesterase-1 inhibitor, exhibits atheroprotective effects by attenuating VCAM-1 expression in endothelial cells through pathways, including reduced activity, as shown in high-fat diet-fed models of . In these preclinical studies, treatment significantly lessened lesion formation and linked to elevated VCAM-1. Integrin antagonists indirectly modulate the VCAM-1 pathway by targeting on leukocytes. , a humanized against the α4 subunit of , blocks binding to VCAM-1 on endothelial cells, inhibiting migration across the blood-brain barrier in preclinical and ex vivo models of . This approach disrupts the VCAM-1/ adhesion critical for inflammatory cell , with demonstrated reductions in T-cell adhesion to activated . Emerging nanocarrier strategies enable targeted silencing of VCAM-1 in endothelial cells (ECs). VCAM-1-targeted nanocarriers delivering (siRNA) or (shRNA) against VCAM-1 or related regulators, such as or Smad3, have shown promise in preclinical models by selectively binding upregulated VCAM-1 on ECs, facilitating and reducing inflammatory adhesion. A 2024 review highlights how these ligand-modified nanoparticles, often conjugated with anti-VCAM-1 antibodies, enhance EC-specific delivery while minimizing off-target effects in vascular tissues. Safety profiles of VCAM-1 pathway inhibitors emphasize selectivity and potential risks. α4 integrin blockers like carry a risk of (PML) due to impaired immune surveillance in the , with incidence estimated at 1:1000 after 18 months of use in models. Achieving selectivity over pathways is crucial, as non-selective inhibition could exacerbate ; for instance, probucol selectively suppresses VCAM-1 expression in cytokine-activated human umbilical vein endothelial cells without altering levels, preserving alternative adhesion routes.

Clinical Developments

Natalizumab, a targeting the α4 integrin subunit, is an approved therapy for relapsing-remitting (MS) that inhibits leukocyte adhesion to VCAM-1 by blocking α4β1 and α4β7 , thereby reducing immune cell trafficking across the blood-brain barrier. In phase 3 clinical trials, monotherapy reduced the annualized relapse rate by 68% compared to over one year and decreased the risk of sustained disability progression by 42-54% over two years. , another approved -targeting , is used for (IBD) including and , where it selectively binds α4β7 to prevent homing to the gut via interactions with MAdCAM-1 and, to a lesser extent, VCAM-1. Clinical data from phase 3 trials demonstrate vedolizumab's efficacy in inducing clinical response in moderate-to-severe IBD, with clinical response rates of approximately 47% at week 6 in patients and clinical remission rates of about 17%; for maintenance therapy in , 42% of responders achieved sustained clinical remission at week 52. Recent 2024-2025 updates on (HF) biomarkers have incorporated VCAM-1 measurements, with elevated levels independently associated with increased risks of hospitalization and mortality in patients with HF with reduced . Soluble VCAM-1 (sVCAM-1) serves as a key in (RA) trials, where higher serum levels correlate with disease activity and , enabling monitoring of therapeutic responses in phase III studies of biologics. A 2025 analysis in JAMA Cardiology integrated sVCAM-1 into HF risk stratification models, showing it enhances predictive accuracy for adverse cardiovascular events when combined with traditional scores like the Seattle Heart Failure Model. Emerging applications involve therapies that modulate VCAM-1 expression to improve homing and anti-inflammatory effects; for instance, VCAM-1-positive human umbilical cord mesenchymal s demonstrated superior in a 2024 experimental autoimmune encephalomyelitis model by reducing demyelination and glial activation. Nanodelivery systems targeting VCAM-1 have advanced for vascular applications, with anti-VCAM-1-conjugated nanoparticles enabling selective drug release to inflamed , as shown in 2024 studies using liposomes for anti-inflammatory payloads in models. In , VCAM-1-targeted nanocarriers have been explored for precise delivery of chemotherapeutics to tumor vasculature, improving while minimizing systemic . Clinical challenges in VCAM-1-targeted cancer therapies include limited efficacy due to compensatory pathways involving , which provides redundant mechanisms for leukocyte and tumor infiltration, as evidenced by preclinical models where single blockade of VCAM-1 failed to fully suppress . However, post-2023 data indicate promise for combining anti-angiogenic therapies with inhibitors in models, enhancing T-cell infiltration and tumor regression.

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