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VCAM-1

Vascular cell adhesion molecule 1 (VCAM-1) is a transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily, encoded by the VCAM1 gene on chromosome 1p21.2 in humans, and serves as a key mediator of leukocyte-endothelial cell interactions during inflammatory responses.^[1] It is primarily expressed on the surface of cytokine-activated endothelial cells, where it facilitates the adhesion, rolling, and transmigration of leukocytes such as lymphocytes, monocytes, and eosinophils into tissues.^[2] Discovered in 1989 as a cytokine-inducible adhesion molecule, VCAM-1 exists in multiple isoforms due to alternative splicing, with the predominant human form featuring seven extracellular Ig-like domains that interact with α4β1 and α4β7 integrins on leukocytes.^[2]^[1] VCAM-1 expression is tightly regulated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1), which activate signaling pathways like NF-κB to upregulate its transcription on endothelial cells lining post-capillary venules.^[2] Beyond endothelium, 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 spleen and lymph nodes, where it shows the highest basal expression levels.^[1]^[2] Functionally, VCAM-1 not only promotes firm adhesion but also triggers intracellular signaling events, including calcium fluxes and reactive oxygen species (ROS) production, which support leukocyte activation and diapedesis across the vascular barrier.^[2] The molecule's dysregulation is implicated in numerous pathological conditions, serving as a biomarker and therapeutic target in inflammatory and immune-mediated diseases. Elevated soluble VCAM-1 levels in serum correlate with disease activity in rheumatoid arthritis, asthma, and atherosclerosis, where it drives excessive leukocyte infiltration leading to tissue damage.^[2] In cancer, VCAM-1 expression on tumor-associated endothelium and malignant cells enhances angiogenesis, metastasis, and immune evasion, with high levels associated with poor prognosis in various solid tumors.^[2] Therapeutic strategies targeting VCAM-1, such as blocking antibodies, have shown promise in preclinical models by reducing inflammation in colitis, transplant rejection, and joint destruction in arthritis.^[2]

Genetics and Structure

Gene Organization

The VCAM1 gene, which encodes vascular cell adhesion molecule 1, is located on the short arm of human chromosome 1 at the cytogenetic band 1p21.2.^[1] This genomic region spans approximately 19 kb, from nucleotide positions 100,719,742 to 100,739,045 on the GRCh38 reference assembly.^[1] 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 immunoglobulin superfamily members.^[1]^[3] 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 signal peptide sequence and exon 9 encodes the transmembrane and cytoplasmic regions.^[3] Alternative splicing 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.^[3]^[4] A third minor isoform involves additional splicing at exon 8, further diversifying potential protein products, though the two main forms predominate in cytokine-activated endothelium.^[1] The VCAM1 gene exhibits strong evolutionary conservation across mammals, with orthologs identified in species such as mouse (Vcam1 on chromosome 3), rat, and non-human primates, reflecting shared roles in leukocyte adhesion.^[1] Key regulatory elements in the promoter region, including multiple NF-κB binding sites, are conserved and mediate inducible expression in response to inflammatory cytokines like TNF-α and IL-1β.^[5]^[6]

Protein Domains and Isoforms

VCAM-1 is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily (IgSF), with a predicted core molecular weight of approximately 81 kDa for the full-length polypeptide.^[7] The mature protein, following post-translational processing, exhibits an apparent molecular weight of around 110 kDa due to extensive glycosylation and other modifications.^[8] 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 amino acids (residues 721-739).^[7] 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.^[7] 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.^[9] 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.^[10] A soluble isoform can also arise from proteolytic cleavage or alternative splicing, but the membrane forms predominate in cellular contexts.^[11] Key structural motifs include multiple N-linked glycosylation 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.^[7] These glycans, primarily complex-type, are essential for the protein's sialoglycoprotein nature and may modulate interactions. Crystal structures derived from X-ray crystallography, 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 integrin engagement through conserved acidic motifs in their C-D loops.^[12]^[13]

Expression and Regulation

Cellular and Tissue Expression

VCAM-1 is primarily expressed on endothelial cells, particularly in post-capillary venules, where its expression is markedly upregulated in response to inflammatory stimuli.^[11] It is also detected on smooth muscle cells, dendritic cells, and fibroblasts under activated conditions.^[11] This inducible expression pattern facilitates leukocyte adhesion during inflammation, with basal levels remaining low in quiescent endothelium.^[11] 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.^[1]^[14] Basal expression is minimal in the brain but increases significantly in inflamed tissues, including atherosclerotic plaques, highlighting its role in localized inflammatory responses.^[11] 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.^[11]^[15] 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.^[11] It is also expressed in neural crest-derived cells contributing to heart organogenesis, aiding in cell migration and tissue remodeling.^[16] Detection of VCAM-1 typically involves immunohistochemistry, which reveals its colocalization with von Willebrand factor in endothelial cells, confirming vascular specificity.^[17] Additionally, enzyme-linked immunosorbent assay (ELISA) quantifies serum sVCAM-1 levels as a non-invasive biomarker for inflammatory states.^[15] Cytokines such as TNF-α induce this expression pattern in endothelial cells.^[11]

Molecular Regulation

The promoter region of the VCAM-1 gene, located in the 5' flanking region, features consensus binding sites for key transcription factors including NF-κB, AP-1, and members of the GATA family, which render it highly responsive to proinflammatory stimuli such as cytokines.^[18] These sites facilitate the recruitment of transcription factors upon cellular activation, enabling precise control over gene expression in endothelial cells exposed to inflammatory cues.^[19] Major inducers of VCAM-1 expression include proinflammatory cytokines TNF-α and IL-1β, which activate the IκB kinase complex, leading to phosphorylation and degradation of IκBα, nuclear translocation of NF-κB, and subsequent binding to the promoter for transcriptional activation.^[20] This pathway results in sustained VCAM-1 expression persisting beyond 24 hours, supporting prolonged leukocyte recruitment during inflammation.^[21] Additionally, disturbed shear stress and oxidative stress contribute to upregulation by enhancing NF-κB activity and promoter accessibility, promoting endothelial activation in vascular environments prone to atherosclerosis.^[22] In contrast, suppressors such as glucocorticoids inhibit VCAM-1 transcription by recruiting histone deacetylase 2 (HDAC2) to the promoter, reducing histone acetylation and blocking NF-κB, AP-1, and GATA binding.^[23]^[24] Statins similarly attenuate expression through PPAR-α activation, which interferes with NF-κB signaling, or via HDAC-mediated mechanisms that limit promoter accessibility.^[25] Post-transcriptionally, microRNAs like miR-126 repress VCAM-1 by directly targeting its 3' untranslated region, thereby dampening mRNA stability and translation in endothelial cells.^[26] Epigenetic modifications further fine-tune VCAM-1 regulation, with increased histone acetylation (e.g., H3K18ac) at the promoter enhancing chromatin openness and transcriptional activity, particularly in settings of chronic inflammation where sustained NF-κB signaling predominates.^[27] This acetylation is dynamically linked to coactivators like p300, amplifying cytokine-driven responses.^[28] The temporal dynamics of VCAM-1 expression reflect its role in adaptive immune responses, with rapid induction occurring within 4 hours of acute inflammatory stimulation by TNF-α or IL-1β, peaking at 6-24 hours and maintaining elevated levels for extended periods to facilitate mononuclear cell adhesion.^[29] This contrasts with the more transient upregulation of ICAM-1, which peaks earlier (within 2-4 hours) but declines more rapidly, emphasizing VCAM-1's suitability for sustained interactions in ongoing inflammation.^[30]

Biological Functions

Cell Adhesion Mechanisms

VCAM-1 primarily facilitates leukocyte adhesion through its interaction with the integrin α4β1 (also known as VLA-4), which is expressed on various leukocytes including lymphocytes, monocytes, and eosinophils. 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 adhesion site (MIDAS) on the α4β1 integrin. The affinity of this interaction in the high-affinity state of the integrin is high, with a dissociation constant (Kd) in the range of approximately 1-10 nM, enabling stable adhesion under physiological conditions.^[31]^[32] In addition to α4β1, VCAM-1 engages secondary integrins such as α4β7 on gut-homing lymphocytes, which binds primarily to D1 of VCAM-1 and supports tissue-specific adhesion, and αDβ2 on certain myeloid cells like eosinophils, which exhibits weaker binding affinity compared to α4β1. These interactions contribute to diverse adhesive 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 integrins.^[33]^[34] The adhesion process mediated by VCAM-1 involves initial tethering and rolling of leukocytes on the endothelial surface under hydrodynamic shear flow in the vasculature, followed by firm arrest that transitions to spreading and transmigration. This stepwise mechanism relies on the conformational activation of α4β1 integrin from low- to high-affinity states, triggered by chemokines, and requires divalent cations such as Mg²⁺ to stabilize the integrin-ligand interface and support bond formation against shear forces.^[35]^[36] Soluble VCAM-1 (sVCAM-1), generated by proteolytic shedding of the membrane-bound form, circulates in plasma and can bind α4 integrins on leukocytes, acting as a competitive inhibitor that reduces adhesion 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 adhesion; this has been visualized through techniques like X-ray crystallography showing alternative domain orientations.^[37]^[38]

Signaling Pathways

Engagement of VCAM-1 on endothelial cells by its ligand VLA-4 triggers intracellular signaling cascades that promote cytoskeletal reorganization and increased vascular permeability. Ligation of VCAM-1 activates Src family kinases, which initiate downstream activation of the PI3K/Akt pathway, leading to phosphorylation events that facilitate actin polymerization and formation of cup-like protrusions around adherent leukocytes.^[11] This process involves Rac1 activation, which coordinates cytoskeletal rearrangement essential for endothelial cell shape changes and enhanced paracellular permeability.^[11] Additionally, VCAM-1 signaling induces calcium fluxes that further support these dynamic alterations in endothelial barrier function.^[11] 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.^[33] ERK activation, in particular, supports leukocyte spreading and directed migration across the endothelium by modulating actin remodeling.^[39] VCAM-1 signaling exhibits crosstalk with ICAM-1, amplifying inflammatory responses through synergistic effects on leukocyte arrest and transmigration. Clustering of ICAM-1 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 NADPH oxidase (NOX2).^[40] This ROS generation, producing approximately 1 μM H₂O₂, activates matrix metalloproteinases (MMP2 and MMP9) that degrade endothelial junctions, thereby enhancing inflammation and leukocyte infiltration.^[41] The cooperative interaction strengthens overall adhesion and facilitates efficient extravasation.^[40] Negative regulation of VCAM-1 signaling is mediated by protein tyrosine phosphatases, including PTPN11, which dephosphorylates key substrates to attenuate pathway duration and prevent excessive activation. PTPN11 acts as a counterbalance by inhibiting sustained phosphorylation in Src and PI3K/Akt cascades.^[11] Similarly, PTP1B is activated downstream of VCAM-1 via PKCα-mediated serine phosphorylation, indirectly limiting signaling by modulating transmigration without direct oxidation by ROS.^[42] Experimental evidence from knockout models underscores these pathways' roles. VCAM-1-deficient mice exhibit impaired leukocyte recruitment, with reduced B-cell homing and diminished eosinophil transmigration in inflammatory models.^[11] NOX2 (CYBB) knockout in non-hematopoietic cells blocks VCAM-1-dependent eosinophil recruitment by 68% in allergen-challenged lungs, highlighting ROS's necessity.^[11] Furthermore, disruption of VCAM-1 signaling correlates with attenuated NF-κB activation in endothelium, as ROS-mediated pathways that sustain NF-κB are impaired, reducing pro-inflammatory gene expression.^[11]

Pathophysiological Roles

Cardiovascular Diseases

VCAM-1 plays a critical role in atherosclerosis by facilitating the recruitment of monocytes to the vascular endothelium, where its upregulation in early atherosclerotic lesions promotes leukocyte adhesion and infiltration into the arterial intima. Studies in animal models demonstrate that reduced VCAM-1 expression significantly attenuates nascent lesion formation, highlighting its essential function in the initiation of plaque development independent of lipid profiles or circulating leukocyte counts.^[43] 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 coronary artery disease.^[44] In hypertension, chronic exposure to low or disturbed shear stress on endothelial cells induces VCAM-1 expression, contributing to endothelial dysfunction and vascular remodeling through enhanced inflammatory cell adhesion. This mechanosensitive upregulation exacerbates arterial stiffness and promotes the progression of hypertensive vascular pathology by amplifying monocyte-endothelial interactions under hemodynamic stress.^[45] In heart failure with reduced ejection fraction (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 heart failure or cardiovascular death, with an adjusted hazard ratio of 1.40, mediated through distinct inflammatory pathways involving myocardial immune infiltration.^[46] Following myocardial infarction (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 apoptosis while improving cardiac function by limiting inflammatory infiltration.^[47]^[48] As a biomarker, sVCAM-1 serum levels above 800 ng/mL signal elevated cardiovascular risk, particularly when integrated with C-reactive protein (CRP) for enhanced prognostic accuracy in predicting events like coronary instability or heart failure progression. This combination leverages sVCAM-1's reflection of endothelial activation alongside CRP's marker of systemic inflammation to stratify patient outcomes more effectively.^[49]

Inflammatory and Autoimmune Diseases

VCAM-1 plays a pivotal role in rheumatoid arthritis (RA) by facilitating leukocyte infiltration into synovial tissues. In RA, synovial endothelium exhibits overexpression of VCAM-1, which interacts with α4β1 integrin on T cells and B cells, promoting their firm adhesion and subsequent transmigration into the inflamed synovium.^[50] 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 biomarker for monitoring inflammatory severity.^[51] In multiple sclerosis (MS), VCAM-1 upregulation at the blood-brain barrier (BBB) is critical for enabling pathogenic T-cell entry into the central nervous system (CNS). Endothelial cells and astrocytes in MS lesions express heightened levels of VCAM-1, which binds to VLA-4 (α4β1 integrin) on encephalitogenic T cells, facilitating their adhesion and diapedesis across the BBB during active disease phases.^[52] This interaction contributes to demyelination and plaque formation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS.^[53] Additionally, sVCAM-1 levels are markedly elevated in the cerebrospinal fluid (CSF) of MS patients, particularly during relapses, reflecting ongoing endothelial activation and BBB disruption.^[54] VCAM-1 also contributes to pathogenesis in other autoimmune diseases, such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). In IBD, VCAM-1 on intestinal endothelium binds to α4β7 integrin on gut-homing lymphocytes, supporting their recruitment to inflamed mucosa and perpetuating chronic colitis.^[55] This adhesion mechanism overlaps with interactions involving mucosal addressin cell adhesion molecule-1 (MAdCAM-1), amplifying leukocyte infiltration in conditions like Crohn's disease.^[56] 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.^[57] Serum VCAM-1 levels correlate with SLE disease activity, underscoring its role in systemic vascular pathology.^[58] In neuroinflammatory contexts like Alzheimer's disease (AD), microglial VCAM-1 expression, induced by interleukin-33 (IL-33), directs chemotaxis toward apolipoprotein E (ApoE) at amyloid-beta (Aβ) plaques, enhancing Aβ clearance while contributing to plaque-associated neuroinflammation.^[59] VCAM-1 is further implicated in vascular dementia, where its upregulation on brain endothelium drives blood-brain barrier dysfunction and post-stroke cognitive impairment, as evidenced by recent studies showing that VCAM-1 blockade preserves cerebrovascular integrity and reduces lymphocyte infiltration after ischemic events.^[60] Sustained VCAM-1 expression underlies chronic inflammation in conditions such as psoriasis through a positive feedback loop involving NF-κB signaling. In psoriatic lesions, pro-inflammatory cytokines like IL-1 and TNF-α activate NF-κB in keratinocytes and endothelial cells, leading to persistent VCAM-1 upregulation that recruits T cells and sustains epidermal hyperplasia.^[61] This NF-κB-mediated loop amplifies adhesion molecule expression, including VCAM-1 on dermal endothelium, contributing to the vicious cycle of plaque formation and immune cell persistence.^[62]

Oncological Involvement

VCAM-1 plays a critical role in cancer progression by facilitating tumor cell adhesion, vascular interactions, and modulation of the tumor microenvironment. In metastasis, tumor cells often express VCAM-1 or its ligand VLA-4 (α4β1 integrin), enabling binding to endothelial VCAM-1 and promoting extravasation during dissemination. This mechanism is particularly prominent in melanoma, where circulating melanoma cells with upregulated α4 integrin adhere to VCAM-1 on activated endothelium, supporting metastatic spread to distant sites such as lungs and brain.^[63] Similarly, in breast cancer, 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.^[64] Blocking the VCAM-1/VLA-4 axis with antibodies or inhibitors has shown potential to reduce metastatic burden in preclinical models of these cancers.^[65] Beyond direct adhesion, VCAM-1 contributes to tumor angiogenesis by recruiting pro-angiogenic monocytes 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.^[66] In ovarian cancer, elevated VCAM-1 expression on tumor-associated endothelium and mesothelium correlates with increased vascular permeability and poor patient prognosis, as it drives ascites formation and metastatic progression.^[67] This recruitment process underscores VCAM-1's role in sustaining the hypoxic tumor microenvironment. 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 VLA-4 binding sites on immune effectors.^[37] In the context of stem cell therapy, a 2024 review emphasizes VCAM-1's involvement in mesenchymal stem cell (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.^[68] Therapeutically, VCAM-1 overexpression in glioblastoma endothelium strengthens tumor-stroma interactions, linking to chemotherapy resistance via NF-κB-mediated signaling that recruits immunosuppressive monocytes and sustains cell survival under drug pressure.^[65] Targeting this pathway may sensitize tumors to agents like temozolomide by disrupting monocyte infiltration. As a prognostic marker, high tissue VCAM-1 levels in colorectal cancer strongly predict lymph node involvement and reduced overall survival, with expression upregulated in 70% of advanced cases and associated with epithelial-mesenchymal transition.^[69]

Pharmacology and Therapeutics

Inhibitors and Modulators

Direct inhibitors of VCAM-1 primarily target the interaction between VCAM-1 and its ligand, very late antigen-4 (VLA-4 or α4β1 integrin), to prevent leukocyte adhesion. Monoclonal antibodies specific to VCAM-1, such as the anti-VCAM-1 antibody 7H, have demonstrated efficacy in preclinical models by blocking this interaction, leading to reduced plaque formation, inflammation, and improved plaque stability in atherosclerotic mice. These antibodies bind to VCAM-1 domains critical for VLA-4 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 integrin attachment in cell-based assays. Although many small molecules like BIO5192 target VLA-4 rather than VCAM-1 itself, they effectively disrupt the VCAM-1/VLA-4 axis, achieving potent inhibition with high selectivity (IC50 ≈ 1.8 nM for α4β1) and minimal off-target effects on other integrins. Indirect modulators of VCAM-1 expression often act through upstream inflammatory pathways. Statins, such as atorvastatin, downregulate VCAM-1 by inhibiting NF-κB activation in endothelial cells, thereby reducing cytokine-induced expression in models of inflammation like lipopolysaccharide-stimulated human coronary artery endothelial cells. This mechanism suppresses VCAM-1 surface levels and subsequent leukocyte recruitment without directly binding the molecule. Similarly, vinpocetine, a phosphodiesterase-1 inhibitor, exhibits atheroprotective effects by attenuating VCAM-1 expression in endothelial cells through anti-inflammatory pathways, including reduced NF-κB activity, as shown in high-fat diet-fed apolipoprotein E knockout mouse models of atherosclerosis. In these preclinical studies, vinpocetine treatment significantly lessened lesion formation and endothelial dysfunction linked to elevated VCAM-1. Integrin antagonists indirectly modulate the VCAM-1 pathway by targeting VLA-4 on leukocytes. Natalizumab, a humanized monoclonal antibody against the α4 subunit of VLA-4, blocks binding to VCAM-1 on endothelial cells, inhibiting lymphocyte migration across the blood-brain barrier in preclinical and ex vivo models of multiple sclerosis. This approach disrupts the VCAM-1/VLA-4 adhesion critical for inflammatory cell extravasation, with demonstrated reductions in T-cell adhesion to activated endothelium. Emerging nanocarrier strategies enable targeted silencing of VCAM-1 in endothelial cells (ECs). VCAM-1-targeted nanocarriers delivering small interfering RNA (siRNA) or short hairpin RNA (shRNA) against VCAM-1 or related regulators, such as NF-κB or Smad3, have shown promise in preclinical atherosclerosis models by selectively binding upregulated VCAM-1 on ECs, facilitating gene knockdown 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 natalizumab carry a risk of progressive multifocal leukoencephalopathy (PML) due to impaired immune surveillance in the central nervous system, with incidence estimated at 1:1000 after 18 months of use in multiple sclerosis models. Achieving selectivity over ICAM-1 pathways is crucial, as non-selective inhibition could exacerbate inflammation; for instance, probucol selectively suppresses VCAM-1 expression in cytokine-activated human umbilical vein endothelial cells without altering ICAM-1 levels, preserving alternative adhesion routes.

Clinical Developments

Natalizumab, a monoclonal antibody targeting the α4 integrin subunit, is an approved therapy for relapsing-remitting multiple sclerosis (MS) that inhibits leukocyte adhesion to VCAM-1 by blocking α4β1 and α4β7 integrins, thereby reducing immune cell trafficking across the blood-brain barrier.^[70] In phase 3 clinical trials, natalizumab monotherapy reduced the annualized relapse rate by 68% compared to placebo over one year and decreased the risk of sustained disability progression by 42-54% over two years.^[70] Vedolizumab, another approved integrin-targeting monoclonal antibody, is used for inflammatory bowel disease (IBD) including ulcerative colitis and Crohn's disease, where it selectively binds α4β7 integrin to prevent lymphocyte homing to the gut endothelium via interactions with MAdCAM-1 and, to a lesser extent, VCAM-1.^[71] 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 ulcerative colitis patients and clinical remission rates of about 17%; for maintenance therapy in ulcerative colitis, 42% of responders achieved sustained clinical remission at week 52.^[71] Recent 2024-2025 updates on heart failure (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 ejection fraction.^[46] Soluble VCAM-1 (sVCAM-1) serves as a key biomarker in rheumatoid arthritis (RA) trials, where higher serum levels correlate with disease activity and endothelial dysfunction, enabling monitoring of therapeutic responses in phase III studies of biologics.^[72] 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.^[46] Emerging applications involve stem cell therapies that modulate VCAM-1 expression to improve homing and anti-inflammatory effects; for instance, VCAM-1-positive human umbilical cord mesenchymal stem cells demonstrated superior neuroprotection in a 2024 experimental autoimmune encephalomyelitis model by reducing demyelination and glial activation.^[73] Nanodelivery systems targeting VCAM-1 have advanced for vascular applications, with anti-VCAM-1-conjugated nanoparticles enabling selective drug release to inflamed endothelium, as shown in 2024 studies using liposomes for anti-inflammatory payloads in atherosclerosis models.^[74] In oncology, VCAM-1-targeted nanocarriers have been explored for precise delivery of chemotherapeutics to tumor vasculature, improving bioavailability while minimizing systemic toxicity.^[75] Clinical challenges in VCAM-1-targeted cancer therapies include limited efficacy due to compensatory pathways involving ICAM-1, which provides redundant mechanisms for leukocyte adhesion and tumor infiltration, as evidenced by preclinical models where single blockade of VCAM-1 failed to fully suppress metastasis.^[76] However, post-2023 data indicate promise for combining anti-angiogenic therapies with immune checkpoint inhibitors in hepatocellular carcinoma models, enhancing T-cell infiltration and tumor regression.

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Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway. Arterioscler. Thromb. Vasc. Biol ...
[25]
Estrogens and glucocorticoids inhibit endothelial vascular cell ...
These results indicate that E(2) decreases VCAM-1 gene expression through the inhibition of NF-kappaB, AP-1, and GATA and suggest novel mechanisms for the ...
[26]
Molecular Mechanisms of Glucocorticoids - ScienceDirect
Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol ...
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Evidence for anti-inflammatory activity of statins and PPARα ...
Our results provide conclusive evidence for a direct suppressive effect of statins and PPARα activators on huCRP expression independent of cholesterol lowering ...
[28]
miR-126 promotes angiogenesis and attenuates inflammation after ...
May 22, 2015 · miR-126 has been found to promote angiogenesis and inhibit vascular inflammation in endothelial cells by repressing three target genes.
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Histone acetyltransferase PCAF regulates inflammatory molecules ...
Moreover, elevated histone acetylation, such as H3K18ac, and up-regulation of some inflammatory genes, such as ICAM-1, VCAM-1, and MCP-1, were found upon these ...
[30]
Involvement of Src/EGFR/PI3-K/Akt pathway - ScienceDirect
In addition, p300 together with NF-κB associate with VCAM-1 promoter, is dynamically linked to histone H3 acetylation stimulated by TNF-α, determined by ...
[31]
Kinetic expression of endothelial adhesion molecules and ... - PubMed
Expression of E-selectin, P-selectin, VCAM-1, and ICAM-1 was assessed using immunohistochemistry and compared with leukocyte localization and ...
[32]
Activation and homologous desensitization of human endothelial ...
Jul 1, 1996 · All three ligands induce transient increases in E-selectin (peak 4 h) and VCAM-1 (peak 8-24 h), as well as sustained increases in ICAM-1 ( ...
[33]
Molecular Basis for the Dynamic Strength of the Integrin α4β1/VCAM ...
The binding of α4β1 to VCAM-1 involves contributions from the N-terminal domains of both α4 and β1 subunits of α4β1. The β1 A-domain contains a metal ion- ...Missing: critical | Show results with:critical
[34]
The Interaction Affinity between Vascular Cell Adhesion Molecule-1 ...
Mar 20, 2015 · The dissociation constant (Kd) of the VCAM-1/VLA-4 interaction was determined to be 41.82 ± 2.36 nM using FRET assay.Missing: α4β1 | Show results with:α4β1
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Targeting integrin pathways: mechanisms and advances in therapy
Jan 2, 2023 · Integrin α4β7 specifically binds VCAM-1 and mucosal address in cell-adhesion molecule-1 (MAdCAM-1) to regulate lymphocyte migration, which ...
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αdβ2 Integrin Is Expressed on Human Eosinophils and Functions as ...
These experiments demonstrate that αdβ2 is an alternative ligand for VCAM-1 ... Integrin α4β7 mediates human eosinophil interaction with MAdCAM-1, VCAM-1 ...Missing: secondary | Show results with:secondary
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The integrin VLA-4 supports tethering and rolling in flow on VCAM-1
The results show that VLA-4 is a versatile integrin that can mediate tethering, rolling, and firm arrest on VCAM-1.Missing: divalent cations Mg2+
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[PDF] Kinetic and Mechanical Basis of Rolling through an Integrin and ...
Tethering to MAdCAM-1 and VCAM-1 under Flow ... Opposed to Firm Adhesion, on MAdCAM-1 and VCAM-1. ... Mg2+ support R4β1 adhesion to VCAM-1, but Mg2+ supports.
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Soluble VCAM-1 binding to α4 integrins is cell-type specific and ...
Soluble VCAM-1 is generated at sites of inflammation and regulates lymphocyte function.9 10 We now report that active cellular processes regulate the binding of ...
[40]
A new conformation of the integrin-binding fragment of human ...
An X-ray crystal structure of two N-terminal integrin-binding IgSF domains of human VCAM-1 is reported. This new crystal form shows an unusual and highly ...
[41]
Endothelial MAPKs Direct ICAM-1 Signaling to Divergent ...
Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating ...
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ICAM-1 Clustering on Endothelial Cells Recruits VCAM-1 - PMC - NIH
Leukocytes adhere through the integrin VLA-4 to VCAM-1 on the endothelium. Similar as for ICAM-1, clustering of VCAM-1 induces intracellular signalling, leading ...
[43]
VCAM-1 signals during lymphocyte migration: role of reactive ... - NIH
VCAM-1 outside-in signals are mediated by NADPH oxidase production of reactive oxygen species and subsequently activation of matrix metalloproteinases.
[44]
VCAM-1 Activation of Endothelial Cell Protein Tyrosine ... - NIH
VCAM-1 activates endothelial cell NADPH oxidase to generate ROS, resulting in oxidative activation of PKCα and then serine phosphorylation of PTP1B.
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A major role for VCAM-1, but not ICAM-1, in early atherosclerosis
VCAM-1 and ICAM-1 are endothelial adhesion molecules of the Ig gene superfamily that may participate in atherogenesis by promoting monocyte accumulation in ...Missing: recruitment | Show results with:recruitment<|separator|>
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Regulation of low shear flow-induced HAEC VCAM-1 expression ...
Here we investigate the hypothesis that low shear-induced activation of NF-κB is responsible for enhanced expression of vascular cell adhesion molecule (VCAM-1) ...Missing: chronic | Show results with:chronic
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Cellular Adhesion Molecules and Adverse Outcomes in Chronic ...
Jun 4, 2025 · Results suggest that VCAM-1 levels may reflect a distinct inflammatory/immune pathophysiological pathway in heart failure with reduced ejection fraction.
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Myocardial infarction causes inflammation and leukocyte recruitment ...
VCAM-1 mRNA was increased in both infarcted and remote myocardium. VCAM-1 protein was also increased in the kidneys of AMI mice (P < 0.05) and ...
[49]
Down-regulation of VCAM-1 in bone mesenchymal stem cells ...
The implantation of sh-VCAM-1 BMSCs into MI rats resulted in more reductions in myocardial infarct size as well as myocardial cell apoptosis, improved cardiac ...Missing: blockade | Show results with:blockade
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Adhesion molecules ICAM-1 & VCAM-1 and coronary heart disease
Subjects with CRP presented elevated coronary risk only if ICAM-1 was high. An elevated level of VCAM-1 was not associated with any risk of future acute ...
[51]
Expression of vascular cell adhesion molecule-1 in normal and ...
EXPERIMENTAL DESIGN: The expression of VCAM-1 on specific cell populations in normal and inflamed synovium was investigated using a range of double-labeling ...<|separator|>
[52]
Vascular cell adhesion molecule-1 in rheumatoid arthritis patients
Serum VCAM-1 increases in RA, and it correlates with disease activity, oxidative stress, and inflammatory markers.Missing: infiltration | Show results with:infiltration
[53]
TNFR1-dependent VCAM-1 expression by astrocytes exposes the ...
In addition, we demonstrate that VCAM-1 expression by astrocytes is crucial for T cell entry into the CNS parenchyma and is required for manifestation of ...Tnfr1-Dependent Vcam-1... · Introduction · T Cell Trafficking To The...
[54]
Interaction of α4-integrin with VCAM-1 is involved in adhesion of ...
It has been concluded that α4-integrin/VCAM-1 interaction plays a critical role in T cell interaction with the blood–brain barrier (BBB) endothelium.Abstract · Introduction · α4β1 And α4β7 Are Both...Missing: upregulation | Show results with:upregulation
[55]
Serum and cerebrospinal fluid levels of soluble adhesion molecules ...
Elevation of CSF sVCAM-1 in MS patients was the most marked finding (P = 0.0001) and an increased sVCAM-1 index indicated that this was due to intrathecal ...
[56]
VCAM-1 and ICAM-1 mediate leukocyte-endothelial cell adhesion in ...
Administration of an anti–α4-integrin MAb that binds α1β7- and α4β7-integrins, both of which are counterreceptors for VCAM-1 expressed on leukocytes, resulted ...
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The role of integrins in the pathogenesis of inflammatory bowel ...
Jun 19, 2019 · The α4β7 integrin heterodimer binds MAdCAM-1; under some circumstances, α4β7 can also bind VCAM-1. ... DCs, dendritic cells; IBD, inflammatory ...1.1 Integrins Overview · 2 Integrins And Ligands In T... · 2.4 Integrin αeβ7 (cd103)
[58]
Dysregulated endothelial cell markers in systemic lupus ...
May 16, 2023 · VCAM-1 was the most reported EC marker (n = 25 articles, 'EC activation') in the selected articles of this systematic review, followed by ...
[59]
Serum levels of PECAM-1, ICAM-1, and VCAM-1 in patients with ...
Sep 9, 2025 · One of the key features of SLE pathogenesis is endothelial dysfunction, which contributes to immune cell infiltration and vascular inflammation.
[60]
The VCAM1–ApoE pathway directs microglial chemotaxis ... - Nature
Sep 21, 2023 · We show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance.Missing: crossing | Show results with:crossing
[61]
The Role of VCAM1 in Post-Stroke Cognitive Impairment
Oct 14, 2025 · VCAM1 knockdown in MCAO rats improves motor function, spatial memory, and reduces infarct size. •. VCAM1 knockdown reduces BBB disruption and ...
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Cytokines in psoriasis - PMC - PubMed Central - NIH
IL-1 also drives the expression of ICAM and VCAM-1 by dermal ... Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
[63]
Signaling pathways and targeted therapies for psoriasis - Nature
Nov 27, 2023 · Genomic studies have revealed that numerous genes encoding components in the NF-κB pathway are linked to the development of psoriasis. GWAS have ...Missing: VCAM- | Show results with:VCAM-
[64]
Molecular Pathways: VCAM-1 as a Potential Therapeutic Target in ...
Circulating melanoma cells expressing α4 integrin have been shown to interact with VCAM-1 on endothelial cells to facilitate extravasation and metastasis in ...
[65]
Macrophage binding to receptor VCAM-1 transmits survival signals ...
Oct 18, 2011 · We report that VCAM-1 provides a survival advantage to breast cancer cells that infiltrate leukocyte-rich microenvironments such as the lungs.
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Ectopic Tumor VCAM-1 Expression in Cancer Metastasis and ...
Dec 4, 2022 · Structurally, VCAM-1 is made up of multiple extracellular Ig-like domains, a single transmembrane domain and a 19 amino acid carboxyl-terminus ...<|control11|><|separator|>
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Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in ...
This review covers the role and relevance of VCAM-1 in inflammation, and also highlights the emerging potential of VCAM-1 as a novel therapeutic target in ...Missing: Asn60 Asn132
[68]
Macrophage-mediated vascular permeability via VLA4/VCAM1 ... - JCI
Targeting the VLA4/VCAM1 axis could attenuate vascular permeability both in vitro and in vivo and, more importantly, could inhibit ascites formation in an OC ...
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Mesenchymal stem cells - the secret agents of cancer immunotherapy
Jan 6, 2024 · This review delves into the role of adoptively transferred MSCs in tumor progression, their interactions with the tumor microenvironment, and ...
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VCAM1 Promotes Tumor Cell Invasion and Metastasis by Inducing ...
Jul 22, 2020 · VCAM1 significantly influenced the invasion and metastasis of CRC cells in vitro and in vivo and activated the EMT program.
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Natalizumab in the Treatment of Multiple Sclerosis - PMC
Natalizumab reduced the rate of clinical relapse at one year by 68% and the risk of sustained progression of disability by 42-54% over 2 years.
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A product review of vedolizumab in inflammatory bowel disease - PMC
Vedolizumab is a monoclonal antibody to the α4β7 integrin that selectively reduces intestinal lymphocyte trafficking, thereby providing a safe and effective ...
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Targeting endothelial vascular cell adhesion molecule-1 in ...
VCAM-1: a promising anti-adhesion target for atherosclerosis. VCAM-1 is a cytokine-inducible surface glycoprotein expressed predominantly on the luminal and ...
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Investigation of serum biomarkers in rheumatoid and psoriatic ... - NIH
Jul 10, 2025 · This is the first study which directly compare serum metabolic markers between diseases and identifies specific disease signatures between RA ...
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VCAM-1+ Mesenchymal Stem/Stromal Cells Reveal Preferable ...
Nov 30, 2024 · We compared the protective effect of VCAM-1 − and VCAM-1 + hUC-MSCs against the clinical symptoms, demyelination, active glia cells and neuroinflammation in ...
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Nanocarriers for targeted drug delivery in the vascular system
Oct 12, 2024 · This approach aims to optimize drug absorption by targeted cells, reduce off-target effects, and improve the efficacy of therapies for glaucoma ...Missing: nanodelivery | Show results with:nanodelivery
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Nanoparticle-Based Drug Delivery for Vascular Applications - PMC
Dec 3, 2024 · A monoclonal anti-VCAM-1 antibody was utilized as a targeting ligand due to the overexpression of VCAM-1 receptors in inflamed endothelial cells ...
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A major role for VCAM-1, but not ICAM-1, in early atherosclerosis - JCI
(a) Alternative RNA splicing produces VCAM-1 isoforms with one or two α4 integrin binding sites (solid circles). Loops, disulfide-linked Ig domains 1–7.<|control11|><|separator|>
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Anti-angiogenic therapy combined with immune checkpoint...
Jun 13, 2025 · At 6, 7, and 8 months post-injection, two mice per time point were euthanized to assess tumor development and liver pathology. Orthotopic HCC ...Mouse Tumor Models · Immune-Related Hevs In Hcc · Vegfc-Induced Hev Formation...