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CD31

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is a 130 kDa type I transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily that plays a central role in vascular cell adhesion and signaling.^[1] Expressed primarily on endothelial cells, platelets, monocytes, neutrophils, and subsets of T cells and B cells, it concentrates at intercellular junctions of the endothelium where it mediates homophilic and heterophilic interactions essential for leukocyte transmigration, angiogenesis, and maintenance of vascular barrier integrity.^[2] Discovered in the mid-1980s and molecularly cloned in 1990, CD31 has since been recognized as a multifunctional regulator of inflammation, immune responses, and hemostasis.^[3] Structurally, PECAM-1 consists of an extracellular domain with six Ig-like C2-type domains (approximately 574 amino acids), a 19-amino-acid transmembrane helix, and a 118-amino-acid cytoplasmic tail featuring two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) at tyrosine residues 663 and 686.^[2] These ITIMs enable phosphorylation-dependent recruitment of tyrosine phosphatases like SHP-2, facilitating signal transduction that modulates integrin activation (e.g., αvβ3, β1, β2) and downstream pathways involving β-catenin for junctional stability.^[2] The gene encoding PECAM-1, located on human chromosome 17q23.3, spans about 75 kb across 16 exons and undergoes alternative splicing to produce isoforms, with the full-length form predominant in endothelial cells.^[3] Approximately 40% of its mass derives from N-linked glycosylation at nine sites, which influences but is not essential for its adhesive properties.^[2] In biological contexts, CD31 is indispensable for leukocyte diapedesis during inflammation, where it promotes the opening of endothelial junctions and supports the lateral border recycling compartment for efficient transmigration without disrupting barrier function.^[1] It also contributes to angiogenesis by facilitating endothelial cell migration and tube formation, as evidenced in PECAM-1-deficient models showing impaired vasculogenesis.^[3] Beyond adhesion, CD31 transduces inhibitory signals to regulate platelet activation and aggregation, inhibiting thrombus formation, and protects against apoptosis in endothelial and hematopoietic cells via pathways involving Akt, Bcl-2, and caspases.^[3] Recent structural studies have elucidated the trans-homophilic binding interface in its first two Ig domains (IgL1-2), involving hydrophobic residues like Leu74 and Ile112, which underpin its role in immune tolerance and endothelial mechanosensing.^[2] Dysregulation of CD31 is implicated in various pathologies, including atherosclerosis (where polymorphisms like Leu125Val correlate with coronary heart disease risk), thrombosis (with elevated levels prognostic in cerebral infarction), and hematologic malignancies (such as leukemia, where it serves as a marker and therapeutic target).^[3] In cancer, CD31 expression on tumor vasculature aids angiogenesis in gliomas and lymphomas, while its blockade shows promise in reducing ischemia-reperfusion injury and neutrophil-mediated tissue damage.^[3] Ongoing research highlights its interactions with pathogens, such as serving as a receptor for Clostridium perfringens β-toxin on endothelial cells, underscoring its broader relevance in host defense.^[1]

Structure and genetics

Gene characteristics

The PECAM1 gene, which encodes the platelet endothelial cell adhesion molecule-1 (PECAM-1) protein, is located on the long arm of human chromosome 17 at the q23.3 cytogenetic band.^[1] In the GRCh38.p14 assembly, the gene spans approximately 71 kb, from genomic position 64,319,415 to 64,390,860 on the reverse strand, and consists of 16 exons interrupted by 15 introns of varying lengths.^[1] This genomic organization supports the production of multiple transcript variants through alternative splicing, with the full-length transcript designated as NM_000442.5 (as of 2025), which encodes the canonical 738-amino-acid isoform NP_000433.4.^[4] Transcriptional regulation of PECAM1 involves a promoter region upstream of exon 1, which includes sequences that drive endothelial-specific expression, as well as enhancers that respond to environmental cues.^[5] Notably, inflammatory cytokines such as tumor necrosis factor-α (TNF-α) modulate PECAM1 expression; treatment of human coronary artery endothelial cells with TNF-α and interferon-γ (IFN-γ) alters steady-state mRNA levels, typically leading to downregulation under inflammatory conditions.^[6] These regulatory elements ensure context-dependent expression, particularly in vascular and hematopoietic tissues. The PECAM1 gene exhibits strong evolutionary conservation across mammals, reflecting its essential role in vascular biology. Orthologs are present in diverse species, including the mouse Pecam1 gene, which maps to chromosome 11 (positions 106,545,043–106,641,454 in GRCm39) and shares high sequence similarity with the human counterpart, enabling cross-species functional studies. This conservation extends to other mammals like rats and non-human primates, with over 250 orthologs identified, underscoring the gene's ancient origin in chordate evolution. Alternative splicing of PECAM1 pre-mRNA generates at least 42 transcript variants in humans, producing isoforms with potential differences in membrane anchoring or ligand binding, though the NM_000442.5 transcript remains the predominant full-length form expressed in endothelial cells and platelets.^[7] This splicing diversity contributes to functional versatility without altering the core genomic structure.

Protein domains and isoforms

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is a type I transmembrane glycoprotein belonging to the immunoglobulin-like superfamily, characterized by a modular domain architecture essential for its adhesive functions.^[8] The extracellular region consists of six immunoglobulin-like (Ig) domains, designated D1 through D6, each featuring a characteristic disulfide-bonded structure with Ig C2-type homology in most domains.^[9] These domains are followed by a single-pass transmembrane domain of 19 amino acids and a cytoplasmic tail comprising 118 amino acids.^[10] The gene encoding this protein is PECAM1, located on chromosome 17q23.^[11] The cytoplasmic tail of CD31 contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which include key phosphorylation sites at tyrosine residues 663 (Tyr663) and 686 (Tyr686).^[12] These sites become phosphorylated upon cellular activation, facilitating the recruitment of Src homology 2 (SH2) domain-containing protein tyrosine phosphatases such as SHP-1 and SHP-2, thereby modulating inhibitory signaling pathways.^[13] Alternative splicing of the PECAM1 pre-mRNA generates multiple isoforms of CD31, primarily affecting the cytoplasmic domain and transmembrane region.^[14] One prominent variant is the soluble form of PECAM-1, produced by exclusion of the exon encoding the transmembrane domain, resulting in a secreted protein that lacks membrane anchoring and can modulate adhesive interactions by competing with the full-length form.^[15] Cytoplasmic isoforms arise from splicing variations in exons 12–15, yielding shorter tails that alter phosphorylation potential and signaling capacity, such as reduced ITIM functionality in certain variants.^[13] Post-translational modifications significantly influence CD31's structure and function, with heavy N-linked glycosylation occurring at nine consensus sites within the extracellular Ig domains, including three in D1 and D2 (e.g., Asn25, Asn57 in D1; Asn124 in D2).^[16] These glycan attachments, which include complex sialylated chains, contribute to protein stability, ligand interactions, and overall molecular weight, elevating it to approximately 130–140 kDa from a predicted unglycosylated mass of about 82 kDa.^[17]

Molecular interactions

CD31, also known as PECAM-1, primarily engages in homophilic interactions through its amino-terminal immunoglobulin-like domains D1 and D2, which mediate both cis (lateral on the same cell) and trans (across adjacent cells) adhesions essential for endothelial cell junction integrity.^[16] These interactions involve specific residues such as Asp11, Asp33, Lys50, Asp51, and Lys89 within D1 and D2, forming an extensive buried interface exceeding 2300 Å² that confers high-affinity binding.^[16] The immunoglobulin-like fold of these domains underpins the specificity and strength of homophilic engagement, distinguishing CD31 from other adhesion molecules.^[18] In addition to homophilic binding, CD31 forms heterophilic interactions with several extracellular partners, including CD38 on leukocytes, where the extracellular domains of CD31 facilitate adhesion to CD38-expressing myeloid cells.^[19] CD31 also binds integrin αvβ3 on endothelial cells via its second immunoglobulin-like domain, enabling cis associations that are independent of RGD motifs and confirmed through co-precipitation and colocalization studies.^[20] Furthermore, CD31 interacts with glycosaminoglycans such as heparin, with binding sites spanning domains 2 and 3 that exhibit pH-sensitive affinity in surface plasmon resonance assays.^[21] Intracellularly, the short cytoplasmic tail of CD31 associates with signaling molecules, including the protein tyrosine phosphatase SHP-2, which binds to phosphorylated immunoreceptor tyrosine-based inhibitory motifs (ITIMs) at tyrosines 663 and 686.^[16] CD31 also links to β-catenin, supporting its localization within junctional structures.^[16] At endothelial adherens junctions, CD31 integrates into complexes with VE-cadherin, where diffusion-trapping mechanisms concentrate CD31 and stabilize intercellular contacts.^[16] Biophysically, the homophilic interactions of CD31 are modulated by shear stress, which strengthens binding affinity and enhances resistance to hydrodynamic forces through the extensive contact area of D1-D2 engagement.^[16] This shear-dependent modulation ensures robust adhesion under vascular flow conditions.^[2]

Expression and distribution

Cellular expression

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is highly expressed on the surface of endothelial cells lining both vascular and lymphatic vessels, as well as on platelets, monocytes, neutrophils, and subsets of T- and B-lymphocytes.^[22]^[23]^[24] This expression pattern positions CD31 as a key marker for cells involved in vascular integrity and immune responses, with particularly dense localization at endothelial cell-cell junctions.^[9] During development, CD31 expression emerges early in embryogenesis on angioblasts within the yolk sac and correlates with the organization of blood islands and nascent vasculature in post-implantation embryos.^[25]^[26] In the adult, expression peaks in mature vasculature, where it constitutes a major component of the endothelial cell surface proteome, while levels remain lower on hematopoietic progenitor cells.^[9]^[27] CD31 expression is dynamically regulated by environmental cues, including upregulation by proinflammatory cytokines such as IL-1β during inflammatory responses and by hypoxia-inducible factors (HIFs) under hypoxic conditions, which enhance its levels in endothelial cells.^[8]^[28] These regulatory mechanisms ensure adaptive responses in vascular and immune contexts.^[29] Expression patterns of CD31 are largely conserved across species, with similar cellular distribution observed in humans and mice, although alternative splicing generates varying isoforms that may influence localization and function in a species-specific manner.^[30]^[2]

Tissue distribution

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is predominantly expressed in the vascular endothelium across various organs, with particularly high levels observed in the heart, lungs, and kidneys.^[31] In the brain, expression is present but at lower levels compared to these highly vascularized tissues.^[16] This vascular-centric distribution underscores its role in endothelial junctions, where it concentrates at cell-cell borders to support barrier integrity.^[16] Beyond major organs, CD31 is notably expressed in the sinusoidal endothelium of the bone marrow, facilitating interactions within the hematopoietic niche.^[32] Similarly, it is detected in the splenic marginal zone, particularly on endothelial and associated stromal cells lining vascular structures.^[33] In contrast, expression is minimal or absent in non-vascular parenchymal cells, such as hepatocytes in the liver or epithelial layers in other tissues, highlighting its specificity to the vasculature. Mature erythrocytes lack CD31 expression, as it is downregulated during terminal erythroid differentiation.^[34] Variations in CD31 distribution occur within the vascular system, with higher expression often noted in microvasculature compared to large vessels, reflecting differences in endothelial density and function.^[8] During inflammation, endothelial CD31 levels can increase in affected tissues, enhancing leukocyte interactions without altering its baseline vascular pattern.^[35] In development, CD31 shows broader transient expression in neural crest-derived cells contributing to vascular formation, which becomes more restricted to endothelium in adulthood.^[36]

Diagnostic applications

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), serves as a key biomarker in diagnostic pathology, particularly for assessing vascular endothelium in clinical samples. Its primary application is in immunohistochemistry (IHC) to evaluate tumor angiogenesis through microvessel density (MVD) scoring, where elevated CD31 expression correlates with increased vascularization and poorer prognosis in cancers such as breast cancer. For instance, monoclonal antibodies like JC/70A are commonly employed to highlight endothelial cells in formalin-fixed, paraffin-embedded tissues, enabling pathologists to quantify neovascularization as a prognostic indicator of tumor recurrence. This method outperforms alternatives like factor VIII-related antigen in sensitivity for detecting microvascular structures in various tumor xenografts. In flow cytometry, CD31 is utilized to identify and enumerate endothelial progenitor cells (EPCs) in peripheral blood, often in combination with markers such as CD34 and VEGF receptor-2, aiding in the diagnosis and monitoring of vascular disorders like cardiovascular disease. This approach allows for the detection of circulating EPCs, which reflect endothelial repair capacity and are reduced in conditions involving vascular injury. Additionally, enzyme-linked immunosorbent assay (ELISA) measures soluble PECAM-1 (sPECAM-1) in serum as a circulating biomarker for endothelial damage, with elevated levels observed in scenarios such as ventilator-induced lung injury and thrombosis, providing a non-invasive indicator of vascular integrity. CD31 demonstrates high specificity for vascular endothelium compared to CD34, which also labels hematopoietic progenitors and stromal cells, making it preferable for precise delineation of blood vessels in diagnostic contexts. However, limitations include cross-reactivity with platelets and megakaryocytes in frozen tissue sections, which can complicate interpretation in cryostat preparations. As of 2025, emerging digital pathology tools are enhancing CD31-based MVD quantification by automating image analysis of IHC slides, improving reproducibility and enabling detailed vascular parameter assessment in tumor environments.

Physiological functions

Cell adhesion and signaling

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), primarily mediates cell-cell adhesion through homophilic interactions between its extracellular immunoglobulin-like domains 1 and 2 (IgD1 and IgD2) on adjacent endothelial cells, forming a large buried interface exceeding 2300 Å² that stabilizes intercellular junctions.^[16] These homophilic bonds are enriched at endothelial borders via a diffusion-trapping mechanism, enhancing barrier integrity under physiological fluid shear stress conditions.^[16] Additionally, CD31 engages in heterophilic interactions, such as cis-association with integrin αvβ3 on the same cell surface, which supports adhesion without relying on its cytoplasmic domain.^[19] Upon ligation, CD31 initiates inhibitory signaling through its two intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) at tyrosine residues Y663 and Y686, which become phosphorylated and recruit Src homology 2 domain-containing protein tyrosine phosphatases SHP-1 and SHP-2.^[13] SHP-2 binds with high affinity to the phosphorylated Y663 ITIM via its N-terminal SH2 domain, while both phosphatases require intact ITIMs for recruitment; this complex dephosphorylates downstream targets, thereby inhibiting the PI3K/Akt signaling pathway in endothelial cells.^[16] SHP-2 further modulates junctional stability by dephosphorylating β-catenin, promoting its association with VE-cadherin.^[37] CD31 exhibits crosstalk with vascular endothelial growth factor (VEGF) receptor signaling, forming a mechanosensory complex with VE-cadherin and VEGFR2 at endothelial junctions to regulate permeability under shear flow.^[37] This interaction allows CD31 to fine-tune VEGF-induced responses, such as tyrosine phosphorylation of CD31 itself, which influences endothelial barrier function without directly activating VEGFR2.^[16] Full signaling activation by CD31 requires multivalent clustering of its extracellular domains, as monovalent engagement fails to induce sufficient tyrosine phosphorylation or phosphatase recruitment.^[13] In vitro models replicate this by using bivalent or multivalent antibodies targeting the IgD6 domain to cluster CD31 on endothelial monolayers, mimicking physiological homophilic adhesion and enhancing junctional barrier restoration.^[16]

Leukocyte transmigration

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), plays a pivotal role in the paracellular diapedesis of leukocytes, particularly neutrophils and monocytes, by mediating homophilic interactions between endothelial and leukocyte surfaces at intercellular junctions. These homophilic CD31-CD31 bonds form at the lateral borders of endothelial cells, providing a stable scaffold that guides leukocytes through the endothelial barrier during inflammation. This process is essential for efficient immune cell extravasation, as disruption of these interactions significantly impairs leukocyte passage without affecting prior steps like rolling or firm adhesion.^[38] In addition to homophilic engagement, CD31 cooperates with CD99 on both endothelial and leukocyte surfaces to facilitate the disassembly of adherens junctions, enabling junctional opening for diapedesis. Leukocyte CD31 and CD99 ligation triggers localized signaling that loosens VE-cadherin-based contacts, allowing leukocytes to squeeze through the paracellular route while preserving overall endothelial integrity. This cooperative mechanism ensures rapid and reversible junctional remodeling, with CD31 primarily handling initial tethering and CD99 contributing to subsequent barrier disassembly.^[39]^[8] During transmigration, endothelial CD31 undergoes transient redistribution, accumulating around the site of leukocyte passage to reinforce the interaction before dispersing post-event, which supports the dynamic and reversible nature of the process. In vivo studies using PECAM-1 knockout mice demonstrate impaired neutrophil recruitment in models of inflammation, such as IL-1β-stimulated cremaster muscle venules and peritonitis, where transmigration is reduced by approximately 55-57% compared to wild-type controls. These findings highlight CD31's quantitative contribution to transmigration efficiency, accounting for roughly half of the process in cytokine-driven inflammatory contexts.^[40]^[38]

Angiogenesis and vascular integrity

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), plays a critical role in angiogenesis by facilitating endothelial cell migration and tube formation through homophilic interactions at cell-cell junctions.^[41] These interactions, mediated by the first two immunoglobulin-like domains (IgD1 and IgD2), stabilize endothelial sprouts during vessel outgrowth, particularly in response to vascular endothelial growth factor (VEGF) signaling.^[42] Disruption of this homophilic adhesion, such as through mutation of key residues like lysine 89, impairs sprout stabilization and angiogenic progression.^[41] In maintaining vascular integrity, CD31 concentrates at endothelial intercellular junctions, where it links adherens junctions (via VE-cadherin) to tight junctions and the actin cytoskeleton, thereby preventing vascular leakage and regulating permeability under shear stress.^[42] This structural role ensures barrier function, with CD31's extracellular domain forming a robust 2300 Å² homophilic interface that withstands hemodynamic forces.^[41] During embryonic development, CD31 contributes to vasculogenesis, but Pecam1-null mice are viable without overt vascular defects at birth, though they exhibit impaired angiogenic responses, such as reduced vessel formation in subcutaneous Matrigel plugs.^[43] In adult tissues, CD31 expression is upregulated during angiogenesis in wound healing, supporting endothelial remodeling and new vessel formation.^[44] Similarly, it is elevated in pathological neovessels. CD31 also interacts with integrins, such as αvβ3, to modulate RhoA signaling and extracellular matrix remodeling, which are essential for endothelial tube formation during angiogenesis. These interactions enable coordinated cytoskeletal dynamics without relying on immune cell involvement.

Neutrophil clearance

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), contributes to the efferocytosis of apoptotic neutrophils by macrophages and endothelial cells through homophilic interactions that facilitate attachment and engulfment. As neutrophils age and undergo apoptosis, they expose phosphatidylserine (PS) on their surface, which serves as an "eat-me" signal recognized primarily by PS receptors on phagocytes, such as TIM-4 and stabilin-2; however, CD31 on phagocytes enhances this process by engaging with inactivated CD31 on the apoptotic neutrophil, promoting stable adhesion. This homophilic binding is particularly effective because viable neutrophils express active CD31 that signals detachment, whereas apoptotic neutrophils downregulate or inactivate CD31, switching the interaction to favor clearance and preventing premature phagocytosis.^[45] Upon ligation, CD31 homophilic binding in phagocytes triggers intracellular signaling that delays membrane repolarization by inhibiting the ether-à-go-go-related gene (ERG) potassium channel, thereby maintaining a depolarized state conducive to firm binding and subsequent engulfment of the apoptotic neutrophil.^[45] This mechanism ensures efficient efferocytosis without requiring opsonization. Additionally, CD31 engagement initiates anti-inflammatory pathways in macrophages, including recruitment of Src homology 2 domain-containing phosphatase-2 (SHP-2) via its immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which suppresses NF-κB activation and reduces production of pro-inflammatory cytokines like TNF-α and IL-6.^[46] The therapeutic potential of enhancing CD31-mediated efferocytosis lies in conditions characterized by dysregulated neutrophil clearance, such as sepsis, where bolstering this process could mitigate excessive inflammation by accelerating apoptotic neutrophil removal and promoting resolution signals. Strategies targeting CD31 ligation, including agonistic antibodies or soluble modulators, may amplify anti-inflammatory outcomes without exacerbating infection.

Pathophysiological roles

In cancer

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), plays a significant role in tumor angiogenesis by promoting the formation of abnormal vasculature that supports tumor growth and progression. Overexpression of CD31 in the endothelium of colorectal cancer tumors is associated with increased microvessel density (MVD), a marker of heightened angiogenesis, which correlates with poor overall survival.^[47] In a meta-analysis of colorectal cancer studies, high MVD assessed via CD31 immunostaining predicted reduced relapse-free survival (risk ratio 2.32, 95% CI 1.39–3.90) and overall survival (risk ratio 1.44, 95% CI 1.08–1.92), highlighting CD31 as a superior prognostic indicator compared to other vascular markers.^[48] Beyond angiogenesis, CD31 facilitates cancer cell metastasis by enabling epithelial-mesenchymal transition (EMT) and leukocyte-like transmigration across endothelial barriers. In hepatocellular carcinoma, CD31 upregulation induces EMT through activation of the integrin β1-FAK/Akt signaling pathway, enhancing tumor cell invasion and distant metastasis.^[49] This mechanism allows cancer cells to mimic leukocyte diapedesis, utilizing CD31-mediated homophilic interactions to breach vascular endothelium, as observed in melanoma models where CD31 redistribution at junctions supports extravasation despite not being strictly essential.^[50] Soluble CD31 (sPECAM-1), the circulating ectodomain shed from cell surfaces, serves as a prognostic biomarker in various malignancies. Elevated serum levels of sPECAM-1 are detected in patients with chronic myeloid leukemia, correlating with disease activity and potentially inhibiting leukemic cell infiltration by blocking surface receptors.^[51] In solid tumors such as gastric cancer, higher sPECAM-1 concentrations alongside other markers like CXCL13 indicate advanced disease and poorer outcomes in elderly patients.^[52] Recent studies from 2025 have elucidated CD31's involvement in immune evasion within the tumor microenvironment, particularly by modulating T-cell adhesion and function. In glioma, CD31-positive T cells and macrophages exhibit strong ligand-receptor interactions, such as SPP1-CD44 between CD8+ T cells and M2 macrophages, which foster an immunosuppressive milieu and hinder effective anti-tumor T-cell responses.^[53] Targeting CD31 in preclinical models demonstrates therapeutic potential against tumor vascularization. In prostate cancer xenograft studies, siRNA-mediated knockdown of CD31 in tumor endothelium significantly inhibited established tumor growth and reduced vascular density compared to controls.^[54]

In cardiovascular diseases

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), plays a critical role in the pathogenesis of atherosclerosis through mechanisms involving its expression, shedding, and signaling functions on endothelial cells and leukocytes. In atherosclerotic lesions, proteolytic shedding of CD31 from activated monocytes and T cells during acute coronary syndromes reduces its homophilic interactions, leading to dysregulated immune responses and impaired vascular repair.^[55] This shedding contributes to plaque instability by promoting thin fibrous caps and poor healing in atherothrombotic regions.^[55] Additionally, reduced CD31 expression at sites of endothelial inflammation correlates with endothelial dysfunction, exacerbating atherosclerosis progression by compromising vascular homeostasis and barrier integrity.^[55] Soluble CD31 (sCD31), particularly the leukocyte-shed isoform, serves as a biomarker of plaque vulnerability in coronary artery disease. Elevated levels of leukocyte-derived sCD31 are strongly associated with high-risk plaque features, including spotty calcifications and multiple adverse characteristics detected via coronary computed tomography angiography, with a positive correlation coefficient of +0.1286 (p<0.0001).^[56] In low-risk patients, sCD31 improves prediction of coronary artery disease (AUC increase from 0.79 to 0.95), highlighting its utility in identifying unstable plaques.^[56] In thrombosis, platelet CD31 modulates hemostatic responses through homophilic interactions that trigger inhibitory signaling pathways. Cross-linking of platelet CD31 inhibits aggregation and secretion in response to collagen and GPVI agonists, acting as a negative regulator to limit thrombus growth.^[57] In vivo studies using PECAM-1-deficient mice demonstrate enhanced thrombus formation, with larger thrombi and shorter occlusion times (8.1 ± 1.1 min vs. 10.0 ± 2.7 min in wild-type, p<0.03), confirming platelet CD31's role in restraining excessive aggregation post-vascular injury.^[58] CD31 exerts protective effects in ischemia-reperfusion injury by maintaining endothelial barrier function and limiting excessive permeability. Signaling through CD31's ITIM motifs in endothelial cells confers protection against inflammatory insults, reducing microvascular leakage in models of myocardial and intestinal ischemia-reperfusion.^[8] Blockade of CD31 suppresses neutrophil infiltration and permeability increases post-reperfusion, underscoring its baseline role in vascular integrity during such injuries.^[8] Recent genetic studies, including 2024-2025 Mendelian randomization analyses using variants as instruments for PECAM-1 levels, link higher genetically predicted CD31 expression to reduced coronary artery disease risk (OR 0.835, 95% CI 0.75-0.93).^[59] These findings indicate that polymorphisms influencing CD31 function may modulate susceptibility to coronary artery disease by altering endothelial and platelet responses. As a biomarker, elevated soluble PECAM-1 levels distinguish acute myocardial infarction from noncardiac chest pain, with plasma concentrations of 64.5 ± 18.3 ng/ml in infarction patients versus 46.2 ± 7.5 ng/ml in controls (p=0.019).^[60] This elevation on admission reflects endothelial activation and injury, providing diagnostic value in acute coronary syndromes.^[61]

In inflammatory disorders

CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), plays a critical role in regulating immune cell trafficking across the blood-brain barrier (BBB) during neuroinflammatory conditions such as multiple sclerosis (MS). Expressed on BBB endothelial cells, CD31 facilitates paracellular T-cell diapedesis while stabilizing BBB integrity to limit excessive leukocyte infiltration; in experimental autoimmune encephalomyelitis (EAE), a model of MS, PECAM-1 deficiency leads to increased BBB permeability and altered T-cell transmigration patterns without abolishing diapedesis entirely.^[62] In rheumatoid arthritis (RA), CD31 is upregulated on synovial macrophages, lining cells, and endothelial cells, contributing to enhanced leukocyte adhesion and infiltration into the inflamed synovium. This overexpression supports the recruitment of immune cells via homophilic interactions, exacerbating synovial inflammation and pannus formation in affected joints.^[63] During disseminated intravascular coagulation (DIC), a sepsis-associated inflammatory coagulopathy, platelet CD31 normally inhibits excessive thrombus formation and dampens inflammatory responses by preventing macrophage pyroptosis and maintaining vascular barrier integrity. However, PECAM-1 deficiency or dysfunction in septic models results in hyperactivation of platelets and monocytes, leading to worsened microvascular thrombosis, heightened cytokine release, and more severe DIC outcomes.^[64] Studies have linked decreased PECAM-1 expression on endothelial cells to COVID-19-related endothelialitis and systemic inflammation, where SARS-CoV-2 spike protein induces PECAM-1 degradation, promoting barrier disruption and leukocyte extravasation in affected tissues. Proinflammatory cytokines such as TNF-α and IFN-γ can also downregulate PECAM-1 expression on endothelial cells.^[65]^[66] In models of sepsis, CD31 signaling exerts an anti-inflammatory effect by limiting leukocyte accumulation in tissues and reducing systemic cytokine production during endotoxemia; PECAM-1-deficient mice exhibit amplified cytokine storms in response to lipopolysaccharide (LPS), underscoring its role in resolving excessive inflammatory responses.^[67]

Therapeutic implications

Monoclonal antibodies targeting CD31 (PECAM-1) have been developed to facilitate targeted drug delivery to vascular endothelium, particularly in cancer therapy, by exploiting CD31's expression on endothelial cells to enhance nanoparticle or carrier accumulation at tumor sites. For instance, anti-PECAM-1 antibodies conjugated to immunonanoparticles enable collaborative binding that improves endothelial internalization and reduces off-target effects in preclinical models of endothelial dysfunction associated with malignancy. Similarly, high-affinity single-chain variable fragments (scFvs) engineered against human PECAM-1 demonstrate cross-reactivity with murine homologs, supporting their use in translating vascular-targeted therapies from animal models to potential clinical applications in oncology. Small molecule inhibitors modulating CD31 signaling show promise in anti-angiogenic strategies for retinopathies, such as diabetic retinopathy and retinopathy of prematurity, by disrupting pathological vessel growth. The thermostable small molecule BT2 inhibits angiogenesis in retinal models by suppressing CD31 expression, phosphorylated ERK, and VEGF-A, achieving vascular leakage reduction comparable to aflibercept without direct receptor antagonism. Additionally, ROCK inhibitor fasudil, when encapsulated in CD31-targeted liposomes, specifically attenuates RhoA signaling in endothelial cells, reducing neovascularization in oxygen-induced retinopathy models while preserving physiological vascular development. Gene therapy approaches aimed at enhancing PECAM-1 function in endothelial progenitor cells (EPCs) are emerging for ischemia repair, leveraging CD31's role in vascular integrity to promote neovascularization in hypoxic tissues. Preclinical studies indicate that strategies increasing PECAM-1 levels in EPCs, such as through partial reprogramming or targeted constructs, improve endothelial barrier function and angiogenic potential, potentially aiding recovery in models of peripheral artery disease or myocardial ischemia. For example, adenoviral delivery of pro-angiogenic factors in ischemic limbs has been shown to upregulate PECAM-1-positive vessels, suggesting a foundation for EPC-based therapies that amplify CD31-mediated repair mechanisms. As of November 2025, clinical trials exploring CD31 modulators remain in early phases, with preclinical data supporting soluble CD31 agonists for atherosclerosis to stabilize plaques by restoring inhibitory signaling on leukocytes and platelets. In experimental models, CD31 receptor globulin reduces lesion progression by dampening T-cell activation, highlighting potential for Phase II evaluation in atherothrombotic disease. For inflammatory bowel disease, anti-CD31 blockade ameliorates colitis in dextran sulfate sodium models by inhibiting leukocyte transmigration, positioning it as a candidate for upcoming trials targeting mucosal inflammation without broad immunosuppression. Key challenges in CD31-targeted therapies include off-target effects on platelet aggregation, as CD31 modulates hemostasis and its inhibition can exacerbate bleeding risks in thrombotic conditions. Additionally, isoform-specific targeting is essential due to differential expression of PECAM-1 variants across cell types, necessitating precise ligands to avoid unintended impacts on non-endothelial functions like immune cell trafficking.

References

[1]
PECAM1 platelet and endothelial cell adhesion molecule 1 [ (human)]
Sep 9, 2025 · CD31/PECAM-1 impacts engraftment, growth and spread of mantle cell lymphoma cells and positively correlates with extramedullary involvement.Missing: 2020-2025 | Show results with:2020-2025
[2]
Structural Basis for Human PECAM-1-Mediated Trans-homophilic ...
Dec 13, 2016 · As a cell adhesion molecule, PECAM-1 functions principally in cell junction but also plays a role in leukocyte trafficking and immune response.
[3]
[PDF] Roles of PECAM-1 in cell function and disease progression
It is proved that PECAM-1 is closely correlative with cell migration, proliferation, apoptosis, signal transduction and cellular immunity.
[4]
https://www.ncbi.nlm.nih.gov/nuccore/NM_000442.5
[5]
Organization of the Gene for Human Platelet/Endothelial Cell ...
The PECAM-1 gene, which has been localized to human chromosome 17, is a single-copy gene of approximately 65 kb in length and is broken into 16 exons by introns ...
[6]
https://pubmed.ncbi.nlm.nih.gov/8558001/
[7]
PECAM-1: A Multi-Functional Molecule in Inflammation and ...
This review will focus on some new developments with respect to the role of PECAM-1 in inflammation and vascular biology, highlighting the emerging ...
[8]
Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1/CD31)
It is able to mediate cell-cell adhesion, as well as transduce intracellular signals that upregulate function of integrins.
[9]
Structural basis for PECAM-1 homophilic binding - PMC - NIH
The extracellular domain of PECAM-1 is composed of 6 immunoglobulin homology domains, followed by a 19-residue single-pass transmembrane domain and a 118-aa ...Missing: review | Show results with:review
[10]
PECAM1 - Platelet endothelial cell adhesion molecule - UniProt
Mar 28, 2018 · PECAM1 is a cell adhesion molecule required for leukocyte transendothelial migration (TEM) under most inflammatory conditions.Missing: transcript | Show results with:transcript
[11]
Role of immunoreceptor tyrosine-based inhibitory motifs of PECAM ...
The cytoplasmic domain of PECAM-1 contains two tyrosine residues, Y663 and Y686, that each fall within an immunoreceptor tyrosine-based inhibitory motif (ITIM).Missing: Tyr713 Tyr749
[12]
Signal Transduction Pathways Mediated by PECAM-1
These data suggest that, in vivo, platelet PECAM-1 plays a major role in regulating signaling pathways of ITAM-containing, but not G protein–coupled, receptors.
[13]
Tissue-specific distributions of alternatively spliced human PECAM ...
The data presented here demonstrate that human PECAM-1 undergoes alternative splicing, generating multiple isoforms in vascular beds of various tissues.Missing: soluble | Show results with:soluble
[14]
Alternative splicing in endothelial cells: novel therapeutic ...
Dec 7, 2020 · Through removal of the TM domain encoding exon, AS also generates a soluble form of PECAM1, which is able to inhibit adhesive interactions of ...
[15]
Endothelial functions of PECAM-1 (CD31) - PMC - NIH
The cytoplasmic domain of PECAM-1 is comprised of eight separate exons that are subject to alternative splicing [27], yielding isoforms that are expressed in a ...
[16]
The Role of Sialylated Glycans in Human Platelet Endothelial Cell ...
PECAM-1 is heavily glycosylated, with ∼30% of its molecular mass contributed by nine complex N-linked carbohydrate chains (3, 19), including two within IgD1 at ...<|control11|><|separator|>
[17]
Structural basis for PECAM-1 homophilic binding | Blood
PECAM-1 is enriched at endothelial cell intercellular junctions, where it regulates leukocyte trafficking and vascular permeability. An atomic-level model of ...Materials And Methods · Results · Discussion
[18]
PECAM-1/CD31 Trans-homophilic Binding at the Intercellular ... - NIH
The region required for PECAM-1 heterophilic binding has not been determined, although several heterophilic ligands have been identified, including CD38 ( ...
[19]
CD31/PECAM-1 is a ligand for alpha v beta 3 integrin involved in ...
Jul 15, 1995 · CD31/PECAM-1 is an adhesion molecule expressed by vascular endothelial cells, platelets, monocytes, neutrophils, and naive T lymphocytes.
[20]
Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) and Its ...
Mar 8, 2008 · Both proteins bound heparin immobilized on a biosensor chip in surface plasmon resonance (SPR) binding experiments. Binding was pH-sensitive but ...
[21]
Lack of Platelet Endothelial Cell Adhesion Molecule-1 Attenuates ...
It is expressed on endothelial cells, platelets, neutrophils, monocytes, and subsets of lymphocytes. 1-4 It has been implicated in facilitating leukocyte ...
[22]
PECAM-1 (CD31) Expression Modulates Bleeding Time in Vivo
It is expressed on endothelial cells, platelets, polymorphonuclear leukocytes, monocytes, and T and B lymphocytes and is thought to serve several functions, ...Pecam-1 (cd31) Expression... · Pecam-1 Expression Is... · Pecam-1 Null Mice Exhibit...
[23]
Lymphatic endothelium expresses PECAM-1 - ScienceDirect.com
Lymphatic endothelium did not express intercellular adhesion molecule-1 and endothelial cell-selectin but expressed platelet-endothelial cell adhesion molecule ...
[24]
Developmental Platelet Endothelial Cell Adhesion Molecule ... - NIH
In a previous study PECAM expression was detected in angioblasts on day 7.5 in the developing yolk sac. ... (PECAM-1)/CD31 modulates β2 integrins on lymphocyte- ...Results · Pecam Expression During Es... · Cd34 Is Expressed Subsequent...
[25]
(PDF) Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31)
Aug 6, 2025 · developmental stages. PECAM-1 expression correlates with the. organization of the blood islands and vasculature in. the post-implantation embryo.
[26]
Human peripheral blood-derived CD31+ cells have robust ... - NIH
CD31+ cells had higher levels of expression of pro-angiogenic genes on microarray and qRT-PCR and generated higher numbers of endothelial progenitor cells (EPCs) ...
[27]
Enhanced expression of CD31/platelet endothelial cell adhesion ...
Results have shown an increased expression of CD31/PECAM1 correlated to HIF-1α expression, confirming evidence demonstrating that different types of tumor are ...
[28]
PECAM-1: Conflicts of Interest in Inflammation - PMC - NIH
PECAM-1 is vital to the regulation of inflammatory responses, as it has been shown to serve a variety of pro-inflammatory and anti-inflammatory functions.
[29]
An alternatively spliced isoform of PECAM-1 is expressed at high ...
The Ig-ITIM family member PECAM-1 is expressed in vascular and endothelial cells, and its functions include suppression of mitochondria-dependent apoptosis.
[30]
Tissue Specific Expression of Alternatively Spliced Murine PECAM-1 ...
We have examined PECAM-1 expression in various mouse tissues and endothelial cells. PECAM-1 mRNA was highly expressed in lung, heart, and kidney, and to a ...
[31]
PECAM-1, Mouse, mAb MEC7.46 - Hycult Biotech
In stockPECAM-1 is detected within the lymphopoietic islands in the spleen of newborn (day 12) and in the bone marrow of adult mice. Capillary endothelial cells of ...
[32]
Immunohistochemical Expression of Endothelial Markers CD31 ...
Jul 29, 2005 · In addi- tion, it is localized on cells of the splenic marginal zone, dendritic interstitial cells around vessels, nerves, hair follicles, ...
[33]
PECAM-1 is expressed on hematopoietic stem cells throughout ...
These results demonstrate CD31 expression on hematopoietic stem cells throughout ontogeny and identify a population of CD31 + short-term erythroid progenitors ...Missing: mature | Show results with:mature
[34]
Increased Endothelial Cell Expression of Platelet ... - ATS Journals
Aug 17, 1995 · These observations suggest that PECAM-1 expression is a relatively early step in the inflammation cascade, and intervention at this phase may be ...
[35]
Developmental dynamics of the neural crest–mesenchymal axis in ...
... cell adhesion molecule (PECAM1; CD31) (Fig. 1A and fig. S1A) (4, 13). The Ly51higp38− phenotype identified neural crest–derived pericytes that surround ...
[36]
PECAM-1: regulator of endothelial junctional integrity - PMC
Finally, PECAM-1 is heavily glycosylated, with nine consensus N-linked glycosylation sites within its extracellular domain (Newman et al. 1990;Newton et al. ...The Vascular Barrier · Pecam-1 Isoforms And... · Pecam-1 As A Biosensor...
[37]
PECAM-1 (CD31) Homophilic Interaction Up-Regulates α 6 β 1 on ...
For this purpose, we employed two IL-1β–driven inflammatory models, namely leukocyte migration through IL-1β–stimulated cremasteric venules (>90% being ...
[38]
Molecular events during leukocyte diapedesis - Petri - 2006
Sep 11, 2006 · Leukocyte transmigration appears to involve homophilic PECAM-1 interactions to link leukocytes to the luminal surface of endothelial cells and ...Leukocyte Diapedesis · Pecam-1 · Cd99
[39]
Endothelial PECAM-1 accumulates around the transmigration spot ...
PECAM-1 is also highly expressed at endothelial cell intercellular junctions, where it functions as a mechanosensor, as a regulator of leukocyte trafficking and ...
[40]
https://www.researchgate.net/figure/Endothelial-PECAM-1-accumulates-around-the-transmigration-spot-A-A-typical-example-of_fig4_49714080
[41]
https://doi.org/10.1182/blood-2015-07-660092
[42]
https://doi.org/10.1074/jbc.M114.557454
[43]
Platelet endothelial cell adhesion molecule (CD31) - PubMed
The ability of anti-PECAM-1 antibodies to block normal endothelial cell-cell contacts and influence cell migration point to a role in angiogenesis and wound ...
[44]
https://pubmed.ncbi.nlm.nih.gov/8313722/
[45]
https://doi.org/10.1189/jlb.0507283
[46]
Role of VEGF, CD105, and CD31 in the Prognosis of Colorectal ...
CRC patients with high VEGF, CD105, and CD31 expression showed poor prognosis. The immunohistochemical markers could be used for stratification of patients.Missing: overexpression | Show results with:overexpression
[47]
Microvessel density and VEGF expression are prognostic factors in ...
Jun 13, 2006 · Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression ...
[48]
CD31 regulates metastasis by inducing epithelial-mesenchymal ...
Aug 10, 2018 · Our experiments show that CD31 promotes metastasis by inducing the epithelial-mesenchymal transition in hepatocellular carcinoma by up-regulating integrin β1.
[49]
Platelet-endothelial cell adhesion molecule-1 (CD31) redistributes ...
We have examined the role of platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) during the transendothelial migration of melanoma cells using a ...Missing: facilitates | Show results with:facilitates
[50]
CD300A promotes tumor progression by PECAM1, ADCY7 and AKT ...
Jun 8, 2018 · Elevated levels of sPECAM-1 were detected in serum of patients with chronic myelogenic leukemia. A recent study demonstrated that PECAM1 may ...
[51]
Single-cell RNA sequencing for characterizing the immune ...
Apr 30, 2025 · This study investigated the role of CD31 + immune cells, specifically macrophages and T cells, in the glioma microenvironment through single-cell RNA ...
[52]
CD31 as a Therapeutic Target in Atherosclerosis
Apr 23, 2020 · CD31, a highly glycosylated Ig-like membrane receptor expressed by leukocytes, platelets, and endothelial cells, is the most abundant membrane ...Importance Of Cd31 In The... · Cd31 As A Therapeutic Target... · Potential Benefits Of A Cd31...
[53]
https://tcr.amegroups.org/article/view/99396/html
[54]
Platelet endothelial cell adhesion molecule-1 signaling inhibits the ...
In this study it is demonstrated that cross-linking PECAM-1 inhibits the aggregation and secretion of platelets in response to collagen and the GPVI-selective ...
[55]
Platelet PECAM-1 inhibits thrombus formation in vivo - PMC
Recent studies in vitro have demonstrated that PECAM-1 signaling inhibits the aggregation of platelets. In the present study we have used PECAM-1–deficient mice ...
[56]
Causal Relationship between PECAM-1 Level and Cardiovascular ...
Aug 15, 2024 · The findings confirmed that elevated PECAM-1 levels may decrease the risk of CAD and MI. These results confirm the causal effect of PECAM-1 on CVDs.Methods · Results · Conclusions
[57]
Soluble PECAM-1, but not P-selectin, nor osteonectin ... - PubMed
Soluble PECAM-1, but not P-selectin, nor osteonectin identify acute myocardial infarction in patients presenting with chest pain. Cardiology. 1999;91(1):50-5.
[58]
Increased soluble platelet/endothelial cell adhesion molecule-1 in ...
Plasma PECAM-1 concentration (ng/ml) on admission was higher in patients with AMI (25.6±4.7) and unstable angina (24.7±4.4) than in stable angina (20.5±4.4) and ...
[59]
PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors ...
Apr 5, 2019 · Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity ...
[60]
Adhesion molecule expression in human synovial tissue - Johnson
CD31 and CD44 are up-regulated on RA macrophages and lining cells, CD44 on RA fibroblasts, and β3-integrin on RA blood vessels. The up-regulation of CD31, CD44, ...Missing: upregulated | Show results with:upregulated<|separator|>
[61]
PECAM-1 protects against DIC by dampening inflammatory ...
Disseminated intravascular coagulation (DIC) is a frequent complication of ... PECAM-1 knockout exhibited more severe DIC and poorer outcome in the LPS ...
[62]
SARS-CoV-2 Spike Protein Induces Degradation of Junctional ...
Jun 10, 2021 · JAM-A gene knockouts showed increased endothelial permeability while TNFα and IFNγ treatment in HUVECs decreased PECAM-1 mRNA and protein ...
[63]
PECAM-1 dampens cytokine levels during LPS-induced ... - NIH
PECAM-1 normally functions to dampen systemic cytokine levels during LPS-induced endotoxemia by diminishing the accumulation of cytokine-producing leukocytes ...