Density of high endothelial venules and PDL-1 expression: relationship with tumor-infiltrating lymphocytes in primary cutaneous melanomas.

Studies have highlighted melanoma immunogenicity, and the prognostic importance of tumor infiltrating lymphocytes (TILs) and mechanisms of tumor immune evasion, such as hyperexpression of programmed cell death ligand 1 (PDL-1). High endothelial venules (HEV) are specialized blood vessels that can facilitate the lymphocytes migration to the tumor. Here we evaluate the association of HEV density and PDL-1 expression in primary cutaneous melanomas with the presence and degree of TILs and with other clinicopathological variables (age, sex, tumor location, melanoma histological type, Breslow thickness, ulceration, regression signs, mitotic index). HEV density and PDL-1 expression were assessed immunohistochemically in 78 melanoma cases, using a specific antibody, and were detected in 59% and 76% of these, respectively. Positive associations were identified between HEV density and PDL-1 expression with the presence and degree of lymphocytic infiltration, melanoma histological type and ulceration presence. No correlation was found between HEV density and PDL-1 expression. Our findings confirm the HEV role in the recruitment and facilitation of lymphocyte transport in cutaneous melanomas, where HEV density is strongly associated with the degree of TILs. Additionally, PDL-1 hyperexpression suggests a possible mechanism of tumor immune evasion, which may lead to inactivation and reduction of the tumor lymphocytes number.

High endothelial venule is a prognostic immune-related biomarker in patients with resected intrahepatic cholangiocarcinoma.

Having been reported to be a crucial prognostic factor in solid tumours, the role of high endothelial venule (HEV) in intrahepatic cholangiocarcinoma (ICC) remains unclear, however. The data of ICC and healthy individuals were downloaded from the Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases. Meanwhile, a cutting-edge ICC high-resolution spatial transcriptome was also acquired before these data were comprehensively analysed using bioinformatics approaches. Moreover, 95 individuals with ICC who had undergone resection surgery were enrolled in this study to investigate the relationship between HEV and tumour microenvironment (TME) applying immunohistochemistry and multiple immunofluorescence techniques. The high-HEV subtype contains rich immune infiltrates including tertiary lymphoid structure (TLS), CD8+ T cells, and CD20+ B cells. Furthermore, HEV and TLS exhibited a strong relationship of spatial colocalization. Correlated with improved prognostic outcomes in ICC, the high-HEV subtype could be an independent prognostic indicator for individuals with ICC. This study revealed the association of HEV with immune function and observed a strong spatial colocalization correlation between HEV and TLS. Moreover, correlated with immunotherapeutic response, HEV could improve prognostic outcomes, which may be a potential indicator of immunotherapy pathology in ICC.

High endothelial venules in cancer: Regulation, function, and therapeutic implication.

The lack of sufficient intratumoral CD8+ T lymphocytes is a significant obstacle to effective immunotherapy in cancer. High endothelial venules (HEVs) are organ-specific and specialized postcapillary venules uniquely poised to facilitate the transmigration of lymphocytes to lymph nodes (LNs) and other secondary lymphoid organs (SLOs). HEVs can also form in human and murine cancer (tumor HEVs [TU-HEVs]) and contribute to the generation of diffuse T cell-enriched aggregates or tertiary lymphoid structures (TLSs), which are commonly associated with a good prognosis. Thus, therapeutic induction of TU-HEVs may provide attractive avenues to induce and sustain the efficacy of immunotherapies by overcoming the major restriction of T cell exclusion from the tumor microenvironment. In this review, we provide current insight into the commonalities and discrepancies of HEV formation and regulation in LNs and tumors and discuss the specific function and significance of TU-HEVs in eliciting, predicting, and aiding anti-tumoral immunity.

Arteriolosclerosis differs from venular collagenosis in relation to cerebrovascular parenchymal damages: an autopsy-based study.

BACKGROUND AND PURPOSE: Cerebrovascular parenchymal damage is prevalent in ageing brains; however, its vascular aetiology has not been fully elucidated. In addition to the underlying role of sclerotic arterioles, the correlation between collagenised venules has not been clarified. Here, we aimed to investigate the associations between microvascular injuries, including arteriolosclerosis and venular collagenosis, and related parenchymal damages in ageing brains, to investigate the underlying correlations. METHODS: We evaluated arteriolosclerosis and venular collagenosis in 7 regions from 27 autopsy cases with no history of stroke or brain tumour. The correlations between the ratio of arteriolosclerosis, venular collagenosis and the severity of cerebrovascular parenchymal damage, including lacunes, microinfarcts, myelin loss, and parenchymal and perivascular haemosiderin deposits, were assessed. RESULTS: Arteriolosclerosis and venular collagenosis became more evident with age. Arteriolosclerosis was associated with lacunes (p=0.004) and brain parenchymal haemosiderin deposits in the superior frontal cortex (p=0.024) but not with leukoaraiosis severity. Venular collagenosis was not associated with the number of lacunes or haemosiderin, while white matter generally became paler with severe venular collagenosis in the periventricular (ß=-0.430, p=0.028) and deep white matter (ß=-0.437, p=0.025). CONCLUSION: Our findings imply an important role for venular lesions in relation to microvessel-related parenchymal damage which is different from that for arteriolosclerosis. Different underlying mechanisms of both cerebral arterioles and venules require further investigation.

High endothelial venules in intracranial germinomas: Implications for lymphocytes infiltration.

PURPOSE: Reactive lymphocytes are substantial components of germinoma, which are believed to be related to the favorable prognosis of this intracranial tumor and better response to immunotherapy. However, the mechanisms managing the recruitment of lymphocytes are poorly understood. High endothelial venules (HEVs) are specialized blood vessels that play key roles in lymphocyte trafficking in Lymph nodes. These vessels are associated with lymphocyte infiltration in chronic inflammatory diseases and various malignant tumors, but their distribution and implications in germinoma are unknown. This study aimed to investigate the distribution and implications of HEVs in intracranial germinomas. METHODS: We investigated the presence and distribution of HEVs in 42 germinomas by immunohistochemical staining of peripheral node addressin (PNAd) and transmission electron microscopic examination. The correlation of the densities of HEVs with the extent of T and B lymphocyte infiltration and several clinicopathological characteristics were also analyzed to determine whether HEVs are responsible for lymphocyte recruitment and their roles in anti-tumor immunity in germinoma. RESULTS: PNAd-positive HEVs were detected in 31% (13/42) of germinomas, and their presence correlated with abundant infiltrating CD3+ T cells, CD20 + B cells and CD8+ cytotoxic T lymphocytes (p = 0.0410, 0.0023, and 0.0061, respectively). Higher HEVs density was also correlated with several clinicopathological parameters, which are recognized indicators for favorable prognosis in germinomas, including typical tumor location (p = 0.0093), lower tumor cell content (p = 0.0428), and younger age at diagnosis (p = 0.0121). Furthermore, bioinformatics analysis showed HEVs-associated genes mainly enriched in immune-related Gene Ontology terms, including innate immune response, inflammatory response, and B cell receptor signaling pathway. The xCell analysis revealed that germinomas with higher HEVs enrichment scores had increased levels of the immune score, microenvironment score, dendritic cells, CD8+ central memory T-cells, CD4+ memory T-cells, and B-cells. CONCLUSIONS: Our findings indicate that HEVs could contribute to lymphocyte recruitment in germinomas, thus may serve as a predictor of favorable prognosis and better response to immunotherapy in this intracranial tumor.

[Regular arrangement of collecting venules (RAC) as a predictor of the absence of Helicobacter pylori infection with conventional endoscopes in a Latin American population, diagnostic performance by subgroups]. / Disposición regular de vénulas colectoras (RAC) como predictor de ausencia de infección por Helicobacter pylori con endoscopios convencionales en población latina, rendimiento diagnóstico por subgrupos.

INTRODUCTION: The regular arrangement of collecting venules has high value to predict the absence of gastric infection by Helicobacter Pylori, the studies that have validated this finding were carried out with magnification images and digital chromoendoscopy, it is common to perform endoscopies with conventional white light equipment without magnification. OBJECTIVE: This study aims to validate this finding as a predictor of the absence of H. Pylori infection using endoscopy equipment with conventional white light without magnification. MATERIAL AND METHODS: An observational study was carried out identifying the presence of RAC with a conventional endoscope, the determination of Helicobacter pylori was established by histopathology. Sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV) were calculated in relation to the presence of RAC and the H. pylori infection status. RESULTS: 241 patients were included, finding a sensitivity of 5%, with a specificity of 89%. The prevalence of H. Pylori decreased with age. CONCLUSION: This study reports a low sensitivity with a high specificity of the regular distribution of collecting venules to establish the state of infection by H. Pylori. The diagnostic performance was lower than that reported in studies carried out with chromium endoscopy with magnification.

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop.

The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTßR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

High endothelial venules associated with better prognosis in esophageal squamous cell carcinoma.

BACKGROUND: High endothelial venules (HEVs) are specialized microvessels for recruiting naïve T cells and B cells from the circulation into secondary lymphoid organs. Its involvement in esophageal squamous cell carcinoma (ESCC) is still unknown. This study mainly investigated the possible presence of HEVs in ESCC and explore its relationship with prognosis. METHOD: Formalin fixed paraffin embedded (FFPE) tissue samples of 52 ESCC patients were stained with immunohistochemically (IHC) to assess the association of HEVs with histological and clinical factors by immunohistochemistry. Furthermore, multiplexed immunofluorescence was performed to explore the microenvironment around HEVs. RESULT: HEVs was widely present in ESCC and was significantly associated with better overall survival (OS). In addition, multiplexed immunofluorescence imaging demonstrated that HEVs is mainly present in the tertiary lymphoid structures (TLS) of the tumor and is surrounded by a large number of lymphocyte cells. CONCLUSION: HEVs represent a better prognostic factor in ESCC.

Automated detection of vascular remodeling in tumor-draining lymph nodes by the deep-learning tool HEV-finder.

Vascular remodeling is common in human cancer and has potential as future biomarkers for prediction of disease progression and tumor immunity status. It can also affect metastatic sites, including the tumor-draining lymph nodes (TDLNs). Dilation of the high endothelial venules (HEVs) within TDLNs has been observed in several types of cancer. We recently demonstrated that it is a premetastatic effect that can be linked to tumor invasiveness in breast cancer. Manual visual assessment of changes in vascular morphology is a tedious and difficult task, limiting high-throughput analysis. Here we present a fully automated approach for detection and classification of HEV dilation. By using 12,524 manually classified HEVs, we trained a deep-learning model and created a graphical user interface for visualization of the results. The tool, named the HEV-finder, selectively analyses HEV dilation in specific regions of the lymph nodes. We evaluated the HEV-finder's ability to detect and classify HEV dilation in different types of breast cancer compared to manual annotations. Our results constitute a successful example of large-scale, fully automated, and user-independent, image-based quantitative assessment of vascular remodeling in human pathology and lay the ground for future exploration of HEV dilation in TDLNs as a biomarker. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy.

Recruitment of lymphocytes into tumors is critical for anti-tumor immunity and efficacious immunotherapy. We show in murine models that tumor-associated high endothelial venules (TA-HEVs) are major sites of lymphocyte entry into tumors at baseline and upon treatment with anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB). TA-HEV endothelial cells (TA-HECs) derive from post-capillary venules, co-express MECA-79+ HEV sialomucins and E/P-selectins, and are associated with homing and infiltration into tumors of various T cell subsets. Intravital microscopy further shows that TA-HEVs are the main sites of lymphocyte arrest and extravasation into ICB-treated tumors. Increasing TA-HEC frequency and maturation increases the proportion of tumor-infiltrating stem-like CD8+ T cells, and ameliorates ICB efficacy. Analysis of tumor biopsies from 93 patients with metastatic melanoma reveals that TA-HEVs are predictive of better response and survival upon treatment with anti-PD-1/anti-CTLA-4 combination. These studies provide critical insights into the mechanisms governing lymphocyte trafficking in cancer immunity and immunotherapy.

Stem-cell-like T cells have a specific entry gate to the tumor.

Tumor-infiltrated T cells with stem-cell-like properties are important for determining the immunotherapy response. In this issue of Cancer Cell, Asrir and colleagues show that their entry requires specialized tumor-associated endothelial cells that resemble immature and inflamed lymph node vessels and that immunotherapy enhances the recruitment capacity of these endothelial cells.

Molecular Signature of Tumor-Associated High Endothelial Venules That Can Predict Breast Cancer Survival.

High endothelial venules (HEV) are specialized post-capillary venules that recruit naïve lymphocytes to lymph nodes. HEVs are essential for the development of adaptive immunity. HEVs can also develop in tumors where they are thought to be important for recruiting naïve T cells and B cells into the tumors and locally enhancing antitumor immunity by supporting the formation of tertiary lymphoid structures. Herein, we used comparative transcriptome analysis of human breast cancer to investigate genes differentially expressed between tumor-associated HEVs and the rest of the tumor vasculature. Tumor vessels highly expressing HEV-upregulated genes, such as the homeobox gene MEOX2 and the tetraspanin gene TSPAN7, were associated with extensive infiltration of T and B cells and the occurrence of tertiary lymphoid structures, which is known to predict therapeutic responses to immune-checkpoint inhibitors. Moreover, high transcript counts of these genes in clinical tumor specimens were associated with a significant survival benefit in advanced breast cancer. The molecular signature of HEVs identified herein may be useful for guiding immunotherapies and provides a new direction for investigating tumor-associated HEVs and their clinical significance. See related Spotlight by Gallimore, p. 371.

Diagnosis of Helicobacter pylori Infection by the Arrangement of Collecting Venules Using White Light Endoscopy: Evaluation of Interobserver Agreement.

BACKGROUND: Regular arrangement of collecting venules (RAC) in gastric mucosa accurately identifies patients without Helicobacter pylori (H pylori) infection. The aim of our study was to evaluate the reproducibility of RAC using white light endoscopy without magnification, in a European country, and to assess the impact of proton pump inhibitors (PPIs). METHODS: A multicenter prospective study with image capture of the distal lesser gastric curvature and gastric biopsies was performed. The presence of starfish-like minute points regularly distributed throughout lesser curvature was considered as RAC positive (RAC+). A set of 20 images was used for the training phase and inter and intra-observer agreements were calculated. RESULTS: 174 patients were included and 85 (48.9%) were taking PPIs. Kappa values for interobserver and intra-observer agreements were substantial (0.786) and excellent (0.906), respectively. H. pylori infection was diagnosed in 29 patients (16.7%): 10/85 with PPIs and 19/89 without PPIs (11.8% vs. 21.3%; p = 0.09). All RAC + patients were free of H. pylori infection, with a sensitivity and negative predictive value of 100%, regardless of PPI intake. CONCLUSION: The endoscopic diagnosis of H. pylori by RAC is an easy-to-learn and highly reproducible technique, even with PPI intake. Our results warrant RAC as a real-time diagnostic method for H. pylori-negative infection in Western practice.

High Endothelial Venules: A Vascular Perspective on Tertiary Lymphoid Structures in Cancer.

High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to bind L-Selectin/CD62L on lymphocytes, thereby facilitating their transmigration from the blood into the lymph nodes (LN) and other secondary lymphoid organs (SLO). HEVs have also been identified in human and murine tumors in predominantly CD3+T cell-enriched areas with fewer CD20+B-cell aggregates that are reminiscent of tertiary lymphoid-like structures (TLS). While HEV/TLS areas in human tumors are predominantly associated with increased survival, tumoral HEVs (TU-HEV) in mice have shown to foster lymphocyte-enriched immune centers and boost an immune response combined with different immunotherapies. Here, we discuss the current insight into TU-HEV formation, function, and regulation in tumors and elaborate on the functional implication, opportunities, and challenges of TU-HEV formation for cancer immunotherapy.

Increased retinal venular calibre in acute infections.

Population-based studies have demonstrated that increased retinal venular calibre is a risk factor for cardiac disease, cardiac events and stroke. Venular dilatation also occurs with diabetes, obesity, dyslipidemia and autoimmune disease where it is attributed to inflammation. This study examined whether the inflammation associated with infections also affected microvascular calibre. Participants with infections and CRP levels  > 100 mg/L were recruited from the medical wards of a teaching hospital and assisted to complete a demographic and vascular risk factor questionnaire, and to undergo non-mydriatic retinal photography (Canon CR5-45NM, Japan). They were then treated with appropriate antibiotics, and underwent repeat retinal imaging when their CRP levels had fallen to less than 100 mg/L. Retinal images were examined for arteriole and venular calibre using validated semi-automated software based on Knudtson's modification of the Parr-Hubbard formula (IVAN, U Wisconsin). Differences in inflammatory markers and calibre were examined using the paired t-test for continuous variables. Determinants of calibre were calculated from multiple linear regression analysis. Forty-one participants with respiratory (27, 66%), urinary (6, 15%), skin (5, 12%), or miscellaneous (3, 7%) infections were studied. After antibiotic treatment, participants' mean CRP levels fell from 172.9 ± 68.4 mg/L to 42.2 ± 28.2 mg/L (p < 0.0001) and mean neutrophil counts fell from 9 ± 4 × 109/L to 6 ± 3 × 109/L (p < 0.0001). The participants' mean venular calibre (CRVE) decreased from 240.9 ± 26.9 MU to 233.4 ± 23.5 MU (p = 0.0017) but arteriolar calibre (CRAE) was unchanged (156.9 ± 15.2 MU and 156.2 ± 16.0 MU, p = 0.84). Thirteen additional participants with infections had a CRP > 100 mg/L that persisted at review (199.2 ± 59.0 and 159.4 ± 40.7 mg/L, p = 0.055). Their CRAE and CRVE were not different before and after antibiotic treatment (p = 0.96, p = 0.78). Hospital inpatients with severe infections had retinal venular calibre that decreased as their infections resolved and CRP levels fell after antibiotic treatment. The changes in venular calibre with intercurrent infections may confound retinal vascular assessments of, for example, blood pressure control and cardiac risk.

Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles.

Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain.

Platelet and Erythrocyte Extravasation across Inflamed Corneal Venules Depend on CD18, Neutrophils, and Mast Cell Degranulation.

Platelet extravasation during inflammation is under-appreciated. In wild-type (WT) mice, a central corneal epithelial abrasion initiates neutrophil (PMN) and platelet extravasation from peripheral limbal venules. The same injury in mice expressing low levels of the ß2-integrin, CD18 (CD18hypo mice) shows reduced platelet extravasation with PMN extravasation apparently unaffected. To better define the role of CD18 on platelet extravasation, we focused on two relevant cell types expressing CD18: PMNs and mast cells. Following corneal abrasion in WT mice, we observed not only extravasated PMNs and platelets but also extravasated erythrocytes (RBCs). Ultrastructural observations of engorged limbal venules showed platelets and RBCs passing through endothelial pores. In contrast, injured CD18hypo mice showed significantly less venule engorgement and markedly reduced platelet and RBC extravasation; mast cell degranulation was also reduced compared to WT mice. Corneal abrasion in mast cell-deficient (KitW-sh/W-sh) mice showed less venule engorgement, delayed PMN extravasation, reduced platelet and RBC extravasation and delayed wound healing compared to WT mice. Finally, antibody-induced depletion of circulating PMNs prior to corneal abrasion reduced mast cell degranulation, venule engorgement, and extravasation of PMNs, platelets, and RBCs. In summary, in the injured cornea, platelet and RBC extravasation depends on CD18, PMNs, and mast cell degranulation.

Immunohistochemical analysis of L1 cell adhesion molecule and high endothelial venules in breast cancer brain metastasis.

BACKGROUND: The vasculature is a crucial factor in tumor development. Vascular co-option achieved by the L1 cell adhesion molecule (L1CAM) and lymphocyte recruitment inside tumors by high endothelial venules (HEVs) are important prognostic factors in primary breast cancer. Their status in breast cancer brain metastasis is unknown. AIM OF THE STUDY: To explore the status of L1CAMs and HEVs in this tumor compartment. MATERIAL AND METHODS: Thirty resected breast cancer brain metastases were immunohistochemically studied for L1CAM and MECA-79, an HEV marker. Clinicopathological factors were recorded. RESULTS: Age at brain metastasis diagnosis ranged from 37 to 80 years (median 55). The time to brain metastasis development after primary tumor diagnosis ranged from 12 to 187 months (median 57). Median overall survival after brain metastasis diagnosis was 29 months. None of the tumors expressed the factors studied. CONCLUSION: L1CAM and high endothelial venules are not found in breast cancer brain metastasis.

High endothelial venules are present in pharyngeal and laryngeal carcinomas and they are associated with better prognosis.

BACKGROUND: Tumors lymphocytic infiltration has prognostic and predictive value. However, the mechanisms involved in lymphocyte recruitment remain poorly characterized. High endothelial venules (HEV) are blood vessels specialized in lymphocyte recruitment, recently showing prognostic significance in some types of cancer. Their implications in laryngeal or pharyngeal cancer is largely unknown. AIM OF THE STUDY: To investigate the possible presence of HEVs in head and neck cancer. MATERIAL AND METHODS: Oropharyngeal (n = 61), hypopharyngeal (n = 53) and laryngeal (n = 21) squamous cell carcinomas were immunohistochemically studied with the MECA-79 antibody, which specifically recognizes HEVs. Histological and clinical factors were correlated with HEVs' presence. RESULTS: HEVs were present in 34% of tumors, showing significant correlations with oropharyngeal localization, higher lymphocytic response, lower tumor budding, lower T status, absence of distant metastases and better overall and progression-free survival. CONCLUSION: HEVs represent an important prognostic factor in head and neck cancer.

Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1.

Ischemia/reperfusion (I/R)-induced rapid inflammation involving activation of leukocyte-endothelial adhesive interactions and leukocyte infiltration into tissues is a major contributor to postischemic tissue injury. However, the molecular mediators involved in this pathological process are not fully known. We have previously reported that caveolin-2 (Cav-2), a protein component of plasma membrane caveolae, regulated leukocyte infiltration in mouse lung carcinoma tumors. The goal of the current study was to examine if Cav-2 plays a role in I/R injury and associated acute leukocyte-mediated inflammation. Using a mouse small intestinal I/R model, we demonstrated that I/R downregulates Cav-2 protein levels in the small bowel. Further study using Cav-2-deficient mice revealed aggravated postischemic tissue injury determined by scoring of villi length in H&E-stained tissue sections, which correlated with increased numbers of MPO-positive tissue-infiltrating leukocytes determined by IHC staining. Intravital microscopic analysis of upstream events relative to leukocyte transmigration and tissue infiltration revealed that leukocyte-endothelial cell adhesive interactions in postcapillary venules, namely leukocyte rolling and adhesion were also enhanced in Cav-2-deficient mice. Mechanistically, Cav-2 deficiency increased plasminogen activator inhibitor-1 (PAI-1) protein levels in the intestinal tissue and a pharmacological inhibition of PAI-1 had overall greater inhibitory effect on both aggravated I/R tissue injury and enhanced leukocyte-endothelial interactions in postcapillary venules in Cav-2-deficient mice. In conclusion, our data suggest that Cav-2 protein alleviates tissue injury in response to I/R by dampening PAI-1 protein levels and thereby reducing leukocyte-endothelial adhesive interactions.NEW & NOTEWORTHY The role of caveolin-2 in regulating ischemia/reperfusion (I/R) tissue injury and the mechanisms underlying its effects are unknown. This study uses caveolin-2-deficient mouse and small intestinal I/R injury models to examine the role of caveolin-2 in the leukocyte-dependent reperfusion injury. We demonstrate for the first time that caveolin-2 plays a protective role from the I/R-induced leukocyte-dependent reperfusion injury by reducing PAI-1 protein levels in intestinal tissue and leukocyte-endothelial adhesive interactions in postcapillary venules.