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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.

Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with an asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream.The selectin ligand PSGL-1 transduced signals emanating from these interactions, resulting in the redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling, and blockade of this domain protected mice against thromboinflammatory injury. These results reveal that recruited neutrophils scan for activated platelets, and they suggest that the neutrophils' bipolarity allows the integration of signals present at both the endothelium and the circulation before inflammation proceeds.

Background Increased intracranial pressure (ICP) in patients with idiopathic intracranial hypertension (IIH) affects the retinal microvasculature, which can be imaged and quantified by optical coherence tomography angiography (OCTA). We aimed to identify the mediating factor between ICP and OCTA parameters association in IIH patients. Methods IIH patients with active intracranial hypertension were enrolled. OCTA imaging was performed after ICP measurement. We quantified the branching complexity of the retinal arterioles and venules from the superficial vascular complex of the OCTA image. Eyes of IIH patients were stratified into eyes with papilledema (IIH-P) and eyes without papilledema (IIH-WP). All participants underwent visual acuity (VA) examination. Results One hundred and thirty-eight eyes from 70 IIH patients and 146 eyes from 73 controls were included. Compared to the control group, IIH patients and IIH-P had reduced arteriole complexity and increased venule complexity ( p  < 0.05). For IIH patients and IIH-P, increased retinal venule complexity correlated with increased ICP and reduced VA ( p  < 0.05); while decreased arteriole complexity only correlated with Frisen scores ( p  = 0.026). Papilledema mediated the effect ( p  < 0.001) between ICP and arteriole complexity while ICP had a direct effect ( p  < 0.001) on venule complexity. Conclusion Retinal venules imaged via OCTA may reflect ICP levels and may underpin the direct effect of increased ICP in IIH patients.

Breast cancers present intricate microenvironments comprising heterotypic cellular interactions, yet a comprehensive spatial map remained to be established. Here, we employed the DNA nanoball-based genome-wide in situ sequencing (Stereo-seq) to visualize the geospatial architecture of 30 primary breast tumors and metastatic lymph nodes across different molecular subtypes. This unprecedented high-resolution atlas unveils the fine structure of the tumor vasculature, highlighting heterogeneity in phenotype, spatial distribution, and intercellular communication within both endothelial and perivascular cells. In particular, venular smooth muscle cells are identified as the primary source of CCL21/CCL19 within the microenvironment. In collaboration with ACKR1-positive endothelial cells, they create a chemokine-rich venular niche to synergistically promote lymphocyte extravasation into tumors. High venule density predicts increased immune infiltration and improved clinical outcomes. This study provides a detailed spatial landscape of human breast cancer, offering key insights into the venular regulation of tumor immune infiltration. This study utilizes Stereo-seq to comprehensively map the geospatial architecture of breast cancer, revealing venular niches that promote immune infiltration and better clinical outcomes, offering new insights into tumor microenvironment regulation.

High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body’s own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn’s disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79+ tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3+ T cell-rich areas or CD20+ B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.

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. Limited understanding of the interactions between nanoparticle drug carriers and the blood-brain barrier underlies many translational failures in treatments of brain disorders. Here the authors use two-photon microscopy in mice to characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery from the blood to the brain in vivo.

OBJECTIVE: Flicker light-induced retinal vasodilation may reflect endothelial function in the retinal circulation. We investigated flicker light-induced vasodilation in individuals with diabetes and diabetic retinopathy. RESEARCH DESIGN AND METHODS: Participants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects. Flicker light-induced retinal vasodilation (percentage increase over baseline diameter) was measured using the Dynamic Vessel Analyzer. Diabetic retinopathy was graded from retinal photographs. RESULTS: Mean ± SD age was 56.5 ± 11.8 years for those with diabetes and 48.0 ± 16.3 years for control subjects. Mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects (1.43 ± 2.10 vs. 3.46 ± 2.36%, P < 0.001 for arteriolar and 2.83 ± 2.10 vs. 3.98 ± 1.84%, P < 0.001 for venular dilation). After adjustment for age, sex, diabetes duration, fasting glucose, cholesterol and triglyceride levels, current smoking status, systolic blood pressure, and use of antihypertensive and lipid-lowering medications, participants with reduced flicker light-induced vasodilation were more likely to have diabetes (odds ratio 19.7 [95% CI 6.5-59.1], P < 0.001 and 8.14 [3.1-21.4], P < 0.001, comparing lowest vs. highest tertile of arteriolar and venular dilation, respectively). Diabetic participants with reduced flicker light-induced vasodilation were more likely to have diabetic retinopathy (2.2 [1.2-4.0], P = 0.01 for arteriolar dilation and 2.5 [1.3-4.5], P = 0.004 for venular dilation). CONCLUSIONS: Reduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and, in individuals with diabetes, with diabetic retinopathy. Our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations.

The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers.

Capillary networks are essential for distribution of blood flow through the brain, and numerous other homeostatic functions, including neurovascular signal conduction and blood–brain barrier integrity. Accordingly, the impairment of capillary architecture and function lies at the root of many brain diseases. Visualizing how brain capillary networks develop in vivo can reveal innate programs for cerebrovascular growth and repair. Here, we use longitudinal two-photon imaging through noninvasive thinned skull windows to study a burst of angiogenic activity during cerebrovascular development in mouse neonates. We find that angiogenesis leading to the formation of capillary networks originated exclusively from cortical ascending venules. Two angiogenic sprouting activities were observed: 1) early, long-range sprouts that directly connected venules to upstream arteriolar input, establishing the backbone of the capillary bed, and 2) short-range sprouts that contributed to expansion of anastomotic connectivity within the capillary bed. All nascent sprouts were prefabricated with an intact endothelial lumen and pericyte coverage, ensuring their immediate perfusion and stability upon connection to their target vessels. The bulk of this capillary expansion spanned only 2 to 3 d and contributed to an increase of blood flow during a critical period in cortical development.

Key Points The shuttling of leukocytes between the blood stream and interstitial tissues involves different locomotion strategies that are governed by locally presented soluble and cell-bound signals. There are key concepts in the regulation of leukocyte migration through venular walls and motility in the extravascular tissue, with common and distinct mechanisms mediating these responses. Integrin-mediated adhesion of leukocytes to endothelial cells lining venular walls is a prerequisite to leukocyte crawling over and migration through endothelial cells. These responses are associated with great morphological changes in both leukocytes and endothelial cells and can support leukocyte transendothelial cell migration through both paracellular and transcellular routes. Leukocyte migration through endothelial cells is dependent on signalling events in both leukocytes and endothelial cells, events that can regulate leukocyte–endothelial cell interactions, as well as contacts between adjacent endothelial cells and/or endothelial cell vesicular trafficking. After endothelial cell migration, leukocytes need to penetrate the pericyte sheath and the venular basement membrane in which pericytes are embedded. Breaching the pericyte layer may occur through gaps between adjacent cells or in a transcellular manner. Migration through the venular basement membrane occurs through regions that may be biochemically or biophysically permissive. Once detached from the perivascular basement membrane, leukocytes approach their final destination by crawling within the three-dimensional interstitial space, which can either be a fibrillar network or a cell-packed environment like many organ parenchymas or lymphatic tissues. Leukocyte migration in the interstitium is driven by actin protrusion at the leading edge and is occasionally supported by actomyosin contraction at the trailing edge. The cytoskeletal forces can be transduced onto the environment either by integrins or by direct physical interaction of the cell body with the extracellular environment. This flexible mode of migration renders leukocytes largely independent of the molecular composition of the interstitium. Leukocytes use different strategies to migrate through the endothelium of venular walls and in interstitial tissues. These strategies are regulated by soluble and cell-bound signals. Studies have identified many of the cellular and subcellular events that govern transendothelial migration and are beginning to elucidate the nature of leukocyte interstitial motility. The shuttling of leukocytes between the bloodstream and interstitial tissues involves different locomotion strategies that are governed by locally presented soluble and cell-bound signals. Recent studies have furthered our understanding of the rapidly advancing field of leukocyte migration, particularly regarding cellular and subcellular events at the level of the venular wall. Furthermore, emerging cellular models are now addressing the transition from an adherent mode to a non-adherent state, incorporating mechanisms that support an efficient migratory profile of leukocytes in the interstitial tissue beyond the venular wall.