Vessel Function Research Articles

Exploring the Involvement of New Members of the Interleukin Family in Cardiovascular Disease.

Cardiovascular diseases remain a significant reason for illness and death globally. Although certain interleukins have been extensively researched about cardiovascular disease (CVD), new findings have identified unique members of the interleukin family that could potentially play a role in cardiovascular well-being and ailments. This review discusses the current understanding of the role of these recently identified interleukins, such as IL-27, IL-31, IL-32, IL-33, and the IL-28 group (IL-28A, IL-28B, IL-29), in the development of cardiovascular diseases. Every interleukin has various impacts achieved through particular receptors and signaling pathways that affect inflammatory processes, differentiation of immune cells, and the functioning of blood vessels. IL-27 controls the development of inflammatory Th17 cells and might decrease inflammation in atherosclerosis. IL-31 plays a role in the interaction between the immune system and nerves, as well as in itching. IL-32 enhances the generation of inflammatory proteins and has been linked to coronary artery disease. IL-33 has beneficial effects on the cardiovascular system, whereas its imitation receptor sST2 could potentially be used as a biomarker. Additional studies are needed to investigate the antiviral and immune-system regulating effects of the IL-28 group in cardiovascular diseases. In general, explaining the ways in which new interleukins contribute to the progression of cardiovascular diseases can help discover fresh targets for therapy and new approaches toward enhancing the prevention and treatment of heart disorders. Additional research on the way these cytokines engage with established disease pathways is necessary.

The Relationship Between Tortuosity and Stenosis of Extracranial Internal Carotid Arteries and Vertebral Arteries Based on Cerebral Digital Subtraction Angiography and Vascular Risk Factors at Pelni Hospital

Background and purpose: Vascular dysfunction is the main key to cardiovascular, cerebrovascular, neurodegenerative diseases, and the aging process causes disruption of blood vessel function. Vascular Tortuosity (VT) and stenosis are types of blood vessel deformities resulting from vascular dysfunction. Both conditions can be diagnosed through cerebral Digital Subtraction Angiography (DSA) examination. This study aims to analyze the relationship between tortuosity and stenosis of extracranial internal carotid arteries and vertebral arteries on vascular risk factors at Pelni Hospital. Methode: This research was a descriptive observational study with a cross-sectional approach on 608 subjects with a history of stroke who met the inclusion criteria. Conducted from January to September 2024, analyzing demographic data and risk factors, the presence or absence of stenosis and Vascular Tortuosity through cerebral DSA, also correlation these factors. Result: From the 608 patients, 334 (54.9%) were male and 274 (45.1%) were female. Most of the subjects were aged 41-59 years (31.1%) with the most common risk factor being hypertension (76.6%). Carotid stenosis was significantly associated with age 51-59 years [odds ratio (OR): 2.452, 95% confidence interval (CI): 1.102-2.481, p=0.031)], female gender (OR): 1.665, 95% CI: 1.102-2.481, p=0.015; and hypertension (OR): 1.761, 95% CI: 1.099-2.821, p=0.019. Vertebral stenosis was significantly associated with female gender (OR): 2.160, 95% CI: 1.176-3.968, p=0.013; and diabetes (OR): 2.079, 95% CI: 1.015-4.255, p=0.045. Both stenosis conditions were significantly correlated with tortuosity conditions with OR: 2.320 for carotid, and OR: 12.090 for vertebral. Carotid tortuosity was significantly associated with diabetes (OR): 2.049, 95% CI: 1.051-4.000, p=0.035. Vertebral tortuosity was significantly associated with dyslipidemia (OR): 2.710, 95% CI: 1.099-6.711, p=0.030 and hypertension (OR): 2.079, 95% CI: 1.234-3.496, p=0.006. The combination of carotid stenosis and tortuosity was significantly associated with female gender (OR): 2.367, 95% CI: 1.378-4.066, p=0.002. The combination of stenosis and tortuosity in both arteries did not show a significant correlation with existing risk factors. Conclusion: Carotid stenosis is correlated with female gender, age, and hypertension. Vertebral stenosis is correlated with female gender and diabetes. Carotid tortuosity is correlated with diabetes. Vertebral tortuosity correlates with dyslipidemia and hypertension. The combination of carotid stenosis and tortuosity correlates with female gender. Keywords: Vascular Tortuosity, Stenosis, Cerebral Digital Subtraction Angiography

Screening Lymphatic Ultrasound to Detect Lymphatic Dysfunction.

Background: We currently perform noncontrast lymphatic ultrasound, which has a higher resolution and is less invasive than contrast lymphatic ultrasound. This study aimed to clarify the usefulness of screening lymphatic ultrasound (SLUS) to evaluate lymphatic function. Methods: A retrospective study was conducted on 22 patients with leg lymphedema. We performed SLUS by dividing the leg into four areas (thigh and calf, lateral and medial) and the dorsum of the foot. Lymphatic findings were recorded according to NECST (Normal, Ectasis, Contraction, and Sclerosis type) classification. If no lymphatics were found, we recorded them as "not found." To differentiate between lymphatic vessels and veins, we referred to D-CUPS (Doppler, Crossing, Uncollapsible, Parallel, and Superficial fascia). The time required for SLUS was recorded. Indocyanine green (ICG) lymphography was also performed in 10 patients. Results: The mean age of the 22 patients was 63.9 years (range 50-86 years). The average time required for SLUS was 6 minutes 45 seconds for both legs. The identification rate of the lymphatic vessels was 95.5% for the medial thigh and medial calf, but decreased in the lateral calf and dorsum of the foot. When examining the distribution of the NECST classification, the ectasis type tended to be more common on the medial side than on the lateral side. Combined with the ICG lymphographic findings, dermal backflow (DB)-positive areas had significantly more ectasis type, and DB-negative areas had significantly more normal type and were not found (p < 0.01). Conclusion: SLUS should be useful for screening lymphatic vessel function.

The cerebral blood flow response to neuroactivation is reduced in cognitively normal men with β-amyloid accumulation

BackgroundAccumulation of β-amyloid (Aβ) in the brain is a hallmark of Alzheimer’s Disease (AD). Cerebral deposition of Aβ initiates deteriorating pathways which eventually can lead to AD. However, the exact mechanisms are not known. A possible pathway could be that Aβ affects the cerebral vessels, causing inadequate cerebrovascular function. In the present study, we examined if Aβ accumulation is associated with a reduced cerebral blood flow response (CBF) to neuronal activation by visual stimulation (ΔCBFVis.Act.) in cognitively normal subjects from the Metropolit Danish Male Birth Cohort.Methods64 subjects participated in the present study. ΔCBFVis.Act. was measured using arterial spin labelling (ASL) combined with blood-oxygen-level-dependent (BOLD) MRI. Neuronal activation was obtained by visual stimulation by a flickering checkerboard presented on a screen in the MRI-scanner. Brain Aβ accumulation and cerebral glucose metabolism were assessed by PET imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) and [18F]Fluorodeoxyglucose (FDG), respectively. Cortical thickness was measured from structural MRI.ResultsΔCBFVis.Act. correlated negatively (β = -32.1 [95% confidence interval (CI): -60.2; -4.1], r = -0.30, p = 0.025) with PiB standardized uptake value ratio (SUVr) in the brain regions activated by visual stimulation. ΔCBFVis.Act. did not correlate with FDG SUVr (β = 1.9 [CI: -23.8; 27.6], r = 0.02, p = 0.88) or cortical thickness (β = 10.3 [CI: -8.4; 29.0], r = 0.15, p = 0.27) in the activated brain regions. Resting CBF did not correlate with PiB SUVr neither in the regions activated by visual stimulation (β = -17.8 [CI:-71.9; 36.2], r =- 0.09, p = 0.51) nor in the remaining cortex (β = 5.2 [CI:-3.9; 14.2], r = 0.15, p = 0.26).ConclusionWe found a correlation between high PiB SUVr and reduced CBF response to neuronal activation, indicating a link between Aβ accumulation and impaired cerebrovascular function. The impairment was not associated with cortical thinning or hypometabolism, suggesting that Aβ accumulation affecting brain vessel function could be a very early pathology leading to neurodegenerative disease.

Vascularized tumor on a microfluidic chip to study mechanisms promoting tumor neovascularization and vascular targeted therapies.

The cascade of events leading to tumor formation includes induction of a tumor supporting neovasculature, as a primary hallmark of cancer. Developing vasculature is difficult to evaluate in vivo but can be captured using microfluidic chip technology and patient derived cells. Herein, we established an on chip approach to investigate the mechanisms promoting tumor vascularization and vascular targeted therapies via co-culture of cancer spheroids and endothelial cells in a three dimensional environment. Methods: We investigated both, tumor neovascularization and therapy, via co-culture of human derived endothelial cells and adjacently localized metastatic renal cell carcinoma spheroids on a commercially available microfluidic chip system. Metastatic renal cell carcinoma spheroids adjacent to primary vessels model tumor, and induce vessels to sprout neovasculature towards the tumor. We monitored real time changes in vessel formation, probed the interactions of tumor and endothelial cells, and evaluated the role of important effectors in tumor vasculature. In addition to wild type endothelial cells, we evaluated endothelial cells that overexpress Prostate Specific Membrane Antigen (PSMA), that has emerged as a marker of tumor associated neovasculature. We characterized the process of neovascularization on the microfluidic chip stimulated by enhanced culture medium and the investigated metastatic renal cell carcinomas, and assessed endothelial cells responses to vascular targeted therapy with bevacizumab via confocal microscopy imaging. To emphasize the potential clinical relevance of metastatic renal cell carcinomas on chip, we compared therapy with bevacizumab on chip with an in vivo model of the same tumor. Results: Our model permitted real-time, high-resolution observation and assessment of tumor-induced angiogenesis, where endothelial cells sprouted towards the tumor and mimicked a vascular network. Bevacizumab, an antiangiogenic agent, disrupted interactions between vessels and tumors, destroying the vascular network. The on chip approach enabled assessment of endothelial cell biology, vessel's functionality, drug delivery, and molecular expression of PSMA. Conclusion: Observations in the vascularized tumor on chip permitted direct and conclusive quantification of vascular targeted therapies in weeks as opposed to months in a comparable animal model, and bridged the gap between in vitro and in vivo models.

3D Printers Future Directions of 3D Printing Cardiac Care

Abstract: Three-dimensional (3D) printing is at the crossroads of printer and materials engineering, non-invasive diagnostic imaging, computer-aided design, and structural heart intervention. Cardiovascular applications of this technology development include the use of patient-specific 3D models for medical teaching, exploration of valve and vessel function, surgical and catheter-based procedural planning, and early work in designing and refining the latest innovations in percutaneous structural devices. In this review, we discuss the methods and materials being used for 3D printing today. We discuss the basic principles of clinical image segmentation, including coregistration of multiple imaging datasets to create an anatomic model of interest. With applications in congenital heart disease, coronary artery disease, and surgical and catheter-based structural disease, 3D printing is a new tool that is challenging how we image, plan, and carry out cardiovascular interventions.

Angiotensin Signaling in the Brain and Blood Vessels: Implications for Neurological and Cardiovascular Disorders

Angiotensin signalling is found to be significant in the regulation of the system that maintains the cardiovascular and neurological balance. This regulatory mechanism affecting blood pressure, volume control, and vasomotor tone is probably mainly controlled through the renin-angiotensin system or RAS. Recent data demonstrate that although Ang II is an important regulator of brain and blood vessel function, it may also be involved in the development of pathological changes. Within the brain tissue, Ang II binds to certain receptors, such as AT1 and AT2; participating in the regulation of neuronal firing, stress and neuroinflammation. Abnormality of this signalling pathway has been linked to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and stroke through free radical-mediated damage, compromised blood-brain barrier integrity and neuronal death. In the vascular compartment, activates endothelial dysfunction, vascular remodelling hypertrophy and inflammation, and oxidative and proliferative changes in the vascular smooth muscle cells. These effects form the basis of the formation of cardiovascular diseases such as atherosclerosis, aneurysms and ischemic heart diseases. Interactions between central and peripheral angiotensin pathways worsen these conditions through nervous and vascular adaptation feedback loops. More recent therapies aimed at individual elements of RAS, including ACEIs, ARBs, and novel receptor ligands, reveal good potential for averting these detrimental consequences.

The Discovery of a Novel AXL/Triple Angiokinase Inhibitor Based on 6-Chloro-Substituted Indolinone and Side Chain Methyl Substitution Inhibiting Pancreatic Cancer Growth and Metastasis.

In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor 11b by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that 11b potently inhibited AXL expression with the IC50 value of 3.75 nM and possessed similar inhibitory activity on KDR as Nintedanib. In the assay of antiproliferative activity on NIH/3T3, HUVEC, Bxpc-3, and MDA-MB-231, 11b showed better inhibitory ability than Nintedanib. In pancreatic cancer xenograft mouse models from Bxpc-3 cells, even when the dosage was halved, 11b exhibited better or comparable effects to Nintedanib (tumor growth inhibition (TGI) based on tumor volume change during the trial or tumor weight). Notably, we also found that 11b prohibited Bxpc-3 resulted lung metastasis by inhibiting its epithelial-mesenchymal transition (EMT) process. Another mechanism assay also proved that 11b inhibited the function of blood vessels and fibroblasts, promoted apoptosis of cancer and fibroblast cells, and exhibited low toxicity and good metabolic stability.

Drug-Coated Balloons for the Treatment of Coronary Artery Disease

Drug-coated balloon (DCB) angioplasty has emerged as an alternative to drug-eluting stent (DES) implantation for percutaneous coronary intervention (PCI) in patients with coronary in-stent restenosis (ISR) as well as de novo coronary artery disease. DCBs are balloons coated with antiproliferative agents and excipients, whose aim is to foster favorable vessel healing after appropriate lesion preparation. By providing homogeneous antiproliferative drug delivery in the absence of permanent foreign body implantation, DCBs offer multiple advantages over DES, including preservation of vessel anatomy and function and positive vessel remodeling. As such, DCBs have become appealing for treatment of ISR, small-vessel disease, long lesions, simplification of bifurcation procedures, and treatment of diffuse distal disease after recanalization of chronic total occlusions. In addition, patients with high bleeding risk, diabetes, and acute coronary syndrome might also stand to benefit from DCB angioplasty. Although commercially available in numerous countries now for more than a decade, DCB only recently obtained US Food and Drug Administration approval for the treatment of coronary ISR. Moreover, preliminary results from newer generation devices tested in different clinical scenarios have raised the interest of the international community. Accordingly, an up-to-date review is timely particularly with the anticipated wave of research on the matter. Herein, this review encompasses DCB technologies, their worldwide usage, details on relevant indications, and key procedural aspects of DCB angioplasty.

Features of isolated systolic and resistant arterial hypertension in patients with type 2 diabetes mellitus

Hypertension and type 2 diabetes mellitus (DM) are often combined and mutually enhance the adverse effects on vascular and renal prognosis. One of the features of hypertension in type 2 diabetes is the frequent occurrence of isolated systolic hypertension (ISG) and resistant hypertension (RH). Objective. To study the features of the structure and function of the left ventricle (LV), categories of circadian rhythm during outpatient blood pressure monitoring (OBPM), as well as the structure and function of blood vessels in people with type 2 diabetes, depending on the presence or absence of ISG and RH. Materials and methods. An observational descriptive one-step study was conducted 139 patients with hypertension in combination with type 2 diabetes (64 men and 75 women aged 73.9±11.7 years). ISAG was isolated if systolic blood pressure (BP) exceeded 140 mmHg, and diastolic blood pressure was less than 90 mmHg. RH was determined if, despite lifestyle changes and taking three classes of antihypertensive drugs, it was not possible to achieve target blood pressure levels. All patients underwent OBPM, echocardiography, ultrasound examination of the brachiocephalic arteries and a reactive hyperemia test. Results. Among 139 patients with hypertension in combination with type 2 DM, systolic-diastolic hypertension was present in 80 (57.6%) cases, ISG in 59 (42.4%), RH in 57 (41.0%), hypertension without resistance to antihypertensive treatment in 82 (59.0%). Conclusions. Patients with ISG characterized by more pronounced and eccentric LV hypertrophy (LVH), types II and III of LV diastolic dysfunction (DD), the "non-dipper" category in OBPM, as well as a significant thickening of the intima-media complex (IMC) of the common carotid artery (CCA). Patients with RH characterized by more pronounced and concentric LVH, types II and III of LV DD, the "night-peaker" category in OBPM, significant thickening of the IMC CCA and impaired brachial artery response in the reactive hyperemia test.

Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice.

Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas-including LMCs-of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.

ET-3/ETBR Mediates Na+-Activated Immune Signaling and Kidney Lymphatic Dynamics.

Lymphatic collecting vessels in the kidney are critical in clearing interstitial fluid, macromolecules, and infiltrating immune cells. Dysfunction of the lymphatic vessels can disrupt this process and exacerbate injury-associated inflammation in many disease conditions. We previously found that sodium accumulates within the kidney interstitium during proteinuric kidney injury and elevated sodium environments stimulate isolevuglandin production in antigen-presenting cells, stimulating T cells, and modulating inflammatory responses. In the present study, we investigated whether proteinuric injury increases production of isolevuglandin-adduct formation in antigen-presenting cells, their effects on lymphatic endothelial cells (LECs), and the role of the ET-3 (endothelin-3)/ETBR (endothelin type B receptor) on lymphatic vessel function. We used a mouse model of nephrotoxin-induced proteinuric injury to show that proteinuric injury expanded the kidney lymphatic network and to immunophenotype the infiltrating immune cells. To determine mechanisms, we analyzed the interaction of migratory immune cells and LECs using an in vitro transwell migration assay, bulk RNA sequencing, and flow cytometric analysis. To determine the effect of ET-3/ETBR axis on lymphatic vessel contractility, we analyzed microdissected lymphangions utilizing a vessel perfusion chamber. We found that animals with proteinuric injury have increased kidney lymphangiogenesis, isolevuglandin-producing dendritic cells, and IFN (interferon)-γ-producing CD4+T cells. The sodium avid environment present in kidney injury enhances the interaction between LECs and migratory antigen-presenting cells and LEC production of isolevuglandin-adducts. Elevated sodium environment-induced isolevuglandin-adduct formation facilitates the ET-3/ETBR communication between LECs and dendritic cells. In addition, the ET-3/ETBR axis modulates lymphatic collecting vessel pumping dynamics. These findings reveal a novel mechanism linking the isolevuglandin-mediated ET-3/ETBR axis with LECs and infiltrating dendritic cells. ET-3/ETBR signaling in lymphatic vessel dynamics is a novel pathogenic component and a possible therapeutic target in kidney disease.

Imitation as an adaptation tool in pottery making in New Spain

Ceramics produced in the Viceroyalty of New Spain in the 16th – 18th centuries serve as a valuable source for studying the history of intercultural contacts and colonization of the American continent. This article focuses on tableware ceramics and their significance in the sociocultural adaptation of colonial populations. The production of pottery on the Iberian Peninsula prior to colonization is described, and the function of ceramic vessels during the initial stages of conquest is explored. The article also examines questions of continuity and innovation in pottery production technology, and presents models for the emergence of new ceramic types in New Spain. Additionally, connections are established between the external appearance of tableware and the social identity of its owner. Particular attention is paid to the study of Tonala Polychrome ceramic type, which is an excellent example of local potters adapting to new standards of tableware. The work is based on the study of collections of Tonaltec pottery from the 17th to 18th centuries found in museums across Russia, Spain, and France.

Hybrid model of tumor growth, angiogenesis and immune response yields strategies to improve antiangiogenic therapy

Solid tumors harbor a complex and dynamic microenvironment that hinders the delivery and efficacy of therapeutic interventions. In this study, we developed and utilized a hybrid, discrete-continuous mathematical model to explore the interplay between solid tumor growth, immune response, tumor-induced angiogenesis, and antiangiogenic drugs. By integrating published data with anti-angiogenic drugs, we elucidate three primary mechanisms by which anti-angiogenesis influences tumor progression and treatment outcomes: reduction in tumor growth rate by mitigating and temporally delaying angiogenesis, normalization of blood vessel structure and function, and improving immune cell extravasation and activation. Our results indicate a significant increase in functional blood vessels and perfusion following anti-angiogenic treatment, which in turn improves the intratumoral distribution of immune cells. The normalization window, or optimal time frame for anti-angiogenic drug administration, and the dose of the drug arise naturally in the model and are highlighted as crucial factors in maximizing treatment benefits. Prolonged anti-angiogenic treatment triggers cancer cell migration into healthy tissue and induces immunosuppression due to hypoxia, potentially leading to negative effects because these cancer cells will rapidly proliferate upon treatment termination. In conclusion, the positive contribution of anti-angiogenic treatment must balance the possible negative effects by choosing a proper treatment protocol as well as combining it with proper anti-cancer treatment. Our findings provide valuable insights and a framework for the design of protocols with anti-angiogenic treatment, targeted immunotherapy, and non-targeted anti-cancer therapies.

Rhythmic Contractions of Lymph Vessels and Lymph Flow Are Disrupted in Hypertensive Rats.

Hypertension increases the risk of lymphedema in patients with comorbidities, but whether hypertension directly compromises lymph vessel (LV) function and lymph flow is unclear. We compared the contractions of mesenteric LVs ex vivo and lymph flow in vivo between normotensive and Ang II (angiotensin II)-induced hypertensive rats and explored the ionic basis of contractile patterns. Key studies were recapitulated in spontaneously hypertensive rats and control Wistar-Kyoto rats. Video microscopy continuously recorded the diameters of cannulated rat mesenteric LVs, and high-speed optical imaging estimated mesenteric lymph flow in vivo. Jess capillary Western electrophoresis evaluated expression levels of ion channel proteins. Isolated LVs from Ang II-induced hypertensive rats exhibited dysrhythmic contractions, whereas LVs from both Ang II-induced hypertensive rats and spontaneously hypertensive rats exhibited reduced diastolic diameters and cross-sectional flow. Mesenteric lymph flow in vivo was 2.9-fold lower in Ang II-induced hypertensive rats compared with normotensive rats. Surprisingly, the LVs from Ang II-induced hypertensive rats expressed fewer intact L-type Ca2+ channel pore proteins and more modulatory cleaved C-terminal fragments. However, pharmacological block of voltage-gated K+ channels but not other K+ channel types in control LVs established the pattern of contractile dysfunction observed in hypertension. Jess capillary Western electrophoresis analysis confirmed a loss of Shaker-type KV1.2 channels in LVs from hypertensive rats. We provide initial evidence of lymphatic contractile dysfunction and compromised lymph flow in hypertensive rats, which may be caused by a loss of KV1.2 channels in the lymphatic muscle cells.

The B-cells paradigm in systemic sclerosis: an update on pathophysiology and B-cell-targeted therapies.

Systemic sclerosis (SSc) is considered a rare autoimmune disease in which there are alterations of both the innate and adaptive immune response resulting in the production of autoantibodies. Abnormalities of the immune system compromise the normal function of blood vessels leading to a vasculopathy manifested by Raynaud's phenomenon, an early sign of SSc . As a consequence of this reactive picture, the disease can evolve leading to tissue fibrosis. Several SSc-specific autoantibodies are currently known and are associated with specific clinical manifestations and prognosis. Although the pathogenetic role of these autoantibodies is still unclear, their production by B cells and plasma cells suggests the importance of these cells in the development of SSc. This review narratively examines B-cell dysfunctions and their role in the pathogenesis of SSc and discusses B-cell-targeted therapies currently used or potentially useful for the management of end-organ complications.

Transport functions of intestinal lymphatic vessels.

Lymphatic vessels are crucial for fluid absorption and the transport of peripheral immune cells to lymph nodes. However, in the small intestine, the lymphatic fluid is rich in diet-derived lipids incorporated into chylomicrons and gut-specific immune cells. Thus, intestinal lymphatic vessels have evolved to handle these unique cargoes and are critical for systemic dietary lipid delivery and metabolism. This Review covers mechanisms of lipid absorption from epithelial cells to the lymphatics as well as unique features of the gut microenvironment that affect these functions. Moreover, we discuss details of the intestinal lymphatics in gut immune cell trafficking and insights into the role of inter-organ communication. Lastly, we highlight the particularities of fat absorption that can be harnessed for efficient lipid-soluble drug distribution for novel therapies, including the ability of chylomicron-associated drugs to bypass first-pass liver metabolism for systemic delivery. In all, this Review will help to promote an understanding of intestinal lymphatic-systemicinteractionsto guide future research directions.

Targeting endoplasmic reticulum stress-induced lymphatic dysfunction for mitigating bisphosphonate-related osteonecrosis.

Bisphosphonates (BPs) are the first-line treatment to stop bone resorption in diseases, including osteoporosis, Paget's disease, multiple myeloma and bone metastases of cancer. However, BPs-related osteonecrosis of the jaw (BRONJ), characterized by local inflammation and jawbone necrosis, is a severe intractable complication. The cumulative inflammatory burden often accompanies impaired lymphatic drainage, but its specific impact on BRONJ and the underlying mechanisms remain unclear. The mouse BRONJ model was established to assess the integrity and drainage function of lymphatic vessels by tissue clearing techniques, injected indocyanine green lymphatic clearance assay, flow cytometry analysis and histopathological staining. RNA sequencing, metabolome analysis, transmission electron microscopy and Western blotting were utilized to analyze the impacts of Zoledronate acid (ZA) on endoplasmic reticulum stress (ERS) and function of lymphatic endothelial cells (LECs). By constructing Lyve1creERT; SIRT6f/f and Lyve1creERT; ATG5f/f mice, we evaluated the role of ERS-induced LECs apoptosis in the progression of BRONJ. Additionally, we developed a nanoparticle-loaded ZA and rapamycin (ZDPR) to enhance autophagy and evaluated its potential in mitigating BRONJ. The mouse BRONJ model displayed impaired lymphatic drainage, accompanied by significant local inflammation and bone necrosis. The prolonged stimulation of ZA resulted in the extension of ERS and the inhibition of autophagy in LECs, ultimately leading to apoptosis. Mechanistically, ZA activated XBP1s through the NAD+/SIRT6 pathway, initiating ERS-induced apoptosis in LECs. The conditional knockout mouse models demonstrated that the deletion of SIRT6 or ATG5 significantly worsened lymphatic drainage and inflammatory infiltration in BRONJ. Additionally, the innovative nanoparticle ZDPR alleviated ERS-apoptosis in LECs and enhanced lymphatic function, facilitating inflammation resolution. Our study has elucidated the role of the NAD+/SIRT6/XBP1s pathway in ERS-induced apoptosis in ZA-treated LECs, and further confirmed the therapeutic potential of ZDPR in restoring endothelial function and improving lymphatic drainage, thereby effectively mitigating BRONJ. Bisphosphonate-induced lymphatic drainage impairment exacerbates bone necrosis. Zoledronate acid triggers endoplasmic reticulum stress and apoptosis in lymphatic endothelial cells via the NAD+/SIRT6/XBP1s pathway. Novel nanoparticle-loaded Zoledronate acid and rapamycin enhances autophagy, restores lymphatic function, and mitigates bisphosphonates-related osteonecrosis of the jaw progression.

Increased TRPV4 Channel Expression Enhances and Impairs Blood Vessel Function in Hypertension.

Endothelial cell TRPV4 (transient receptor potential vanilloid 4) channels provide a control point that is pivotal in regulating blood vessel diameter by mediating the Ca2+-dependent release of endothelial-derived vasoactive factors. In hypertension, TRPV4-mediated control of vascular function is disrupted, but the underlying mechanisms and precise physiological consequences remain controversial. Here, using a comprehensive array of methodologies, endothelial TRPV4 channel function was examined in intact mesenteric resistance arteries from normotensive Wistar-Kyoto and spontaneously hypertensive rats. Our results show there is a notable shift in vascular reactivity in hypertension characterized by enhanced endothelium-dependent vasodilation at low levels of TRPV4 channel activation. However, at higher levels of TRPV4 activity, this vasodilatory response is reversed, contributing to the aberrant vascular tone observed in hypertension. The change in response, from dilation to constriction, was accompanied by a shift in intracellular Ca2+ signaling modalities arising from TRPV4 activity. Oscillatory TRPV4-evoked IP3 (inositol triphosphate)-mediated Ca2+ release, which underlies dilation, decreased, while the contraction inducing sustained Ca2+ rise, arising from TRPV4-mediated Ca2+ influx, increased. Our findings also reveal that while the sensitivity of endothelial cell TRPV4 to activation was unchanged, expression of the channel is upregulated and IP3 receptors are downregulated in hypertension. These data highlight the intricate interplay between endothelial TRPV4 channel expression, intracellular Ca2+ signaling dynamics, and vascular reactivity. Moreover, the data support a new unifying hypothesis for the vascular impairment that accompanies hypertension. Specifically, endothelial cell TRPV4 channels play a dual role in modulating blood vessel function in hypertension.

Pericytes Modulate Third-Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR-Mutated Lung Cancer Cells Through IL32-β5-Integrin Paracrine Signaling.

EGFR-mutated lung cancer patients sometimes display restricted responses to third-generation tyrosine kinase inhibitors (TKIs), potentially attributable to undervalued input from stromal cells, notably pericytes (PCs). The study shows that PCs isolated from EGFR-mutated patients have a unique secretome profile, notably secreting IL32 and affecting signaling pathways and biological processes linked to TKI sensitivity. Clinical evidence, supported by single-cell RNA sequencing and multiplex immunostaining of tumor tissues, confirms the presence of IL32-expressing pericytes closely interacting with β5-integrin-expressing cancer cells in EGFR-mutated patients, impacting therapeutic response and prognosis. Co-culture and conditioned medium experiments demonstrate that PCs reduce TKI effectiveness in EGFR-mutated cancer cells, a reversible phenomenon through silencing IL32 expression in PCs or depleting the IL32 receptor β5-integrin on cancer cells, thereby restoring cancer cell sensitivity. Mechanistically, it is shown that YY1 signaling upregulates IL32 secretion in PCs, subsequently activating the β5-integrin-Src-Akt pathway in EGFR-mutated cancer cells, contributing to their TKI sensitivity. In animal studies, co-injection of cancer cells with PCs compromises TKI effectiveness, independently of blood vessel functions, while inhibition of β5-integrin restores tumor cell sensitivity. Overall, the findings highlight direct crosstalk between cancer cells and pericytes, impacting TKI sensitivity via IL32-β5-integrin paracrine signaling, proposing an enhanced therapeutic approach for EGFR-mutated patients.