Harnessing the lymphatic system.

Heart failure (HF) is a growing concern, with significant implications for mortality, morbidity, and economic sustainability. Traditionally viewed primarily as a hemodynamic disorder, recent insights have redefined HF as a complex systemic syndrome, emphasizing the importance of understanding its multifaceted pathophysiology. Fluid overload and congestion are central features of HF, often leading to clinical deterioration and hospital admissions, with the role of the lymphatic system previously largely overlooked, partly due to diagnostic challenges and visualization difficulties. With the advancement of those techniques, pathophysiological changes occurring in the lymphatic system during HF, such as enlargement of the thoracic duct and the increased lymphatic flow, are now becoming apparent. This emerging research has begun to uncover the interplay between lymphatic dysfunction and HF, suggesting novel therapeutic targets. Advances in molecular biology, such as targeting vascular endothelial growth factor and promoting lymphangiogenesis, hold promise for improving lymphatic function and mitigating HF complications. This article provides a comprehensive overview of the evolving landscape of lymphatic system-targeted therapies for HF. It explores various intervention levels, from mechanical lymphatic decongestion to pharmaceutical interactions and lymphatic micro-circulation, offering insights into future directions and potential clinical implications for HF management.

A cost-effectiveness analysis of sentinel lymph node biopsy compared with lymphadenectomy in intermediate- and high-risk endometrial carcinoma.

BACKGROUND: Sentinel lymph node biopsy (SLN) is increasingly used for surgical staging of endometrial carcinoma. OBJECTIVE: To estimate the effect and cost-effectiveness of the implementation of an SLN algorithm for surgical staging in patients with intermediate- and high-risk endometrial carcinoma compared with lymphadenectomy. METHODS: We performed a model-based, cost-effectiveness analysis using primary data from a tertiary referral hospital that included 829 patients with endometrial carcinoma undergoing surgical staging. We quantified the health and economic outcomes from two time periods, before and after implementation of the SLN algorithm by robotic surgery. Costs were measured directly from the hospital's financial department, while long-term health outcomes were estimated using self-reported lymphedema and health-related quality-of-life among survivors. Sensitivity analyses were conducted to evaluate uncertainty. RESULTS: We projected that the SLN implementation period, predominately reflecting use of robotic SLN, simultaneously improved health outcomes (0.08 incremental quality-adjusted life-years) and lowered costs (US$1051) compared with the prior period involving robotic or open lymphadenectomy. SLN remained more beneficial and less costly across key sensitivity analyses-namely, varying the cost of the robotic platform, surgical equipment, number of yearly robotic procedures, percentage of robotic procedures versus percentage of laparotomies, length of stay, and lymphedema development. After 1000 simulations of the model, SLN implementation provided greater health benefits for lower costs (ie, cost saving) in 89% of simulations. CONCLUSION: Implementation of an SLN algorithm in the staging of intermediate- and high-risk endometrial carcinoma improved health outcomes for lower costs compared with lymphadenectomy. Cost-effectiveness could further improve by continuing to increase the proportion of robotic procedures.

Lymph nodes in oral squamous cell carcinoma: a comprehensive anatomical perspective.

Oral squamous cell carcinoma (OSCC) often exhibits a propensity for metastasis to lymph nodes (LNs), significantly influencing prognosis. Neck dissection (ND) is an important part in the treatment of OSCC. Variations in the preference for and pathways of lymph node metastasis (LNM) in different regions of the oral cavity have been observed. Currently, there is a lack of sufficient emphasis on the anatomical perspectives of LNM and ND. This review elucidates the lymphatic system of the maxillofacial regions from an anatomical standpoint, details the distribution of the sentinel LNs across different subsites, and summarizes the various classifications of the cervical LNs. Additionally, we elaborate on the methods used to study the lymphatic system, particularly imaging techniques. Furthermore, we investigate the pathways of cervical LNM and evaluate the efficacy of ND from an anatomical viewpoint. The overall objective of this review is to provide essential anatomical knowledge for managing LNs in OSCC, in the hope of providing patients with effective treatment modalities to enhance their quality of life.

Physiology and Functional Pathology of the Lymphatic System with Implications for the Fontan Patient.

Contractile function of the collecting lymphatic vessels depend on smooth muscle cells, one-way valves, surrounding tissues, and regulation by the autonomic nervous system. The potentially deleterious effects of the Fontan procedure and elevated central venous pressure on lymphatic function leading to life-threatening complications are described. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease.

The role of ferroptosis resistance in lymph-associated tumour metastasis.

Tumour metastasis is a crucial factor in determining clinically challenging tumours. In this respect, the lymphatic system may act as potential entry portals for tumour metastasis, whilst, clinical detection of tumour-infiltrated lymph nodes also indicates poorer prognosis and higher metastatic risk. Whether tumour cells gain ferroptosis resistance in lymph that make them exhibit a stronger propensity for lymphatic dissemination compared to hematogenous spread might be a breakthrough for elucidating lymph-associated tumour metastasis. This review discusses how the lymphatic system endows tumour cells with ferroptosis resistance character, which makes them more propensity for lymph node pre-metastasis and distant metastasis through lymphatic circulation. Comprehensively considering the distinct structure and property of lymph and the unique metabolic characteristics of tumours, all of the lymphatic vessels, intestinal lymph and lymph nodes collectively manipulate an intricate interaction with the hematogenous system and afford substances exchange with tumour cells and extracellular vesicles, upon which make a ferroptosis resistant microenvironment for subsequent metastasis in distant organs and lymph nodes.

Panax Notoginseng Saponins promotes the meningeal lymphatic system-mediated hematoma absorption in intracerebral hemorrhage.

BACKGROUND: Hematoma clearance is crucial for treating intracerebral hemorrhage (ICH). Currently, there is a lack of pharmacological therapy aimed at promoting hematoma absorption. Meningeal lymphatic system, as a drain of brain, is a potential therapeutic approach in ICH. Panax Notoginseng Saponins (PNS), proven to promote lymphangiogenesis in periphery, effectively reduces hematoma in ICH patients. However, the potential pharmacological effect of PNS on meningeal lymphatic vessels (MLVs) remains unknown. PURPOSE: In this study, we aimed to investigate the impact of PNS on the meningeal lymphatic system and ICH. METHODS: The collagenase-ICH model was conducted to investigate the effect of PNS. Behavioral tests, including modified neurological severity score (mNSS) and foot-fault test, and hematoma volume were used to estimate the neurological function and curative effect. The structure and drainage function of MLVs was detected by immunohistochemical staining. Visudyne intracisternal magna injection combined with red laser photoconversion was performed to ablate MLVs. RNA-sequencing was used to obtain mRNA profiles for mechanistic investigation. RESULTS: The meningeal lymphatic drainage function was enhanced after ICH on day 14 without obvious lymphangiogenesis. Additionally, PNS further facilitated the process of drain with simultaneously inducing lymphangiogenesis. Moreover, ablation of MLVs by photoconverting of visudyne significantly blocked the benefits of neurological deficits improvement and hematoma absorption conducted by PNS. Furthermore, RNA-sequencing revealed that PNS regulated axonogenesis and inflammation, relying on the intact MLVs. In which, solute carrier family 17 member 7 (Slc17a7) and tumor necrosis factor (Tnf) were identified as bottleneck and hub nodes of the protein-protein interaction network of target genes, respectively. CONCLUSION: PNS might be effective for ICH treatment by enhancing lymphangiogenesis and the meningeal lymphatic drainage function, thereby attenuating inflammation and promoting neurological recovery. The role of PNS in regulation of MLVs was investigated for the first time. This study provides a novel insight for PNS in the medical therapy of ICH.

Subarachnoid hemorrhage distinctively disrupts the glymphatic and meningeal lymphatic systems in beagles.

Subarachnoid hemorrhage (SAH) induced acute impairment of the glymphatic system, but few have investigated the dysfunction of the meningeal lymphatic system and their contribution to the pathophysiology of SAH. In addition, most studies were conducted in rodent animals. We aimed to investigate the impact of SAH on glymphatic and meningeal lymphatic function in a large animal model using beagles and to evaluate the effects of intermittent cistern magna CSF drainage on these systems. Methods: The SAH model was created in beagles via endovascular perforation using a digital subtraction angiography machine. Intermittent cistern magna CSF drain was performed daily from 1 d to 3 d after SAH. We examined CSF pressure, neuronal death, enlargement of perivascular space (PVS), hydrocephalus, and neurological and cognitive deficits before and after SAH. The dynamics of glymphatic and meningeal lymphatic functions were analyzed by quantifying the signal intensity of dimeglumine gadopentetate (Gd-DTPA) using T1-weighted magnetic resonance imaging (MRI). Measurements were taken before SAH and at 1 h, 1 week, and 2 weeks post-SAH. Results: SAH in beagles caused significant blood clots, neuronal death, increased CSF pressure, hydrocephalus, and neurological and cognitive deficits. MRI revealed dilated ventricles and enlarged PVS post-SAH. The glymphatic system's function, assessed by Gd-DTPA distribution, showed reduced CSF influx and glymphatic impairment after SAH, particularly in the ipsilateral hemisphere, persisting for a week with partial recovery at 2 weeks. For lymphatic clearance, Gd-DTPA rapidly filled the olfactory bulbs, optic nerves, facial and vestibulocochlear nerves, and spinal nerves under normal conditions. SAH caused delayed and reduced Gd-DTPA efflux outflow in these areas, disrupting lymphatic clearance. Despite initial dysfunction, increased hemoglobin levels in cervical lymph nodes indicated active blood clearance post-SAH, with recovery by 2 weeks. Treatment with intermittent cistern magna CSF drain significantly ameliorated the glymphatic and meningeal lymphatic dysfunction after SAH. Conclusion: SAH impaired both glymphatic and meningeal lymphatic functions in beagles, with better restoration of lymphatic function post-SAH, which may contribute to functional recovery after SAH. External CSF drain is an effective therapeutic approach to facilitate the recovery of glymphatic and meningeal lymphatic function following SAH.

Evaluation of Postoperative Anastomotic Patency in Lymphaticovenular Anastomosis Using Photoacoustic Imaging.

BACKGROUND AND OBJECTIVES: Lymphaticovenular anastomosis (LVA) is a surgical technique used to alleviate lymphedema by bypassing the lymphatic and venous vessels and facilitating lymphatic fluid drainage. Accurate evaluation of anastomotic patency is crucial for assessing LVA outcomes. Traditional near-infrared fluorescence lymphography has limitations, including fluorescence diffusion in subcutaneous fat and difficulty evaluating areas beneath the dermal backflow. Photoacoustic imaging (PAI) is a potential alternative for high-resolution visualization of lymphatic and blood vessels. We aimed to evaluate the utility of PAI for assessing LVA patency. METHODS: Using the LUB0 PAI system, we examined patients who underwent LVA. Imaging was conducted using subcutaneously injected indocyanine green (ICG) to visualize lymphatic vessels. RESULTS: Results showed clear patency in some cases, inability to evaluate it in others, and confirmed occlusion in certain instances. CONCLUSIONS: While PAI provides valuable insights, challenges remain, including the potential for ambiguous results from the intermittent nature of lymphatic flow and difficulty visualizing low-ICG-concentration lymphatic vessels. Nonetheless, PAI offers a promising method for detailed 3D evaluation of anastomoses. It may improve surgical outcomes and contribute to future evidence in the field. Further advancements, including real-time video assessment, may enhance the accuracy and reliability of LVA patency evaluation.

The Regulation of Cerebral Lymphatic Drainage in the Transverse Sinus Region of the Mouse Brain.

Cerebral lymphatic drainage is an important pathway for metabolic waste clearance in the brain, which plays a crucial role in the progression of central nervous system diseases. Recent studies have shown that norepinephrine (NE) is involved in the regulation of cerebral lymphatic drainage function, but the modulation mechanism remains unknown. In this study, we confirmed that NE rapidly reduced glymphatic influx and enhanced meningeal lymphatic clearance. Moreover, the transverse sinus (TS) was the vital region of cerebral lymphatic drainage regulation by NE. Further analysis revealed that NE inhibition could simultaneously enhance glymphatic drainage and dorsal meningeal lymphatic drainage, mainly acting on the TS region. This study demonstrated that the cerebral lymphatic drainage system can be regulated by NE, with the TS region serving as the primary modulating site. The findings provide a potential regulatory target for the amelioration of neurological diseases associated with cerebral lymphatic drainage function.

Cystic lymphangioma of the omental bursa in adult: A rare case report.

Cystic lymphangioma is a benign lymphatic malformation that primarily affects children, with rare occurrences in adults. These malformations are most commonly found in the head and neck region, though their presence in the abdominal cavity is infrequent. In this report, we present the case of 71-year-old women with a cystic lymphangioma located in the omental bursa. The rarity of this condition in adults, combined with its unusual abdominal location, highlights the unique aspects of this case. This report explores the clinical presentation, diagnostic challenges, and management strategies for these uncommon lymphatic malformations.

The role of vascular and lymphatic networks in bone and joint homeostasis and pathology.

The vascular and lymphatic systems are integral to maintaining skeletal homeostasis and responding to pathological conditions in bone and joint tissues. This review explores the interplay between blood vessels and lymphatic vessels in bones and joints, focusing on their roles in homeostasis, regeneration, and disease progression. Type H blood vessels, characterized by high expression of CD31 and endomucin, are crucial for coupling angiogenesis with osteogenesis, thus supporting bone homeostasis and repair. These vessels facilitate nutrient delivery and waste removal, and their dysfunction can lead to conditions such as ischemia and arthritis. Recent discoveries have highlighted the presence and significance of lymphatic vessels within bone tissue, challenging the traditional view that bones are devoid of lymphatics. Lymphatic vessels contribute to interstitial fluid regulation, immune cell trafficking, and tissue repair through lymphangiocrine signaling. The pathological alterations in these networks are closely linked to inflammatory joint diseases, emphasizing the need for further research into their co-regulatory mechanisms. This comprehensive review summarizes the current understanding of the structural and functional aspects of vascular and lymphatic networks in bone and joint tissues, their roles in homeostasis, and the implications of their dysfunction in disease. By elucidating the dynamic interactions between these systems, we aim to enhance the understanding of their contributions to skeletal health and disease, potentially informing the development of targeted therapeutic strategies.

Chronic Cellulitis in Elephantiasis: A Rare Debilitating Phenomenon.

Chronic edema, which has multiple etiologies, is predicted to be a significant underlying cause of lymphedema, potentially leading to serious complications. Elephantiasis, characterized by massive swelling of any body part, is a rare but debilitating condition often associated with lymphatic obstruction or anomalies in the lymphatic system. Lymphedema can predispose a patient to cellulitis, an infectious condition with multiple risk factors. This case study presents a 45-year-old male with a history of chronic lymphatic obstruction due to elephantiasis and recurrent cellulitis in his lower limb. Despite receiving multiple courses of antibiotics, the patient continued to experience multiple episodes of cellulitis, along with worsening lymphedema and functional impairment of the limb. The mainstay of treatment for this condition includes compression stockings and surgery, but addressing the root cause of the disease is crucial. Typically, a multidisciplinary approach is required, involving antibiotics, lymph drainage, and compression therapy. This case highlights the challenges faced in managing elephantiasis and its related complications and emphasizes the need for preventive strategies.

Advantages of the intradermal lymphoscintigraphy.

Lymphoscintigraphy is a nuclear medicine procedure that uses a small quantity of radioactive particles for visualizing the lymphatic system. Traditionally, the radiotracer was injected subcutaneously, but the quality of lymphatic path imaging was scarce due to high background. Intradermal radiotracer injection is considered the modern-day intralymphatic injection. We propose rest/stress intradermal lymphoscintigraphy for the diagnosis, staging and surgical planning of lymphedema. Major and minor findings were described in primary and secondary lymphedema. Based on the in-depth information of the lymphatic pathways, physiotherapists and microsurgeons can obtain important functional information in patients' selection to treat with physical treatments and/or undergo microsurgery.

Rictor, an mTORC2 Protein, Regulates Murine Lymphatic Valve Formation Through the AKT-FOXO1 Signaling.

BACKGROUND: Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation. METHODS: In vivo and in vitro techniques were used to investigate the role of Rictor, a critical component of mTORC2, in lymphatic endothelium. RESULTS: Here, we showed that embryonic and postnatal lymphatic deletion of Rictor, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels. RICTOR knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in Rictor knockout mesenteric lymphatic endothelial cells in vivo. Deletion of Foxo1 in Rictor knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery. CONCLUSIONS: Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.

The Anatomy of the Thoracic Duct and Cisterna Chyli: A Meta-Analysis with Surgical Implications.

Background: The thoracic duct (TD) and the cisterna chyli (CC) exhibit a high degree of variability in their topographical and morphometric properties. Materials and Methods: PubMed, Scopus, Embase, Web of Science, Cochrane Library, and Google Scholar were searched to identify all studies that included information regarding the morphometric and topographical characteristics of the TD and CC. Results: The most frequent location of the TD termination was the left venous angle, with a pooled prevalence of 45.29% (95% CI: 25.51-65.81%). Moreover, the TD terminated most commonly as a single vessel (pooled prevalence = 78.41%; 95% CI: 70.91-85.09%). However, it divides into two or more terminating branches in approximately a quarter of the cases. The pooled prevalence of the CC was found to be 55.49% (95% CI: 26.79-82.53%). Conclusions: Our meta-analysis reveals significant variability in the anatomy of the TD and CC, particularly regarding TD termination patterns. Despite the predominance of single-vessel terminations, almost a quarter of cases exhibit branching, highlighting the complexity of the anatomy of the TD. These findings demonstrate the importance of detailed anatomical knowledge for surgeons to minimize the risk of accidental injury during head and neck, as well as thoracic surgeries. Our study provides essential insights that can enhance surgical safety and efficacy, ultimately improving patient outcomes.

The paravertebral lymphatic system is involved in the resorption of the herniated nucleus pulposus and the regression of inflammation associated with disc herniation.

OBJECTIVE: To investigate the role of the paravertebral lymphatic system in the nucleus pulposus herniation (NPH) resorption and the inflammation regression. DESIGN: Clinical specimens (n = 10) from patients with lumbar disc herniation (LDH) were collected, C57BL/6 (n = 84) and conditional Vegfr3 knockout mice (n = 14) were used. Immunofluorescence staining detected lymphatic vessels (LVs) and NP cells. Near-infrared imaging assessed lymphatic drainage function, and Alcian Blue/Orange determined inflammation. RESULTS: Lymphangiogenesis was observed in the herniated NP of patients with LDH, and the proportion of capillary LVs was higher than that of collecting LVs (mean 68.2% [95% confidence interval: 59.4, 77.1]). In NPH mice, NP cells were detected in paravertebral tissue (38.6 [32.0, 45.2]) and draining lymph nodes (dLN) at 4 h (76.9 [54.9, 98.8]). A significant increase of NP cells in dLNs was observed at 24 h (157.1 [113.7, 200.6]). Most of the herniated NP cells were cleared in paravertebral tissue after 1 week (7.5 [4.4, 10.6]), but disc inflammation peaked at 1 week (19.9% [14.7, 25.1]), along with persistent lymphangiogenesis (9.5 [7.2, 11.8]). However, conditional Vegfr3 knockout mice exhibited impaired lymphangiogenesis (5.7 [4.4, 7.0]) and herniated NP cell clearance (6.1 [1.8, 10.5]) during NPH, leading to exacerbated disc inflammation (23.7% [19.3, 28.2]). CONCLUSION: The paravertebral lymphatic system is involved in the NPH resorption and inflammation regression. Promoting lymphangiogenesis may be a novel strategy for facilitating NPH resorption and inflammation regression in patients with LDH.

Mesenteric cystic lymphangiomas in an 11-year-old female: A rare case report.

Mesenteric cystic lymphangiomas are a rare benign abdominal malformation of lymphatic vessels, with an estimated incidence of 1 per 250,000. Clinical presentation ranges from asymptomatic masses to acute abdominal pain. Diagnostic investigation includes ultrasound, abdominal computed tomography, or magnetic resonance imaging. Complete surgical excision is the recommended treatment. We present an 11-year-old female with abdominal cramps, and a 6-month history of gradually developing distension, constipation, and polyuria, without the occurrence of vomiting. Clinical examination revealed a soft, movable, painless abdominal mass with dullness on palpation. Ultrasound showed multi-cavity cystic masses in the abdomen, and a contrast-enhanced computed tomography scan revealed a large multi-cavity cystic mass involving most of the abdomen. A complete surgical excision was performed, and microscopic examination confirmed the diagnosis of mesenteric cystic lymphangioma. This case underscores the importance of considering mesenteric cystic lymphangiomas in the differential diagnosis of abdominal masses in pediatric patients, even in rarer age groups. Imaging aids in diagnosis and surgery planning. Complete excision curbs the risk of infection and recurrences.

Lower Extremity Lymphatic Flow/Drainage Assessment by Indocyanine Green Fluorescent Lymphography in Heart Failure Patients.

The purpose of this study was to present a protocol for visualizing lymphatic flow in patients with heart failure (HF) by using indocyanine green fluorescence lymphography. We studied 37 subjects: 20 patients with acute heart failure (AHF) and lower limb edema, 7 patients with chronic heart failure (CHF) without lower limb edema, and 10 control subjects (no HF, no limb edema). All subjects were assessed at rest, and 11 subjects (6 control and 5 with CHF) were assessed again after a 10-minute walk. The lymph flow was visualized in all selected patients without complications. At rest, there was either no lymph flow or minimal lymph flow in all control subjects and patients with CHF, whereas the majority of patients with AHF demonstrated significant lymph flow. This study describes a new method to visualize/assess lymphatic flow in patients with HF, allowing for continuous, real-time tracking of lymphatic flow in the lower extremity.

Microbiota-gut-brain axis: interplay between microbiota, barrier function and lymphatic system.

The human gastrointestinal tract, boasting the most diverse microbial community, harbors approximately 100 trillion microorganisms comprising viruses, bacteria, fungi, and archaea. The profound genetic and metabolic capabilities of the gut microbiome underlie its involvement in nearly every facet of human biology, from health maintenance and development to aging and disease. Recent recognition of microbiota - gut - brain axis, referring to the bidirectional communication network between gut microbes and their host, has led to a surge in interdisciplinary research. This review begins with an overview of the current understandings regarding the influence of gut microbes on intestinal and blood-brain barrier integrity. Subsequently, we discuss the mechanisms of the microbiota - gut - brain axis, examining the role of gut microbiota-related neural transmission, metabolites, gut hormones and immunity. We propose the concept of microbiota-mediated multi-barrier modulation in the potential treatment in gastrointestinal and neurological disorders. Furthermore, the role of lymphatic network in the development and maintenance of barrier function is discussed, providing insights into lesser-known conduits of communication between the microbial ecosystem within the gut and the brain. In the final section, we conclude by describing the ongoing frontiers in understanding of the microbiota - gut - brain axis's impact on human health and disease.

Unlocking potential of oxytocin: improving intracranial lymphatic drainage for Alzheimer's disease treatment.

Background: The impediment to ß-amyloid (Aß) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aß from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.