Search Results (415)

Background/Objectives: Metabolic syndrome (MetS) conditions lead to structural and functional alterations in cardiomyocytes, microvasculature, and extracellular matrix (ECM), leading to myocardial fibrosis and impaired diastolic function. Cardiac lymphatic vessels (LVs) are increasingly recognized as key regulators of myocardial homeostasis, yet their response to MetS remains poorly understood. Therefore, we aimed to investigate transcriptional changes in cardiac lymphatic endothelial cells (LECs) in db/db mice, a well-established model of MetS. Methods: Using flow cytometry-sorted LECs and RT-PCR, we analyzed mRNA expression of genes involved in lymphangiogenesis, metabolism, mechanotransduction, immune cell trafficking, and ECM interactions. Results: Our findings show the transcriptional plasticity of cardiac LECs in response to MetS. Conclusions: Although our study is limited by the lack of protein-level validation and functional assays, our approach provides a broader interpretative framework and identifies potential directions for future research, including functional studies and pathway-specific investigations of the identified genes to assess their impact on lymphatic flow and cardiac function. Understanding LEC responses to metabolic stress may uncover novel therapeutic targets for heart failure associated with MetS. Full article

Lymphatic vessels are a kind of heterogeneous and versatile component of the lymphatic system, with a unique ability to respond to environmental changes in different organs. The heterogeneity and plasticity of lymphatic endothelial cells (LECs) and defective lymphatic architecture are critical for organ-specific lymphatic function. Moreover, lymphatic vessels have a dual effect on tumor microenvironment (TME), and lymphangiogenesis, an active and dynamic player, is a hallmark of cancer progression and treatment resistance. Dysregulation of lymphatic vessels and uncontrolled lymphangiogenesis contribute to the pathogenesis of many diseases, including cancer. Increasing evidence has indicated that lymphangiogenesis provides a critical target for inhibiting lymphatic metastasis, in which immune checkpoint inhibitors, either alone or combined with chemotherapy, may have a therapeutic value. This article reviews the current status of tumor-associated lymphangiogenesis and lymphatic remodeling, as well as the crosstalk among LECs, immune cells and cancer cells, which will help to further understand the role of lymphangiogenesis in cancer progression, metastasis, and therapy. Full article

Cerebral Amyloid Angiopathy (CAA) is a neurovascular condition characterized by the accumulation of amyloid-beta (Aβ) in the walls of small blood vessels, particularly affecting the leptomeninges and cortical regions in elderly populations. Initially recognized for its association with spontaneous lobar intracerebral hemorrhage, recent studies have highlighted the broader implications of CAA on cognitive decline and vascular health. This narrative review aims to elucidate the mechanisms of dural involvement in CAA, an aspect that has been largely overlooked in existing literature. This paper provides a detailed examination of the potential role of the dura mater and its associated lymphatic system in the clearance of interstitial amyloid and the maintenance of cerebrospinal fluid (CSF) homeostasis. Dural lymphatic vessels may facilitate the efflux of Aβ from the brain, and any impairment in this drainage system could contribute to the pathological accumulation of amyloid, exacerbating CAA and its neurological consequences. Additionally, the significant association between CAA and subdural hematoma (SDH) has been explored, indicating that the presence of SDH may complicate the clinical management of CAA patients by signaling an increased risk of hemorrhagic events. The mechanisms linking CAA and SDH, including vascular fragility and chronic inflammatory processes, are discussed to provide insight into potential pathways for therapeutic intervention. Full article

Neurodegenerative diseases pose major clinical challenges partly due to the underappreciation of the brain’s vascular and clearance systems. Evidence suggests that neurovascular dysfunction and glymphatic impairment are early contributors to disease onset, preceding established markers such as protein aggregation. This review synthesizes recent advances in understanding how disruption of the neurovascular unit (NVU) and glymphatic pathways contributes to neurodegeneration. We analyzed published literature documenting the temporal relationship between vascular dysfunction, glymphatic clearance impairment, and subsequent neurodegenerative pathology, with a focus on identifying therapeutic targets within this axis. Current research demonstrates that blood-brain barrier BBB breakdown, pericyte dysfunction, and compromised cerebral perfusion precede protein aggregation in multiple neurodegenerative disorders. Glymphatic dysfunction, characterized by aquaporin-4 (AQP4) depolarization and abnormalities in meningeal lymphatic vessels, impairs the clearance of neurotoxic metabolites. Novel therapeutic opportunities include the preservation of pericyte function, restoration of AQP4 polarity, enhancement of meningeal lymphatic drainage via vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 VEGFR-3 signaling, and targeted modulation of microRNA and complement pathways that regulate neuroinflammation. By targeting the earliest vascular and glymphatic disruptions, emerging therapeutic strategies may halt or delay disease progression before irreversible neuronal loss occurs. This neurovascular-glymphatic approach represents an unexplored frontier that complements traditional protein-centric therapeutic paradigms, offering new possibilities for early intervention in neurodegenerative disorders. Full article

Background and Objectives: The axillary lateral vessel thoracic junction (ALTJ) is a key lymphatic drainage pathway for the arm and a potential structure to spare during regional nodal irradiation (RNI) to reduce lymphedema risk in breast cancer patients. This study aims to demonstrate the feasibility of ALTJ-sparing radiation therapy (RT) planning using Tomotherapy. Materials and Methods: Ten breast cancer patients who had undergone axillary lymph node dissection and whose dissected axillary levels were excluded from the RNI target volume were included. A TomoDirect intensity-modulated RT plan was generated at a dose of 50 Gy in 25 fractions. The dissected axilla was not designated as an organ at risk (OAR) in the original treatment plan. For this study, the axillary lymph node level I (AXL1) and the ALTJ were delineated retrospectively, with the ALTJ considered an OAR in the newly generated study plan. A total of 20 RT plans (10 per group) were statistically compared using various dose-volume parameters. Results: Compared to the original plans, the study plans with ALTJ as an OAR significantly reduced the incidental dose to both the ALTJ (mean: 41.7 ± 3.4 Gy vs. 27.2 ± 1.3 Gy; p = 0.005) and the AXL1 (mean: 43.9 ± 2.0 Gy vs. 37.7 ± 1.9 Gy; p = 0.005). All other dosimetric parameters (V25Gy, V35Gy, V40Gy, Dmin, Dmax) for the ALTJ were also significantly lower in the study plans. This ALTJ sparing was achieved while maintaining all required dose-volume constraints for target volumes and standard OARs such as the lung and heart. Conclusions: This study demonstrates that simply excluding the dissected axilla from the target volume without designating it as an OAR still results in a substantial incidental dose to this region. Our findings also show the feasibility of using Tomotherapy to selectively spare the axilla, particularly the ALTJ subregion of AXL1, which is critical for lymphedema risk in breast cancer patients. Full article

Modern therapies aimed at stimulating heart vascularization are critical for regenerating damaged heart tissue and treating ischemic heart disease. Approaches based on developmental biology concepts, particularly those involving the use of cells to coordinate vascular network formation, are of great interest. In this context, epicardial mesothelial cells (MCs) have emerged as a key regulator of blood and lymphatic vessel development during cardiogenesis. However, therapeutic targeting of MCs remains challenging because of anatomical constraints and the difficulties related to isolation of viable cell cultures for research. In this study, we demonstrate for the first time that the pericardial fluid contains cell layers, being an easily accessible source of cardiac MCs. These cells exhibit a characteristic epithelial-like morphology and robust in vitro proliferation, and an ability to undergo epicardial-to-mesenchymal transition in response to TGFβ1. They secrete a broad range of proangiogenic and proinflammatory factors and exert a potent effect on endothelial cells, stimulating proangiogenic behavior and promoting vascular structure formation on Matrigel^TM. Treating MCs with TGF-β1 enhances the secretion of VEGF, G-CSF, GM-CSF and MCP-3, thereby boosting their proangiogenic properties. Therefore, pericardial fluid is an easily accessible source of MCs for studying their regulatory mechanisms, for being applied in tissue engineering, and for developing approaches to improve heart vascularization. Full article

Recent studies show that obesity significantly increases disease severity and progression in several forms of inflammatory arthritis, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout. Obesity increases the risk for developing inflammatory arthritis. Similarly, obesity negatively impacts disease severity and treatment outcomes. The underlying mechanisms driving these relationships are not fully understood. One emerging area of investigation is the role of the lymphatic vasculature. Obesity profoundly impacts lymphatic function. Excess adipose tissue can compress and disrupt lymphatic vessels, leading to impaired flow and drainage. Additionally, obesity-associated inflammation and metabolic dysregulation have been linked to lymphatic endothelial cell dysfunction, further compromising transport and immunoregulatory capacities. This impairment fosters an environment for the accumulation of inflammatory cells and mediators, sustaining chronic inflammation. In this review, we will provide new perspectives on the detrimental triangle of obesity, lymphatic dysfunction, and inflammation in chronic inflammatory arthritis and find new starting points for therapeutics. Full article

Background: Lymphatic malformations (LM) are rare congenital vascular anomalies caused by abnormal development and growth of lymphatic vessels. These malformations can lead to a wide range of symptoms, from mild swelling to more severe complications. Treatment options remain limited, especially for complex cases. Recent research has suggested that PIK3CA mutations play a key role in the pathogenesis of LM, potentially offering new possibilities for targeted treatment strategies. Methods: In this study, a cohort of 36 patients diagnosed with LM, Klippel-Trenaunay syndrome (KTS), and Proteus syndrome was analyzed. PIK3CA mutations were assessed in tissue samples obtained from the LM during clinically indicated procedures using digital droplet polymerase chain reaction (ddPCR), targeting five hotspots. Results: PIK3CA mutations were found in 18 patients (50%). The most frequent mutation was p.E542K (c.1624G>A), found in 19.44% of patients, followed by p.H1047R (c.3149A>G), p.E545K (c.1633G>A), and p.H1047L (c.3140A>T) each occurring in 11.11% of the cases. Mutations were more common in isolated LMs, with 63.16% of patients exhibiting PIK3CA mutations. Conclusions: PIK3CA mutations are common in LM, supporting the potential for targeted therapies like PI3K inhibitors in treating complex cases. This research highlights the importance of genetic analysis in the management of LM and offers a new therapeutic approach. Full article

Ovarian hormones are essential regulators of vascular homeostasis, yet their deficiency’s effects on the meningeal microvasculature remain incompletely understood. We used high-resolution imaging to assess the cranial dura mater (CDM) blood and lymphatic microvasculature in ovariectomized (OVX) and control (intact or sham-operated) mice, followed by morphometric analysis of microvessel architecture. Immunofluorescent staining and Western blotting were employed to evaluate markers of vascular remodeling and profibrotic signaling. Blood microvascular quantification revealed a significant reduction in total microvessel length two weeks post-OVX, primarily due to arteriolar, but not venular, shortening. At the same time, the lengths of individual segments of both arterioles and venules were also significantly decreased, indicating microvascular fragmentation. Despite these changes, total vessel surface area remained preserved, suggesting compensatory dilation, particularly in arterioles. OVX also increased overall vessel tortuosity, again selectively affecting arterioles. Region-specific analysis of lymphatic networks associated with the coronal suture (CS) showed significantly increased surface area of podoplanin-positive lymphatic vessels. Elevated α-smooth muscle actin (α-SMA) expression in vascular and stromal compartments in OVX animals, along with increased transforming growth factor beta (TGF-β) levels, indicated early profibrotic changes. These findings highlight the selective vulnerability of arterial and lymphatic microvascular structures to hormonal deficiency post-OVX and suggest an association between hormonal status, microvascular remodeling, and profibrotic alterations in the CDM. Full article

Lymphedema is a chronic, progressive, and debilitating disease of the lymphatic system with no current cure. Physiologic procedures, which address the underlying pathophysiology of lymphatic dysfunction, have gained traction in both treatment and prevention of lymphedema. This narrative review examines current physiologic lymphedema surgical techniques and emerging developments in this rapidly evolving field. While the two most common physiologic surgeries remain lymphovenous bypass (LVB) and vascularized lymph node transfer (VLNT), newer physiologic surgery techniques such as vascularized lymph vessel transfer (VLVT) and lymph node to vein anastomosis (LNVA) have been described in an effort to reduce donor site morbidity, with early promising clinical outcomes. The use of bioengineering with stem cells, pro-lymphangiogenic growth factors, and biomaterials such as Biobridge can be applied in conjunction with surgery to help promote lymphangiogenesis. Technological advances in robotic surgical systems and 3D exoscopes are helping to make supermicrosurgery more technically feasible and ergonomic, and increasing accessibility to lymphedema surgery. As our surgical armamentarium expands, treatment algorithms must be updated to determine how various surgical techniques can be combined and sequenced, how the indications for physiologic surgery can be expanded, and how surgical treatment can be tailored to the patient and disease process. Full article

Post-traumatic lymphedema (PTL) is a chronic and often under-recognized sequela of soft tissue trauma, leading to persistent swelling, functional impairment, and increased risk of infection. While lymphedema is traditionally associated with oncologic interventions, growing evidence highlights the significant burden of PTL in trauma patients. This review provides a comprehensive analysis of the current understanding of PTL, including epidemiology, risk factors, pathophysiology, diagnostic modalities, and treatment strategies. PTL often occurs after high-impact musculoskeletal injuries (such as open fractures with significant soft tissue loss) or burns (especially if deep or circumferential). This risk is increased if injury occurs at critical areas of increased lymphatic density (such as anteromedial leg, medial knee, medial thigh, medial elbow, or medial arm). Advances in imaging techniques, including indocyanine green lymphography and magnetic resonance lymphangiography, have improved early detection and classification of PTL. Management approaches range from conservative therapies, such as complete decongestive therapy (CDT), to surgical interventions, including lymphaticovenous anastomosis (LVA), vascularized lymph node transfer (VLNT), and vascularized lymph vessel transfer (VLVT)/lymph-interpositional-flap transfer (LIFT). We report on our experience with two patients. At our center, we diagnose and stage PTL with ICG lymphography and trial CDT for 6 months. If there is no significant improvement, we recommend LVA. If there is insufficient improvement after 12 months, we recommend LIFT/repeat LVA/VLNT. We also treat open fractures with significant soft tissue defects with LIFT, as prophylaxis against PTL. PTL remains an underdiagnosed condition, necessitating increased awareness and intervention to prevent long-term disability. Full article

Regulated proteolysis via autophagy is essential for cellular homeostasis, yet the specific role of autophagy-related gene 7 (ATG7) in corneal epithelial maintenance remains unclear. Using a conditional knockout mouse model (Atg7^f/f K14Cre^+/−), we investigated the impact of ATG7 deficiency on corneal epithelial autophagy, morphology, and vascular dynamics. Loss of ATG7 disrupted autophagosome formation, evidenced by increased LC3B expression but reduced LC3B-positive puncta and absence of autophagosomes ultrastructurally. Although gross corneal morphology was preserved, ATG7 deficiency led to thickened epithelium and increased peripheral lymphatic vessel sprouting, indicating a pro-inflammatory and pro-lymphangiogenic microenvironment. Proteomic analysis revealed upregulation of RAB8, TM9S3, and RETR3, suggesting activation of compensatory pathways such as exophagy, reticulophagy, and Golgiphagy. Inflammatory and angiogenic components were downregulated, suggesting a moderate loss of inhibitory capacity based on the lymphatic phenotypes observed. At the same time, while these two compensatory changes occur, other proteins that positively regulate lysosome formation are reduced, resulting in a phenotype linked to deficient autophagy. These findings demonstrate that ATG7-mediated autophagy maintains corneal epithelial homeostasis and immune privilege, with implications for understanding corneal inflammation and lymphangiogenesis in ocular surface diseases. Full article

Background/Objectives: The potential role of robotic surgery in segmental colectomy for the treatment of splenic flexure and mid-transverse colon cancers remains underexplored. These sites are technically demanding because of the occurrence of vascular variability, the need for dual lymphatic drainage, and the close anatomical relationship to surrounding organs. This systematic review evaluated surgical strategies, anastomotic techniques, perioperative outcomes, and the oncological adequacy of robotic segmental colectomies in this context. Methods: The review followed the PRISMA guidelines (PROSPERO ID: CRD420251119736). Studies were eligible if they included ≥3 patients who were undergoing a robotic segmental colectomy for malignant tumors of the splenic flexure or mid-transverse colon. Data on patient demographics, operative details, complications, and oncological outcomes were extracted. The risk of bias was assessed using the Newcastle–Ottawa Scale and ROBINS-I. Results: Five retrospective studies reporting on 74 patients were included. All the procedures involved a fully robotic approach. Vascular ligation was uniform for transverse tumors (middle colic vessels point of origin), but varied for splenic flexure lesions. Anastomotic reconstruction was extracorporeal stapled (55.4%), intracorporeal stapled (16.2%), or intracorporeal hand sewn (4.1%). Operative times were in the range of 157.5–268 min; conversion occurred in 4.1% of cases. The overall morbidity was 16.2%, with anastomotic leaks in 5.4% of cases. No 30-day mortality was observed, and one reoperation was required. All patients achieved R0 resection, with a mean lymph node yield of 16.9. Only one recurrence was documented during the follow-up period. Conclusions: Robotic segmental colectomy for splenic flexure and mid-transverse colon malignancies is feasible and safe, achieving consistent perioperative and oncological outcomes. Larger multicenter prospective studies are needed to validate the oncological adequacy, standardize anastomotic strategies, and assess the cost effectiveness of the approach. Full article

Recurrent erysipelas is a common and clinically significant condition that poses challenges for both patients and healthcare systems. Each episode may damage lymphatic vessels, leading to chronic lymphedema, which perpetuates the risk of further relapses. Recurrence rates remain high, ranging from 11% in outpatients during the first year to up to 46% of hospitalized patients within three years. The lower limbs are the most frequent site, although recurrences may also occur in other regions, such as the upper limb after mastectomy with lymph node dissection. This review summarizes current knowledge on risk factors, preventive measures, and chemoprophylaxis in recurrent erysipelas. Modifiable risk factors such as obesity, diabetes, venous insufficiency, tinea pedis, and poor hygiene play an important role, while non-modifiable factors include age, sex, and a history of prior episodes. Non-pharmacological strategies—weight reduction, glycemic control, smoking cessation, compression therapy, and meticulous skin care—form the cornerstone of prevention and may reduce the need for long-term antibiotics. Antibiotic prophylaxis, most commonly with oral penicillin V or intramuscular benzathine penicillin, has been shown to lower recurrence rates. However, efficacy may be reduced in patients with chronic edema or severe obesity. Macrolides serve as alternatives in penicillin-allergic patients, but concerns remain about resistance, adverse effects, and drug–drug interactions. In conclusion, recurrent erysipelas requires a multifaceted approach. While antibiotic prophylaxis is effective, its long-term success depends on simultaneous management of underlying conditions. Further studies are needed to define optimal regimens, treatment duration, and non-antibiotic alternatives. Full article

Enlarged perivascular spaces (EPVS) are MRI markers of impaired glymphatic clearance and have been associated with neurodegenerative diseases. However, their clinical significance in amyotrophic lateral sclerosis (ALS) and underlying mechanisms remain poorly understood. This study investigated the prevalence, clinical relevance, and pathophysiological basis of EPVS in ALS. MRI data from 114 ALS patients and 119 matched controls were analyzed, with high-degree EPVS defined as more than 20 visible spaces. High-degree EPVS in the centrum semiovale (CSO) was more prevalent in ALS patients (49.1%) than in controls (15.1%, p < 0.001). Age, male sex, and ALS diagnosis were independent predictors, while disease severity and aggressiveness were not associated. ALS patients with high-degree CSO-EPVS were older at disease onset and MRI but showed similar clinical progression. In SOD1/G93A ALS mice, cerebral perivascular spaces were significantly enlarged at 5 months compared to wild-type and younger ALS mice. Cervical lymphatic ligation promoted misfolded SOD1 accumulation in motor neurons and cerebral vessels, further increasing perivascular space width without altering motor function. These findings suggest that about half of ALS patients exhibit high-degree CSO-EPVS, reflecting impaired protein clearance rather than disease aggressiveness. Full article