Lymphatic Vessel Development Research Articles

Differential vegfc expression dictates lymphatic response during zebrafish heart development and regeneration.

Vascular endothelial growth factor C (Vegfc) is crucial for lymphatic and blood vessel development, yet its cellular sources and specific functions in heart development remain unclear. To address this, we created a vegfc reporter and an inducible overexpression line in zebrafish. We found vegfc expression in large coronary arteries, circulating thrombocytes, cardiac adipocytes, and outflow tract smooth muscle cells. Notably, while coronary lymphangiogenesis aligns with Vegfc-expressing arteries in juveniles, it occurs only after coronary artery formation. Vegfc overexpression induced ectopic lymphatics on the ventricular surface prior to arterial formation, indicating that Vegfc abundance, rather than arterial presence, drives lymphatic development. However, this overexpression did not affect coronary artery coverage, suggesting a specific role for Vegfc in lymphatic, rather than arterial, development. Thrombocytes emerged as the initial Vegfc source during inflammation following heart injuries, transitioning to endocardial and myocardial expression during regeneration. Lower Vegfc levels in the amputation model corresponded with a lack of lymphatic expansion. Importantly, Vegfc overexpression enhanced lymphatic expansion and promoted scar resolution without affecting cardiomyocyte proliferation, highlighting its role in regulating lymphangiogenesis and promoting heart regeneration.

Cardiac Lymphatics and Therapeutic Prospects in Cardiovascular Disease: New Perspectives and Hopes.

The lymphatic system is the same reticular fluid system as the circulatory system found throughout the body in vascularized tissues. Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in maintaining tissue fluid homeostasis, immune cell transport, and lipid absorption. The heart also has an extensive lymphatic network, and as research on cardiac lymphatics has progressed in recent years, more and more studies have found that cardiac lymphangiogenesis may ameliorate certain cardiovascular diseases, and therefore stimulation of cardiac lymphangiogenesis may be an important tool in the future treatment of cardiovascular diseases. This article briefly reviews the development and function of cardiac lymphatic vessels, the interaction of cardiac lymphatic vessels with cardiovascular diseases (including atrial fibrillation, coronary atherosclerosis, and heart failure), and finally discusses the therapeutic potential of targeted cardiac lymphatic therapy for cardiovascular diseases.

Effects of Angiogenic Factors on the Epithelial-to-Mesenchymal Transition and Their Impact on the Onset and Progression of Oral Squamous Cell Carcinoma: An Overview.

High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels' formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy.

Meeting Report for the 2023 International Scientific Conference on Complex Lymphatic Anomalies

Objectives: Complex lymphatic anomalies (CLAs) are rare diseases with variable clinical manifestations caused by the abnormal development of lymphatic vessels. The Lymphatic Malformation Institute (LMI), Lymphangiomatosis & Gorham’s Disease Alliance (LGDA), and LGD Alliance Europe sponsored an international conference on CLAs so leaders in the field could discuss recent advances in research on CLAs. Methods: The conference occurred in Dallas, Texas, between September 29th and September 30th, 2023. The event had 22 distinguished speakers and 38 attendees. Additional researchers, clinicians, and patients attended the conference virtually. Results: In this article, we summarize the key takeaways from the meeting. The conference emphasized the crucial role of the patient voice in guiding research, and attendees heard stories from patients and parents of children with CLAs. The conference covered topics such as the genetic causes of CLAs, preclinical models, clinical advances, new technologies for CLA research, lymphatic imaging, and patient-centered research. Videos of all the presentations can be found on the LGDA website. Conclusions: The meeting revealed that while progress has been made, many challenges still exist surrounding the diagnosis and treatment of CLAs. Sustained research efforts are necessary to fill the gaps in knowledge and improve the care and quality of life of CLA patients.

Angpt1 binding to Tie1 regulates the signaling required for lymphatic vessel development in zebrafish.

Development of the vascular system is regulated by multiple signaling pathways mediated by receptor tyrosine kinases. Among them, angiopoietin (Ang)/Tie signaling regulates lymphatic and blood vessel development in mammals. Of the two Tie receptors, Tie2 is well known as a key mediator of Ang/Tie signaling, but, unexpectedly, recent studies have revealed that the Tie2 locus has been lost in many vertebrate species, whereas the Tie1 gene is more commonly present. However, Tie1-driven signaling pathways, including ligands and cellular functions, are not well understood. Here, we performed comprehensive mutant analyses of angiopoietins and Tie receptors in zebrafish and found that only angpt1 and tie1 mutants show defects in trunk lymphatic vessel development. Among zebrafish angiopoietins, only Angpt1 binds to Tie1 as a ligand. We indirectly monitored Ang1/Tie1 signaling and detected Tie1 activation in sprouting endothelial cells, where Tie1 inhibits nuclear import of EGFP-Foxo1a. Angpt1/Tie1 signaling functions in endothelial cell migration and proliferation, and in lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling. Thus, we show that Angpt1/Tie1 signaling constitutes an essential signaling pathway for lymphatic development in zebrafish.

Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function.

Zinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specific Zmiz1 knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling of ZMIZ1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migration in vitro. We also presented evidence that Zmiz1 regulates Prox1 expression in vitro and in vivo by modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss of Zmiz1 in mesenteric lymphatic vessels significantly reduced valve density. Collectively, our results highlight a novel role of Zmiz1 in LECs and as a transcriptional regulator of Prox1, shedding light on a previously unknown regulatory factor in lymphatic vascular biology.

β-arrestin1/2 are essential for embryonic lymphatic vessel development

Lymphatic dysfunction can lead to fetal loss due to interstitial edema known as hydrops fetalis during development and lymphedema in adulthood. Lymphedema affects an estimated 250 million individuals worldwide, yet there is no effective treatment available. Numerous studies have established G protein-coupled receptors (GPCRs) as key lymphangiogenic signaling pathways and ideal druggable therapeutical targets. β-arrestins (β-arrestin 1 and 2) are ubiquitously expressed cytosolic adaptor proteins which perform a wide range of functions in GPCR pathways, such as promoting agonist-induced internalization and forming signaling scaffolds with internalized GPCRs in endosomes. However, the roles of β-arrestins in lymphatic vessel development and function remain undefined. We hypothesize that β-arrestin1/2 are essential in embryonic lymphatic vessel development. To test this hypothesis, I used an inducible β-arrestin1fl/fl (Arrb1 fl/fl), β-arrestin2fl/fl (Arrb2 fl/fl);Prox1 CreERT2 mouse line. β-arrestin1 and 2 were deleted by oral gavage of tamoxifen at embryonic day 10.5 (E10.5) and E12.5, critical points for developmental lymphangiogenesis. Compared to Arrb1/2fl/flembryos, the Arrb1/2fl/fl;Prox1CreERT2 embryos exhibit profound hydrops fetalis, subcutaneous hemorrhages, and increased embryonic lethality between E14.5 and E16.5. At E15.5, the Arrb1/2fl/fl;Prox1CreERT2 embryos with edema show decreased weight indicating growth restriction compared to controls. Jugular lymphatic sacs are enlarged and filled with blood in Arrb1/2fl/fl;Prox1CreERT2 embryos compared to controls. Dermal lymphatic vessel length in the Arrb1/2fl/fl;Prox1CreERT2 embryos is shorter than controls. Collectively, our results demonstrate that loss of β-arrestin1/2 expression in lymphatics causes mid-gestational arrest in lymphatic development and fetal growth restriction, indicating that β-arrestins are required for developmental lymphangiogenesis in mammals. American Physiological Society postdoctoral Fellowship (to YT) and NIH R01 HL129086 (to KMC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 1064: Creation Of Lymphatic Endothelial Cells From Induced Pluripotent Stem Cells For Use In Regenerative Therapy For Lymphedema

Background/Objective: Lymphedema is a condition characterized by impaired flow of interstitial fluid through the lymphatic system and chronic obliteration of distal lymphatic collecting vessels. Despite advances in our knowledge of the development of lymphatic vessels, there has been little progress translating this knowledge into clinically relevant regenerative therapies. Although lymphatic endothelial cells (LECs) share a lineage with arterial and venous endothelial cell progenitors, currently described processes to derive LECs from stem cells in vitro take up to a month, require embryoid body formation, and have been minimally characterized. Methods: We have developed a protocol for the generation of lymphatic endothelial cells from induced pluripotent stem cells (iPSCs) over 11 days. First, iPSCs are directed to become endothelial cell progenitors over 6 days and purified with CD144 magnetic beads. Then, ECs are directed to differentiate into LECs using a 5-day treatment with 10 ng/mL Ang1 alone or in combination with 200 ng/mL VEGFc. Human primary LECs were used as a positive control and iPSC-ECs without Ang1 or VEGFc treatment as well as fibroblasts were negative controls. Results: Treating iPSC-derived endothelial cells for 5 days with Ang1 +/- VEGFc yields iPSC-LECs with morphological similarity to primary lymphatic controls and expression of multiple lymphatic markers including Podoplanin, Lyve1, Prox1, and VEGFR3, verified by immunofluorescent staining, western blotting, and flow cytometry across two independent cell lines. In flow cytometry studies, 75% of LECs treated with Ang1 and 72% of LECs treated with Ang1 and VEGFc co-express Podoplanin and Lyve1. There was more than a three-fold increase compared to CD144+ endothelial progenitors (20.4%, p<0.001) while fibroblast expression was negligible (0.6%, p<0.001). Finally, the overall transcriptome of LECs treated with Ang1 was compared to primary human lymphatic cells using single cell RNA sequencing. Conclusions: Treatment with Ang1 with or without VEGFc allows fast and efficient generation of LECs from iPSCs. This allows LEC differentiation in vitro from a wide variety of patient specific cell types and improves the practicality of regenerative therapy for lymphedema.

Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.

Impaired meningeal lymphatic drainage in Listeria monocytogenes infection.

Previous studies have demonstrated an association between lymphatic vessels and diseases caused by bacterial infections. Listeria monocytogenes (LM) bacterial infection can affect multiple organs, including the intestine, brain, liver and spleen, which can be fatal. However, the impacts of LM infection on morphological and functional changes of lymphatic vessels remain unexplored. In this study, we found that LM infection not only induces meningeal and mesenteric lymphangiogenesis in mice, but also impairs meningeal lymphatic vessels (MLVs)-mediated macromolecules drainage. Interestingly, we found that the genes associated with lymphatic vessel development and function, such as Gata2 and Foxc2, were downregulated, suggesting that LM infection may affect cellular polarization and valve development. On the other hand, photodynamic ablation of MLVs exacerbated inflammation and bacterial load in the brain of mice with LM infection. Overall, our findings indicate that LM infection induces lymphangiogenesis and may affect cell polarization, cavity formation, and valve development during lymphangiogenesis, ultimately impairing MLVs drainage.

Piezo1 regulates meningeal lymphatic vessel drainage and alleviates excessive CSF accumulation

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.

New targets of nascent lymphatic vessels in ocular diseases.

Recent advancements in the field of endothelial markers of lymphatic vessels and lymphangiogenic factors have shed light on the association between several ocular diseases and ocular nascent lymphatic vessels. The immune privilege of corneal tissue typically limits the formation of lymphatic vessels in a healthy eye. However, vessels in the eyes can potentially undergo lymphangiogenesis and be conditionally activated. It is evident that nascent lymphatic vessels in the eyes contribute to various ocular pathologies. Conversely, lymphatic vessels are present in the corneal limbus, ciliary body, lacrimal glands, optic nerve sheaths, and extraocular muscles, while a lymphatic vasculature-like system exists in the choroid, that can potentially cause several ocular pathologies. Moreover, numerous studies indicate that many ocular diseases can influence or activate nascent lymphatic vessels, ultimately affecting patient prognosis. By understanding the mechanisms underlying the onset, development, and regression of ocular nascent lymphatic vessels, as well as exploring related research on ocular diseases, this article aims to offer novel perspectives for the treatment of such conditions.

The cytoskeleton adaptor protein Sorbs1 controls the development of lymphatic and venous vessels in zebrafish.

Lymphangiogenesis, the formation of lymphatic vessels, is tightly linked to the development of the venous vasculature, both at the cellular and molecular levels. Here, we identify a novel role for Sorbs1, the founding member of the SoHo family of cytoskeleton adaptor proteins, in vascular and lymphatic development in the zebrafish. We show that Sorbs1 is required for secondary sprouting and emergence of several vascular structures specifically derived from the axial vein. Most notably, formation of the precursor parachordal lymphatic structures is affected in sorbs1 mutant embryos, severely impacting the establishment of the trunk lymphatic vessel network. Interestingly, we show that Sorbs1 interacts with the BMP pathway and could function outside of Vegfc signaling. Mechanistically, Sorbs1 controls FAK/Src signaling and subsequently impacts on the cytoskeleton processes regulated by Rac1 and RhoA GTPases. Inactivation of Sorbs1 altered cell-extracellular matrix (ECM) contacts rearrangement and cytoskeleton dynamics, leading to specific defects in endothelial cell migratory and adhesive properties. Overall, using in vitro and in vivo assays, we identify Sorbs1 as an important regulator of venous and lymphatic angiogenesis independently of the Vegfc signaling axis. These results provide a better understanding of the complexity found within context-specific vascular and lymphatic development.

The development of early human lymphatic vessels as characterized by lymphatic endothelial markers

Lymphatic vessel development studies in mice and zebrafish models have demonstrated that lymphatic endothelial cells (LECs) predominantly differentiate from venous endothelial cells via the expression of the transcription factor Prox1. However, LECs can also be generated from undifferentiated mesoderm, suggesting potential diversity in their precursor cell origins depending on the organ or anatomical location. Despite these advances, recapitulating human lymphatic malformations in animal models has been difficult, and considering lymphatic vasculature function varies widely between species, analysis of development directly in humans is needed. Here, we examined early lymphatic development in humans by analyzing the histology of 31 embryos and three 9-week-old fetuses. We found that human embryonic cardinal veins, which converged to form initial lymph sacs, produce Prox1-expressing LECs. Furthermore, we describe the lymphatic vessel development in various organs and observe organ-specific differences. These characterizations of the early development of human lymphatic vessels should help to better understand the evolution and phylogenetic relationships of lymphatic systems, and their roles in human disease.

The emerging role of Piezo1 in the musculoskeletal system and disease.

Piezo1, a mechanosensitive ion channel, has emerged as a key player in translating mechanical stimuli into biological signaling. Its involvement extends beyond physiological and pathological processes such as lymphatic vessel development, axon growth, vascular development, immunoregulation, and blood pressure regulation. The musculoskeletal system, responsible for structural support, movement, and homeostasis, has recently attracted attention regarding the significance of Piezo1. This review aims to provide a comprehensive summary of the current research on Piezo1 in the musculoskeletal system, highlighting its impact on bone formation, myogenesis, chondrogenesis, intervertebral disc homeostasis, tendon matrix cross-linking, and physical activity. Additionally, we explore the potential of targeting Piezo1 as a therapeutic approach for musculoskeletal disorders, including osteoporosis, muscle atrophy, intervertebral disc degeneration, and osteoarthritis.

Trametinib inhibits lymphatic vessel invasion of bone in a mouse model of Gorham-Stout disease.

Gorham-Stout disease (GSD) is a rare lymphatic anomaly that can be caused by somatic activating mutations in KRAS. This discovery has led investigators to suggest that MEK inhibitors could be a novel treatment for GSD. However, the effect of MEK inhibitors on bone disease in animal models of GSD has not been investigated. We recently reported that Osx-tTA;TetO-Vegfc mice exhibit a phenotype that resembles GSD. Osx-tTA;TetO-Vegfc mice overexpress VEGF-C in bone, which stimulates the development of lymphatic vessels in bone and the gradual loss of cortical bone. The objective of this study was to characterize the effect of trametinib, an FDA-approved MEK1/2 inhibitor, on lymphangiogenesis and osteolysis in Osx-tTA;TetO-Vegfc mice. Immunoblotting was performed to assess the effect of trametinib on VEGF-C-induced phosphorylation of ERK1/2, AKT, and S6 in primary human lymphatic endothelial cells (LECs). Prevention and intervention experiments were performed to determine the effect of trametinib on lymphangiogenesis and osteolysis in Osx-tTA;TetO-Vegfc mice. We found that trametinib blocked VEGF-C-induced phosphorylation of ERK1/2 in primary human LECs. We also found that trametinib prevented VEGF-C-induced lymphatic invasion of bone and cortical bone loss in Osx-tTA;TetO-Vegfc mice. Additionally, trametinib slowed the progression of disease in Osx-tTA;TetO-Vegfc mice with established disease. However, it did not reverse disease in Osx-tTA;TetO-Vegfc mice. Our results show trametinib impacts bone disease in Osx-tTA;TetO-Vegfc mice. These findings further support the testing of MEK inhibitors in patients with GSD and other RAS pathway-driven complex lymphatic anomalies with bone involvement.

Mean platelet volume and platelet distribution width as predicting biomarkers of hepatitis C related hepatocellular carcinoma

Background and Aims: Besides their role in hemostasis and thrombosis; platelets have roles in innate and adaptive immune responses, atherosclerosis, lymphatic vessel development, angiogenesis and carcinogenesis .The relation between platelets and cancer is well-known and thrombocytosis may occur as a paraneoplastic syndrome. Several studies reported a correlation of high platelet count with poor prognosis in different malignancies. The aim of this study was to explore the predictive values of platelet count (PLC), mean platelet volume (MPV) & platelet distribution width (PDW) in HCV related HCC, as well as their association with tumor burden. Method: The study was conducted on two groups of patients, group 1; included patients with naive HCV related HCC and group 2; included patients with chronic HCV cirrhosis. Liver biochemical tests, AFP, serum creatinine, multi-phasic contrast enhanced abdominal CT and or MRI were done at baseline for all cases. In Group 1, non-invasive diagnosis of HCC in cirrhotic patients according to the EASL guidelines & Barcelona Clinic Liver Cancer (BCLC) staging was done. In Group 2, liver cirrhosis was diagnosed through liver histology or a combination of radiographic, clinical, and laboratory findings. CBC was done for all participating patients using automated hematology analyzer with reporting of PLC, MPV& PDW. Results: Group 1 included 144 patients, while group 2 included 116 patients. In group 1, the age was significantly older & the number of males was significantly higher. PLC was significantly lower in group 1 than group 2. In group 1, PLC was < 150× 109/L (thrombocytopenia) in 71.6% of the cases, while it was normal in 28.4% of them. The median HCC diameter was significantly larger in patients with normal PLC than thrombocytopenic patients. There was significant positive correlation of PLC with BCLC stage. PLC was significantly higher in late than early BCLC stage. In group 1; PLC at cut off value of 134.5×109/L predicted late BCLC stages; with sensitivity of 44.1%, specificity of 82.5%, AUC of 0.65 & p = 0.006. There was insignificant difference between both groups regarding PDW. There was insignificant difference between both groups regarding PDW. There was insignificant difference between both groups regarding the MPV. In group 1; PDW was ≥14.5% in 79% & <14.5% in 21% of the patients while MPV was ≥10.4 fl in 52.1% of the patients & <10.4 fl in 47.9% of them. There was insignificant correlation of MPV & PDW with BCLC stage. PDW at cut off value of 15.05% predicted HCV related HCC with sensitivity = 62, 2%, specificity = 58, 1 %, AUC = 57, 8 %, p = 0.043. There was significant negative correlation of the MPV with serum AFP level. MPV was significantly smaller in late than early BCLC stage. On multivariate logistic regression analysis, gender, patient status of performance (PS), Alpha fetoprotein (AFP), PLC, Albumin -Bilirubin (ALBI) grade and Model of End stage Liver Disease (MELD) score, were significant predictors of HCV related HCC, while age, PDW, MPV and Child -Turcotte -Pugh (CTP) score were not significant predictors. Conclusion: PLC was significant predictors of HCV related HCC. HCV related HCC patients with normal PLC had larger tumor diameter. PLC positively correlated with BCLC stage. In HCV related HCC cases, PLC at cut off value of 134.5×109/L may predict late BCLC stages. PDW at cut off 15.05% may predict HCV related HCC. MPV was significantly smaller in late than early BCLC stages & it negatively correlated with serum AFP level. MPV was not significant predictors of HCV related HCC.

Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function.

Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here, we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1 K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs.

Postoperative constrictive pericarditis caused rupture of lymphatic collaterals: a rare etiology of chylothorax

BackgroundChylothorax after cardiovascular surgery is primarily caused by direct injury to the thoracic duct or its branches, and occurs in early postoperative period. In the present case, we describe a rare case of chylothorax manifesting three months after surgery secondary to constrictive pericarditis.Case presentationA 71-year-old man underwent mitral valve replacement, tricuspid valve annuloplasty, and the maze procedure. He developed acute perioperative myocardial infarction on postoperative day one due to plaque rupture in the left anterior descending artery and underwent percutaneous coronary intervention. Although the patient was discharged on postoperative day 36, he required readmission on postoperative day 83 because of right side chylothorax associated with constrictive pericarditis. Lymphangiography revealed thoracic duct interruption and development of lymphatic collateral vessels via the right hilum. Single-photon emission computed tomography revealed abnormal tracer accumulation in the right hilum, suggesting a lymphatic leakage site. A catheter study indicated biventricular dip and plateau patterns with a reduced cardiac index (1.6 L/min/m2) and elevated central venous pressure (18 mmHg). Conservative treatment for chylothorax, including a low-fat diet and continuous drainage with chest tube, was unsuccessful. Drainage of chyle at approximately 500 mL/day continued. On hospitalization day 50, complete pericardiectomy via median sternotomy was performed because the patient’s cardiac function deteriorated. The central venous pressure dramatically decreased, and the chylothorax gradually subsided. There was no recurrence of symptoms 1 year postoperatively.ConclusionsChylothorax associated with constrictive pericarditis subsequent to cardiac surgery is extremely rare. Although conservative management failed, the present case was successfully treated via pericardiectomy alone and did not require any additional precedures, such as thoracic duct ligation via a right thoracotomy.

An unusual instance of acquired intraoral cavernous lymphangioma

Lymphangiomas refers to hamartoma group and can be defined as rare congenital deformities caused by aberrant lymphatic vessel development, typically appear in infancy and the early years of childhood.