Embryonic Veins Research Articles

Surgical treatment of varicose veins and venous malformations in Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a mixed mesenchymal malformation characterised by varicose veins, venous and capillary malformations, and hypertrophy of soft tissue and bone. The purpose of this study was to evaluate the surgical outcomes in KTS patients to provide standards for comparison with endovenous therapy. The clinical data of consecutive patient with KTS who underwent open venous surgical treatment between January 1987 and December 2008 were reviewed. Demographics, clinical presentation, operative data, and clinical outcomes were recorded. Follow-up information was obtained from the medical records, mailed questionnaires and phone calls. Descriptive statistics, the Kaplan-Meier method and Log-rank statistics were used where appropriate. Twenty-seven females and 22 males, (mean age 26.5 years, range 7.7-55.8) were included in this study. All had varicose veins, 36 (73%) had limb hypertrophy, and 33 (67%) had capillary malformations, with two of three clinical features present in all. The most frequent symptom was pain (N = 43, 88%). Forty-nine patients underwent operations on 53 limbs. Stripping of the GSV, small and accessory saphenous and lateral embryonic veins was performed in 17 (32%), 10 (19%), 9 (17%), and 15 (28%) limbs, respectively. Two patients developed deep vein thrombosis, one had pulmonary embolism (PE), and one patient had peroneal nerve palsy. Freedom from disabling pain at 1, 3 and 5 years was 95%, 77% and 59%, respectively, and freedom from secondary procedures was 78% at 3 years, and 74% at 5 years. At the last follow-up visit, the venous clinical severity score had decreased from 9.48 ± 3.27 to 6.07 ± 3.20 (P < 0.001). In selected symptomatic patients with KT syndrome, open surgical treatment is safe and durable. Three-fourths of the patients remain free of disabling pain at five years, but secondary procedures are required in one-fourth of the patients. These data can serve as standards for comparison of endovenous therapy for KT syndrome.

Nonvenous origin of dermal lymphatic vasculature.

The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. We aimed to clarify the origin of the murine dermal lymphatic vasculature. We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.

Marginal vein is not a varicose vein; it is a venous malformation

Marginal vein (MV) is one form of venous malformation (VM); MV is not a varicose vein. MV is the outcome of defective development during the later stage of embryogenesis while the vein trunk is formed. It is an embryonic vein tissue remnant remaining on birth following the failure of normal involutional process. MV is the most common VM involved to Klippel-Trenaunay syndrome (KTS); together with the lymphatic malformation, MV is one of two clinically most important congenital vascular malformation components among KTS. MV causes chronic venous insufficiency (CVI) due to a unique condition of avalvulosis (lack of venous valve development) it accompanies with. Besides, it accompanies a high risk of venous thromboembolism (VTE) due to its structural defect with a lack of smooth muscle cell to form the media properly as a truncular VM infrequently causing fatal pulmonary embolism. Therefore, the MV is indicated for the surgical excision whenever feasible not only for the prevention of VTE and CVI but also for abnormal long bone growth known as vascular bone syndrome as well as lymphatic complication precipitated by MV.

Anomalous External Jugular Vein with variant Omohyoid – anatomico-clinical appraisal

Variability in size, formation, course and termination of superficial system of veins of Head and Neck are common. This is due to the complex development of veins and various stages of evolution and involution of multiple paired embryonic veins. These variations often noticed during routine anatomical dissection, may provide invaluable assistance for the clinicians, surgeons and radiologist. External Jugular Vein is routinely used in the estimation of Central Venous Pressure, IV Catheterization for haemodialysis, parental nutrition in critically ill patients and in trans – jugular procedures. An unusual termination of left External Jugular Vein (EJV) and atypical left Omohyoid muscle was noticed during routine dissection of a 65 year old male cadaver. The left EJV crossed the jugular notch in the midline and drained into the right Subclavian vein. On the same side Omohyoid had a single belly that originated from the medial half of the clavicle and was inserted into the hyoid bone. This unilateral spectrum of anatomic variation makes it a rare special case.

Emerging from the PAC: Studying zebrafish lymphatic development

Recently the zebrafish has emerged as a promising vertebrate model of lymphatic vasculature development. The establishment of numerous transgenic lines that label the lymphatic endothelium in the zebrafish has allowed the fine examination of the developmental timing and the anatomy of their lymphatic vasculature. Although many questions remain, studying lymphatic development in the zebrafish has resulted in the identification and characterization of novel and established mediators of lymphatic development and lymphangiogenesis. Here, we review the main stages involved in the development of the lymphatic vasculature in the zebrafish from its origins in the embryonic veins to the formation of the primary lymphatic vessels and highlight some of the key molecules necessary for these stages.

Development of the mammalian lymphatic vasculature

The two vascular systems of our body are the blood and lymphatic vasculature. Our understanding of the cellular and molecular processes controlling the development of the lymphatic vasculature has progressed significantly in the last decade. In mammals, this is a stepwise process that starts in the embryonic veins, where lymphatic EC (LEC) progenitors are initially specified. The differentiation and maturation of these progenitors continues as they bud from the veins to produce scattered primitive lymph sacs, from which most of the lymphatic vasculature is derived. Here, we summarize our current understanding of the key steps leading to the formation of a functional lymphatic vasculature.

Petrosquamosal Sinus

Petrosquamosal sinus (PSS) is an embryonic emissary vein of the temporal bone connecting the intracranial and extracranial venous networks, which is present in some variants of venous cerebral drainage. The aim of the present study was to analyze 20 cases of PSS and to present its clinical characteristics and implications. Retrospective case review. Tertiary referral center. Diagnostic. By reviewing retrospective medical records and TBCT findings, a total of 20 PSS cases were found. Based on the shapes of PSS demonstrated on TBCT, PSS was classified into tortuous and straight types. The course and thickness of PSS were also investigated. The average thicknesses of PSS between tortuous and straight types were compared. The mean age of the patients was 54.1 ± 16.2 years. The study group consisted of 7 male (35.0%) and 13 female (65.0%) patients. Eleven cases were found on the right side and 8 cases on the left side. The mean diameter of the bony canal that PSS courses on TBCT was 2.57 ± 0.88 mm. Its maximal and minimal diameters were 4.2 and 0.7 mm. The average diameter of tortuous type PSSs (3.04 ± 0.75 mm) was significantly larger compared with that of straight-type PSSs (2.09 ± 0.76 mm) (p < 0.05). Preoperative identification of PSS using TBCT may be important for safe mastoid surgery. The presence of PSS should be identified with thorough examination of radiographic findings before mastoid surgery.

Accessory Embryonic Residual Vein Circulation in Adult Detected during Patent Foramen Ovale Percutaneous Closure

Inferior vena cava (IVC) anomalies may display with different anatomical features due to the complexity of the embryogenetic process. These vascular anatomical variants occur in 0.4-3.5% of patients. We present the case of a 41 year old woman with a previous transient ischemic attack, positive brain Computed Tomography (CT) scan and Magnetic Resonance (MRI) showing an ischemic frontal area and Patent Foramen Ovale (PFO) with right to left shunt. During the advancement of a .035” J-tipped guide wire via the right femoral vein for PFO closure, a paravertebral supplementary venous circulation was detected and confirmed by CT scan. The incidental diagnosis of venous accessory circulation associated with PFO raised the awareness to the existence of these rare anatomical variations for both the clinician and the interventionalist.

Umbilical Cord Vein

In the article by Tritschler et al. (1), with its list of therapeutic alternatives to treat long urethral strictures with a free graft, total urethral replacement by using the umbilical cord vein should definitely be mentioned. In several male trauma cases, total or partial replacement of the urethra with human umbilical cord vein, harvested in the peripartum period or cryopreserved, was done successfully, without any graft rejection reaction (lowest antigen presentation) (2). In longer urethral strictures, but also in those that are extremely narrow, partial or total replacement of the urethra by means of transplanting embryonic umbilical cord veins has yielded excellent long-term results, especially in patients with longer strictures, after the umbilical cord vein had already been tried and tested as a ureteric replacement in clinical use.

Congenital inferior vena cava anomalies: a review of findings at multidetector computed tomography and magnetic resonance imaging

Inferior vena cava anomalies are rare, occurring in up to 8.7% of the population, as left renal vein anomalies are considered. The inferior vena cava develops from the sixth to the eighth gestational weeks, originating from three paired embryonic veins, namely the subcardinal, supracardinal and postcardinal veins. This complex ontogenesis of the inferior vena cava, with multiple anastomoses between the pairs of embryonic veins, leads to a number of anatomic variations in the venous return from the abdomen and lower limbs. Some of such variations have significant clinical and surgical implications related to other cardiovascular anomalies and in some cases associated with venous thrombosis of lower limbs, particularly in young adults. The authors reviewed images of ten patients with inferior vena cava anomalies, three of them with deep venous thrombosis. The authors highlight the major findings of inferior vena cava anomalies at multidetector computed tomography and magnetic resonance imaging, correlating them the embryonic development and demonstrating the main alternative pathways for venous drainage. The knowledge on the inferior vena cava anomalies is critical in the assessment of abdominal images to avoid misdiagnosis and to indicate the possibility of associated anomalies, besides clinical and surgical implications.

The persistent embryonic vein in Klippel–Trenaunay syndrome

Klippel-Trenaunay syndrome (KTS) is a congenital malformation syndrome with prominent vascular anomalies. A persistent embryonic vein (PEV) may be located on the affected leg(s) of patients with KTS. Our understanding of PEVs of the legs is limited and their nomenclature is confusing. The objective of this study was to obtain further insight in the prevalence, nomenclature and etiology of PEVs of the legs in KTS and to propose a standardized description of anomalous leg veins in KTS. We investigated 70 KTS patients for the presence of PEVs (lateral marginal vein, LMV) of the legs by duplex ultrasonography. We performed histopathological analysis of a surgically excised PEV (LMV) of a typical KTS patient, and we conducted an extensive literature study. Duplex ultrasonography showed LMVs in 12/70 (17.1%) patients. The terms used to describe PEVs in the leg are quite variable, while indicating only two types: lateral marginal vein (LMV) and persistent sciatic vein (PSV). The histology of the excised LMV showed remarkable similarity with that of varicose veins found in the general population. In conclusion, the prevalence of LMVs in our KTS cohort is 17.1%. Two PEVs can be found in the legs and we propose nomenclature based on anatomical criteria, thereby using only the terms persistent lateral marginal vein and persistent sciatic vein, combined with the patency of the deep venous system. We hypothesize that PEVs are most likely caused by a genetic defect leading to abnormal venous pattern formation, which is further supported by our histopathological findings.

Aneurismas Venosos: Achado Ultrassonográfico Inédito Na Síndrome De Klippel-Trenaunay-Weber Venous Aneurysms: Unpublish Sonographic Findings in Klippel-Trenaunay-Weber Syndrome

Klippel-Trenaunay-Weber Syndrome (KTWS) is characterized by the presence of complex vascular malformations, including venous, arterial and lymphatic anomalies and arteriovenous fistulas (AVFs). Objective: To describe the identification of venous aneurysms, unpublished sonographic findings in KTWS. Between June 2009 and November 2012, 80 patients with clinical diagnosis of KTWS (ages ranging from 5 months to 45 years, 61% women, 75% in the lower limbs, 15% in upper limbs, 10% bilateral) underwent Ultrasound (US) Doppler. 28 patients (35%) presented persistence of the embryonic lateral marginal vein. 12 patients (15%) presented 20 aneurisms, with an average diameter of 18mm, localized in the following veins: popliteal (5); great saphenous (2); minor saphenous (2); Giacomini (2); basilic (2); cephalic (2); embryonic lateral marginal (5). Anomalous Arterial Branches were identified in 96% of the patients and AVFs were found in 88%, confirmed by angiography in 100% of the treated patients (12). 7 (35%) of the 20 identified venous aneurisms presented AVFs in the regions of the dilatations. We can conclude that venous aneurisms are unpublished findings in KTWS and that US-Doppler is important in the hemodynamic evaluations, especially when associated with anomalous arterial branches and AVFs, allowing adequate treatment of these lesions.

MayThurner Syndrome Associated With KlippelTrenaunay Syndrome

We present an unusual case of a 23-year-old man who had symptomatic lower extremity varicosities that have been present since birth. He was complaining of pain and swelling of several years duration. Evaluation revealed Klippel-Trenaunay syndrome with associated compression of the left common iliac vein by the overriding left common iliac artery (May-Thurner syndrome). The patient was treated with left common iliac vein stenting followed by high ligation and inversion stripping of his grossly incompetent left small saphenous vein, stripping of his aberrant left lateral embryonic veins, and also by multiple stab phlebectomies, with excellent early result.

Prevalence of various congenital vascular malformations in patients with Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a condition defined by the association of three physical features: capillary malformation, varicosities, and hypertrophy of bony and soft tissues. However, KTS is characterized by congenital vascular malformations (CVMs) that are difficult to classify. Therefore, the present study was undertaken to analyze the various CVMs in patients with KTS. Sixty-one patients with KTS were enrolled, and their CVMs were divided into predominantly venous defects, predominantly lymphatic defects, and mixed vascular defects using the Hamburg Classification. Capillary malformations were subdivided into port-wine stain, telangiectasia, and angiokeratoma. Truncular and extratruncular vascular malformations were detected using duplex ultrasound and magnetic resonance imaging. Reflux in the superficial and deep venous systems was also evaluated. Forty-five patients (74%) had predominantly venous defects, four (6%) had predominantly lymphatic defects, and 12 (20%) had mixed vascular defects. Capillary malformations were detected in 54 patients (89%), among which port-wine stain was the most predominant (40 patients, 66%), followed by telangiectasia (31 patients, 51%) and angiokeratoma (18patients, 30%). Extratruncular venous malformations were detected in 47 patients (77%). In contrast, truncular venous malformations were found in 50 patients (82%). Among these, embryonic lateral marginal vein showed the highest occurrence, accounting for 53% (32 patients). However, reflux in this vein was detected in only nine patients (15%). Twelve patients (20%) had reflux in the great saphenous vein, and four (7%) had reflux in the small saphenous vein. Deep vein hypoplasia was found in seven patients (12%), and only five patients (8%) had deep vein aplasia. Extratruncular lymphatic malformations were found in 13 patients (21%) and truncular lymphatic malformations in 17 (28%). Patients with KTS have a variety of CVMs, but both extratruncular and truncular venous malformations continue to be targets for intervention.

The neglected emissary vein in mastoidectomy; persistent petrosquamosal sinus in the laterally located sigmoid sinus

The emissary veins are residual connections between intracranial venous sinuses and their extracranial drainage, which if not diagnosed preoperatively could be a cause of severe hemorrhage at the time of surgery which may be life threatening. The petrosquamosal emissary sinus (PSS) which is a rare embryonic emissary vein along the petrosquamosal fissure of the temporal bone connects dural sinuses with external jugular venous system. The PSS has been known to regress during fetal and early postnatal life. The imaging diagnosis of the PSS has been rarely reported in humans. We report the presence of the PSS with laterally located sigmoid sinus in patient with chronic otitis media. Our hope is that this report will be useful to the otologist during surgery.

Exploitation of chick embryo environments to reprogram MYCN-amplified neuroblastoma cells to a benign phenotype, lacking detectable MYCN expression

Neuroblastoma is a paediatric cancer that arises from the sympathetic ganglia (SG) or adrenal gland. Tumours that occur in patients under 18 months of age have a particularly good prognosis and frequently undergo spontaneous regression. This led to the hypothesis that developmental cues in the youngest patients may prompt belated differentiation and/or apoptosis of the tumour cells. To test our hypothesis, we have injected MYCN-amplified neuroblastoma cells into the extra embryonic veins of chick embryos at embryonic day 3 (E3) and E6 and analysed the response of these Kelly cells at E10 and E14. Amplification of the MYCN gene occurs in up to 30% of tumours and is normally associated with a very poor prognosis. Kelly cells injected at E3 follow neural crest pathways and integrate into neural locations such as SG and the enteric nervous system although never into the adrenal gland. Additionally they migrate to non-neural locations such as the heart, meninges, jaw regions and tail. The cells respond to their respective microenvironments and in SG, some cells differentiate, they show reduced cell division and crucially all cells have undetectable MYCN expression by E10. In non-neural locations, cells form more rapidly dividing clumps and continue to express MYCN. The downregulation of MYCN is dependent on continuous and direct interaction with the sympathetic ganglion environment. We propose that the MYCN-amplicon in the Kelly cells retains the ability to correctly interpret the environmental cues leading to downregulation of MYCN.

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

AbstractCOVER PHOTOGRAPH: Confocal image of live 36 hpf double transgenic appais22Gt; Tg(flk1:moesin‐gfp)is1 embryo. The image shows accumulation of appaRFP fusion proteins specifically at the veinous vessels in the head and anterior region of the trunk, including the midcerebral and common cardinal veins. Arteries and veins are visualized by expression of moesin:GFP throughout all endothelial cells of the vasculature. From Liao et al., Developmental Dynamics 241:415–425, 2012.

MiR-27b controls venous specification and tip cell fate

AbstractWe discovered that miR-27b controls 2 critical vascular functions: it turns the angiogenic switch on by promoting endothelial tip cell fate and sprouting and it promotes venous differentiation. We have identified its targets, a Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). miR-27b knockdown in zebrafish and mouse tissues severely impaired vessel sprouting and filopodia formation. Moreover, miR-27b was necessary for the formation of the first embryonic vein in fish and controlled the expression of arterial and venous markers in human endothelium, including Ephrin B2 (EphB2), EphB4, FMS-related tyrosine kinase 1 (Flt1), and Flt4. In zebrafish, Dll4 inhibition caused increased sprouting and longer intersegmental vessels and exacerbated tip cell migration. Blocking Spry2 caused premature vessel branching. In contrast, Spry2 overexpression eliminated the tip cell branching in the intersegmental vessels. Blockade of Dll4 and Spry2 disrupted arterial specification and augmented the expression of venous markers. Blocking either Spry2 or Dll4 rescued the miR-27b knockdown phenotype in zebrafish and in mouse vascular explants, pointing to essential roles of these targets downstream of miR-27b. Our study identifies critical role of miR-27b in the control of endothelial tip cell fate, branching, and venous specification and determines Spry2 and Dll4 as its essential targets.

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

The single spanning transmembrane amyloid precursor protein (APP) and its proteolytic product, amyloid-beta (Ab) peptide, have been intensely studied due to their role in the pathogenesis of Alzheimer's disease. However, the biological role of the secreted ectodomain of APP, which is also generated by proteolytic cleavage, is less well understood. Here, we report Tol2 red fluorescent protein (RFP) transposon gene trap integrations in the zebrafish amyloid precursor protein a (appa) and amyloid precursor-like protein 2 (aplp2) genes. The transposon integrations are predicted to disrupt the appa and aplp2 genes to primarily produce secreted ectodomains of the corresponding proteins that are fused to RFP. Our results indicate the Appa-RFP and Aplp2 fusion proteins are likely secreted from the central nervous system and accumulate in the embryonic veins independent of blood flow. The zebrafish appa and aplp2 transposon insertion alleles will be useful for investigating the biological role of the secreted form of APP.

Rapid in vivo testing of drug response in multiple myeloma made possible by xenograft to turkey embryos

Background:The best current xenograft model of multiple myeloma (MM) in immune-deficient non-obese diabetic/severe-combined immunodeficient mice is costly, animal maintenance is complex and several weeks are required to establish engraftment and study drug efficacy. More practical in vivo models may reduce time and drug development cost. We recently described a rapid low-cost xenograft model of human blood malignancies in pre-immune turkey. Here, we report application of this system for studying MM growth and the preclinical assessment of anticancer therapies.Methods:Cell lines and MM patient cells were injected intravenously into embryonic veins on embryonic day 11 (E11). Engraftment of human cells in haematopoietic organs was detected by quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry and circulating free light chain.Results:Engraftment was detected after 1 week in all embryos injected with cell lines and in 50% of those injected with patient cells. Injection of bortezomib or lenalinomide 48 h after cell injection at therapeutic levels that were not toxic to the bone marrow dramatically reduced MM engraftment.Conclusion:The turkey embryo provides a practical, xenograft system to study MM and demonstrates the utility of this model for rapid and affordable testing therapeutics in vivo. With further development, this model may enable rapid, inexpensive personalised drug screening.