Immature Endothelial Cells Research Articles

Generation of human iPSC-derived 3D bile duct within liver organoid by incorporating human iPSC-derived blood vessel

In fetal development, tissue interaction such as the interplay between blood vessel (BV) and epithelial tissue is crucial for organogenesis. Here we recapitulate the spatial arrangement between liver epithelial tissue and the portal vein to observe the formation of intrahepatic bile ducts (BDs) from human induced pluripotent stem cells (hiPSC). We co-culture hiPSC-liver progenitors on the artificial BV consisting of immature smooth muscle cells and endothelial cells, both derived from hiPSCs. After 3 weeks, liver progenitors within hiPSC-BV-incorporated liver organoids (BVLO) differentiate to cholangiocytes and acquire epithelial characteristics, including intercellular junctions, microvilli on the apical membrane, and secretory functions. Furthermore, liver surface transplanted-BVLO temporarily attenuates cholestatic injury symptoms. Single cell RNA sequence analysis suggests that BD interact with the BV in BVLO through TGFβ and Notch pathways. Knocking out JAG1 in hiPSC-BV significantly attenuates bile duct formation, highlighting BVLO potential as a model for Alagille syndrome, a congenital biliary disease. Overall, we develop a novel 3D co-culture method that successfully establishes functional human BDs by emulating liver epithelial-BV interaction.

CENPF May Act as a Novel Marker and Highlight the Influence of Pericyte in Infantile Hemangioma.

Infantile hemangioma (IH), a benign microvascular tumor, is marked by early and extensive proliferation of immature hemangioma endothelial cells (Hem-ECs) that naturally regress through differentiation into fibroblasts or adipocytes. However, a challenge persists, as the unique biological behavior of IH remains elusive, despite its general sensitivity to propranolol treatment. Recent evidence suggests that abnormal volume proliferation in IH is primarily attributed to the accumulation of hemangioma pericytes (Hem-Pericytes), in addition to Hem-ECs. Centromere protein F (CENPF) is involved in regulating mitotic processes and has been associated with malignant tumor cell proliferation. It is a key player in maintaining genomic stability during cell division. Our findings revealed specific expression of CENPF in Hem-Pericytes, with a proliferation index (PI) approximately half that of Ki67 (3.28 vs 6.97%) during the proliferative phase of IH. This index decreased rapidly in the involuting phase (P < .05), suggesting that the contribution of pericytes to IH development was comparable to that of Hem-ECs. Tumor expansion and shrinkage may be due to the proliferation, reduction, and differentiation of Hem-Pericytes. In conclusion, we speculate CENPF as a novel marker for clinical pathological diagnosis and a potential therapeutic target, fostering advancements in drug development.

Lead toxicity

Lead is a heavy metal. It is frequently used in life as a result of its distinct physical and chemical features. It is, nonetheless, a hazardous and widespread heavy metal. Lead is not only a common occupational and environmental toxin, but it also has a significant effect on children's brain development. Additionally, despite the fact that studies on the biochemical and molecular mechanisms underlying lead's harmful effects are still lacking, some research suggests that there may be indirect mechanisms at play. By examining lead's effects on various human body parts and therapeutic strategies for lead poisoning, this essay highlights the pathogenic factors and responses of lead on human tissues. As a result of lead's ability to quickly cross the blood-brain barrier and the growing brain's immature endothelial cells, the data demonstrate that lead is particularly detrimental to the central nervous system. The creation of synaptic connections and neuronal migration are significantly influenced by the normal growth of glial cells. Glial cells may prematurely differentiate as a result of lead exposure, impairing their ability to communicate with neurons. Lead appears to have genotoxic effects not just directly but also indirectly through free radical generation or DNA repair inhibition. The current study provides useful information for future toxicological research on lead poisoning.

The hepatic extramedullary hematopoiesis during experimental murine Schistosomiasis mansoni.

Many years ago, our research group has demonstrated extramedullary hematopoiesis in the peripheral zone of murine hepatic schistosomal granulomas. In the present study, we revisit this phenomenon using new technical and conceptual approaches. Therefore, newborn mice were percutaneously infected by Schistosoma mansoni cercariae and euthanized between 35- and 60-days post infection. Liver samples were submitted to histopathology and immunohistochemical analyses. Cells under mitosis and/or expressing Ki67 demonstrated the proliferation of hematopoietic cells both around the parasite’s eggs trapped in the liver and around hepatic vessels. After 50 days post infection, proliferating cells at different levels on differentiation were located preferentially in the peripheral zone of the granulomas, around the vessels and inside the sinusoids. The presence of acidic and sulfated glycoconjugates, reticular fibers and the absence of fibronectin characterized the microenvironment for attraction and maintenance of hematopoiesis. Some neutrophils secreted MMP9 from the earliest points of infection, indicating degradation of the extracellular matrix in regions of histolysis and a possible chemoattraction of hematopoietic stem cells to the liver. Fall-3+ cells and Sca-1+ cells indicated that early hematopoietic progenitors could be mobilized to the liver. Groups of vWF+ megakaryocytes suggest chemoattraction of these cells and/or migration, proliferation, and differentiation of very immature progenitors to this organ. The increase of blood vessels and extramedullary hematopoiesis in this environment, where markers of immature hematopoietic and endothelial cells have been identified, points to the possibility of the presence of progenitors for endothelial and hematopoietic cells in the liver during the infection. There is also the possibility of concomitant migration of more differentiated hematopoietic progenitors, that proliferate and differentiate in the liver, and the occurrence of angiogenesis caused by inflammation or release of ovular antigens that stimulate the activation and proliferation of endothelial cells. Altogether, these data increase knowledge about a murine model that is of interest for investigating the pathology of the schistosomiasis and also the dynamics of hematopoiesis.

Role of Stromal Cell-Derived Factor-1 in Endothelial Progenitor Cell-Mediated Vascular Repair and Regeneration.

Endothelial progenitor cells (EPCs) are immature endothelial cells that participate in vascular repair and postnatal neovascularization and provide a novel and promising therapy for the treatment of vascular disease. Studies in different animal models have shown that EPC mobilization through pharmacological agents and autologous EPC transplantation contribute to restoring blood supply and tissue regeneration after ischemic injury. However, these effects of the progenitor cells in clinical studies exhibitmixed results. The therapeutic efficacy of EPCs is closely associated with the number of the progenitor cells recruited into ischemic regions and their functional abilities and survival in injury tissues. In this review, we discussed the regulating role ofstromal cell-derived factor-1(also known CXCL12, SDF-1) in EPC mobilization, recruitment, homing, vascular repair and neovascularization, and analyzedthe underlying machemisms of these functions. Application of SDF-1 to improve the regenerative function of EPCs following vascular injurywas also discussed. SDF-1plays a crucial role in mobilizing EPC from bone marrowinto peripheral circulation, recruiting the progenitor cells to target tissue and protecting against cell death under pathological conditions; thus improve EPC regenerative capacity. SDF-1 are crucial for regulating EPC regenerative function, andprovide a potential target for improve therapeutic efficacy of the progenitor cells in treatment of vascular disease.

Case report: risk of skin necrosis related to injectable vancomycin in critically ill newborn infants

BackgroundVancomycin is commonly used as part of empiric antibiotic therapy in the preterm infants who develop signs and symptoms of infection. Although skin necrosis has been noted to occur following injection of vancomycin into a peripheral vein in an adult patient, this complication has not been previously described in a preterm infant.Case presentationWe report the case of a very low birthweight male infant born at 30 weeks gestational age who developed skin necrosis, most likely as a complication of vancomycin administration via a peripheral venous catheter. The immature skin and endothelial cells of this preterm infant may have increased the risk of drugs related venous and skin toxicity. In this case, assumption of a cumulative toxicity with other drugs administered concomitantly via the same catheter can’t be excluded.ConclusionsTo prevent the risk of skin damage, we advocate that in newborn infants, the administration of vancomycin should be limited to a concentration of < 2.5 mg/mL via a peripheral intravenous catheter if a central venous catheter is not available.

Coordination of endothelial cell positioning and fate specification by the epicardium

The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.

Neovascularization and tissue regeneration by endothelial progenitor cells in ischemic stroke

Endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) capable of proliferating and differentiating into mature ECs. These progenitor cells migrate from bone marrow (BM) after vascular injury to ischemic areas, where they participate in the repair of injured endothelium and new blood vessel formation. EPCs also secrete a series of protective cytokines and growth factors that support cell survival and tissue regeneration. Thus, EPCs provide novel and promising potential therapies to treat vascular disease, including ischemic stroke. However, EPCs are tightly regulated during the process of vascular repair and regeneration by numerous endogenous cytokines that are associated closely with the therapeutic efficacy of the progenitor cells. The regenerative capacity of EPCs also is affected by a range of exogenous factors and drugs as well as vascular risk factors. Understanding the functional properties of EPCs and the factors related to their regenerative capacity will facilitate better use of these progenitor cells in treating vascular disease. Here, we review the current knowledge of EPCs in cerebral neovascularization and tissue regeneration after cerebral ischemia and the factors associated with their regenerative function to better understand the underlying mechanisms and provide more effective strategies for the use of EPCs in treating ischemic stroke.

TNF\u03b1 priming through its interaction with TNFR2 enhances endothelial progenitor cell immunosuppressive effect: new hope for their widespread clinical application

BackgroundBone marrow derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNFα is one of the main mediators of EPC activation that recognizes two distinct receptors, TNFR1 and TNFR2. We have recently reported that human EPCs are immunosuppressive and this effect was TNFα-TNFR2 dependent. Here, we aimed to investigate if an adequate TNFα pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatory functions.MethodsEPCs were pre-treated with several doses of TNFα to find the proper dose to up-regulate TNFR2 while keeping the TNFR1 expression stable. Then, co-cultures of human EPCs and human T cells were performed to assess whether TNFα priming would increase EPC immunosuppressive and immunomodulatory effect.ResultsTreating EPCs with 1 ng/ml TNFα significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNFα priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, blocking TNFR2 using anti-TNFR2 mAb followed by 1 ng/ml of TNFα treatment led to the TNFα-TNFR1 interaction and polarized EPCs towards pro-inflammatory and immunogenic functions.ConclusionsWe report for the first time the crucial impact of inflammation notably the TNFα-TNFR signaling pathway on EPC immunological function. Our work unveils the pro-inflammatory role of the TNFα-TNFR1 axis and, inversely the anti-inflammatory implication of the TNFα-TNFR2 axis in EPC immunoregulatory functions. Priming EPCs with 1 ng/ml of TNFα prior to their administration could boost them toward a more immunosuppressive phenotype. This could potentially lead to EPCs’ longer presence in vivo after their allogenic administration resulting in their better contribution to angiogenesis and vascular regeneration.6Hzxhpu_E57htd_nED83pdVideo

Differentiation and Pro-Angiogenic Potential of Infantile Hemangioma Stem Cells

ABSTRACT Objectives Infantile hemangioma (IH) is defined as a benign vascular tumor composed of immature vascular endothelial cells, with the unique characteristics of rich vascularization and self-regression into fibro-fatty tissue. CD133-positive hemangioma stem cells (HemSCs), present in the proliferating IH tissue, can be used to establish the IH animal model, which has highlighted the pathogenesis of IH in recent years. This study focused on the biological characteristics and differentiation capacity of HemSCs and aimed to provide a theoretical possibility for its application in tissue engineering. Methods To further confirm our hypothesis, we used fluorescence-activated cell sorting (FACS), in vitro multipotent induced differentiation, angiogenesis assay, and antibody array to identify the surface markers, multipotent differential potential, angiogenesis potential, and secreted factors of HemSCs, respectively, utilizing human adipose stem cells(hADSCs) as the control. Results We successfully isolated and cultured HemSCs. FACS indicated that, on average, more than 80% of HemSCs matched the criteria of mesenchymal stem cell (MSC) surface markers. Our results confirmed that HemSCs could differentiate into adipocytes, osteocytes, and chondrocytes. Additionally, compared with fibroblasts or hADSCs, HemSCs could promote angiogenesis through para-secretion. Conclusions HemSCs may originate from normal MSCs, and owing to their powerful proliferative and angiogenic abilities, they could be considered an IH pathogenic factor. These characteristics demonstratet heir potential as a candidate seed cell in tissue engineering.

Isolation of induced pluripotent stem cell-derived endothelial progenitor cells from sac-like structures

Transplanted endothelial progenitor cells (EPCs) repair blood vessels and exert regenerative effects on disorders such as lower limb ischemia. EPCs serve as a model for pathophysiological and pharmacokinetic studies, which is important for drug discovery. However, primary human EPCs are phenotypically unstable, which limits their clinical utility. Therefore, we employed human induced pluripotent stem (iPS) cells to circumvent this problem. Here we focused on human iPS cell-derived sac-like structures (iPS-sacs), which contain endothelial lineage cells and hematopoietic lineage cells. Previous studies isolated only hematopoietic lineage cells from iPS-sacs. Therefore, here we attempted to isolate EPCs. However, iPS-sacs generated by a published protocol did not contain sufficient EPCs. Therefore, to generate iPS-sacs highly enriched in EPCs, we added the glycogen synthase kinase 3 beta (GSK3β) inhibitor CHIR-99021 to the culture medium early during differentiation. The cells rapidly differentiated into mesoderm to yield abundant EPCs, and CHIR-99021 increased the proportion of EPCs contained in iPS-sacs. EPCs, which were purified using anti-platelet endothelial cell adhesion molecule (PECAM1) antibody-conjugated beads, expressed markers of immature endothelial cells. Purified EPCs formed tube-like structures and incorporated acetylated low density lipoprotein (Ac-LDL), reflecting endothelial phenotypes. The simple method described here will likely improve regenerative medicine and facilitate basic studies on the endothelial lineage.

Endothelial Progenitor Cells and Liver Cirrhosis

Endothelial progenitor cells (EPCs) are immature endothelial cells. Experiments showed that endothelial progenitor cell function was impaired in liver fibrosis [1].

Endothelial Progenitor Cells and Notch-1 Signaling as Markers of Alveolar Endothelium Regeneration in Pulmonary Emphysema.

We studied the effects of elastase, cigarette smoke extract, D-galactosamine hydrochloride, and tyrosine kinase inhibitor SU5416 on endothelial progenitor cells and angiogenesis precursors, as well as on Notch-1 expression by immature endothelial cells. Simultaneously with pulmonary emphysema, different damaging factors with diverse mechanisms of action caused pathological changes in the microvascular network of the lungs and destroyed the alveolar endothelium in female C57Bl/6 mice. D-galactosamine hydrochloride disturbed mobilization of endothelial progenitor cells expressing VEGFR (CD45-CD309+) and angiogenesis progenitors (CD45-CD309+CD117+) and their migration into emphysema expanded lungs. Elastase inhibited VEGFR-expressing endothelial progenitor cells, while cigarette smoke extract inhibited cells with CD45-CD31+CD34+ phenotype. In pulmonary emphysema provoked by elastase or D-galactosamine hydrochloride, angiogenesis was provided by endothelial cells with CD45-CD31+CD34+ phenotype, whereas in emphysema modeled with SU5416 or cigarette smoke extract, it was provided by the endothelial VEGFR-expressing cells and mature CD31+ endothelial cells, respectively. Replenishment of immature endothelial cells damaged by elastase and SU5416 involved Notch-1+ angiogenesis precursors and Notch-1+ endothelial progenitor cells with VEGFR.

133. The role of vitamin D in cell-cell interaction of endothelial cells and trophoblasts in a preeclampsia-like model

Objective The obstetric history of women is an important part of their cardiovascular risk profile, but also of their offspring. Preeclampsia is a separate, independent risk factor. We hypothesize that fetal endothelial cell functional limitations can already be demonstrated in pregnancies complicated by preeclampsia and that therapeutic use, e.g. with 1.25 (OH)2 Vitamin D3 can balance the negative effects of preeclampsia on cell function. Methods Human umbilical venous endothelial cells (HUVEC) and endothelial colony-forming cells (ECFC) were obtained from umbilical veins and cord blood. Furthermore, a trophoblast cell line (HTR8-SVneo) as well as human uterine venous endothelial cells (HUtMVEC) were available. Serum from uncomplicated and preeclamptic pregnancies was collected. Functional properties such invasion and migration as well as cell interaction of endothelial cells and trophoblasts were investigated with or without 1,25 (OH)2 vitamin D3 treatment. Results In a co-culture and invasion model of HUVEC and ECFC as well as of HUtMVEC and HTR8, the simulation of preeclampsia-like conditions led to a reduced invasion of ECFC or trophoblasts into an endothelial cell monolayer consisting of mature endothelial cells. Vitamin D neutralized the evoked negative effects on functional properties. Furthermore, immunocytochemical studies revealed a cell-cell interaction between immature and mature endothelial cells as well as mature endothelial cells and trophoblasts. Discussion Limited functional capacity of fetal endothelial cells under preeclamptic conditions suggests that pathogenic factors of the dysfunctional placenta adversely affect fetal endothelial cells and thus contribute intracellularly to cellular changes. Physiological concentrations of vitamin D promote important cell functions of endothelial cells. Whether the observed cellular changes persist in the neonatal period and childhood and are a possible early marker of an increased cardiovascular risk of the progeny of preeclamptic pregnancies has to be investigated by further studies.

Intracellular interactions of serum-derived C3 in human B cells – Regulation of gene transcription

For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency.The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group.The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day.

&lt;b&gt;Pathological and immunohistochemical studies on hemangiosarcoma in tigers &lt;I&gt;Panthera tigris&lt;/I&gt; and lions &lt;I&gt;Panthera Leo&lt;/I&gt;&lt;/b&gt;

Five cases of hemangiosarcoma were documented in three tigers and two lions during post-mortem examinations. Grossly, reddish-black coloured elevated masses were noticed with metastasis to the spleen. In one tiger, an enlarged liver with severe oozing of blood on a cut section was noticed without any elevated masses. In a white tiger, the tumour mass was located near the abdominal region. Histopathological features revealed the presence of immature plump endothelial cells forming blood filled irregular vascular spaces. Immunohistochemically, strong immunoreactivity in the cytoplasm of neoplastic endothelial cells with vascular endothelial growth factor (VEGF) was noticed. No positive reaction was noticed with the proliferative markers, i.e., Ki67 and p53, indicating VEGF is the appropriate marker to diagnose hemangiosarcoma.

Stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties.

Hemangioblastoma is composed of neoplastic stromal cells and a prominent capillary network. To date, the identity of stromal cells remains unclear. Mesenchymal stem cells can give rise to committed vascular progenitor cells, and ephrin-B2/EphB4 and Notch signaling have crucial roles in these steps. The aim of our study was to elucidate that stromal cells of central nervous system hemangioblastomas have mesenchymal stem cell-derived vascular progenitor cell properties. Ten hemangioblastomas were investigated immunohistochemically. CD44, a mesenchymal stem cell marker, was detected in stromal cells of all cases, suggesting that stromal cells have mesenchymal stem cell-like properties. Neither CD31 nor α-SMA was expressed in stromal cells, suggesting that stromal cells have not acquired differentiated vascular cell properties. Both ephrin-B2 and EphB4, immature vascular cell markers, were detected in stromal cells of all cases. Jagged1, Notch1, and Hesr2/Hey2, which are known to be detected in both immature endothelial cells and mural cells, were expressed in stromal cells of all cases. Notch3, which is known to be detected in differentiating mural cells, was also expressed in all cases. These results suggest that stromal cells also have vascular progenitor cell properties. In conclusion, stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties.

Assessment of Micro-vessel Density in Brain Glioma by CD105 Expression

Micro-vascular proliferation is an important histological feature of brain glioma with more vascular proliferation is present in higher grades of glioma. CD 105 is expressed in new actively proliferating and immature endothelial cells in tumor environment and appears to be capable to distinguish between malignant neo-vasculature and normal vessels. This study was designed to evaluate the Micro-Vessel Density(MVD) in different grades of brain glioma based on CD 105 expression byImmunohistochemistry method to determine whether it can be a helpful marker for rumor grading or not.Paraffin blocks of formalin fixed samples of brain astrocyticglioma were retrieved and IHC was performed using anti-CD105 monoclonal mouse antibody. Total number of 48cases of low and high grade astrocyticgliomas were evaluated.We noted that there was a positive correlation between MVD evaluated by CD105 and tumor grade, meaning that expression was significantly greater in tumors with higher grade (P=0.019). We concluded that MVD quantified by CD 105 has positive correlation with tumor grade. Also we think that expression of CD 105 specially in low-grade glioma can serve as a basis for selective treatment option in combination with current standard care.

Co-expression of tissue factor and IL-6 in immature endothelial cells of cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are congenital abnormal clusters of capillaries that are prone to leaking and thought to result from a disorder of endothelial cells. The underlying pathology of CCM is not fully understood. We analyzed the expression of tissue factor (TF) and interleukin-6 (IL-6) in CCMs to determine the association of TF and IL-6 with clinical and pathological findings. Thirteen cases of operative specimens of sporadic CCMs were included in this study. The expression of messenger RNA of TF and IL-6 was assayed and the association with clinical factors was investigated. Then, the distribution of TF and IL-6 was examined with immunofluorescence. The mRNA expression of TF of CCMs was significantly higher than that of the control (p=0.017), and was correlated with the number of hemorrhage appearances (p=0.190, ρ=0.62). The mRNA expression level of IL-6 was significantly correlated with the mRNA expression level of TF (p=0.034, ρ=0.58). Examination of immunostained sections indicated that TF+ cells were also positive for IL-6, and distributed around normal endothelial cells. Moreover, the TF+/IL-6+ cells expressed CD31 and VEGFR2. The expressions of IL-6 and TF were correlated, and both were present in the same immature endothelial cells. TF is elevated in CCM and might mediate progressive events. These factors may play a prognostic role in CCM.

Combretastatins: In vitro structure-activity relationship, mode of action and current clinical status.

For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency. The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group. The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day.