285, 1182–1186. Biol. (2018). J. In this specific oncological situation, it is imperative that after the resection of the metastatic site the future remnant liver can cope with its normal homeostatic functions and hemodynamic stress. ECs of large embryonic vessels like the precursors of portal veins express CD34 and are surrounded by a tenascin-rich matrix, whereas the precursors of sinusoids, such as the capillary vessels of septum transversum, still behave like a continuous endothelium and are generally surrounded by a laminin-1-rich matrix (Gouysse et al., 2002). Although tumor vessels remodeling is often characterized by the physical repositioning of the cellular components, molecular alterations often accompany the process (Farnsworth et al., 2014). (2010). Macrophages, which usually are critical effector cells in immune response, can support tumor progression (Quail and Joyce, 2013). RNA-Seq transcriptome profiling in three liver regeneration models in rats: comparative analysis of partial hepatectomy. Nat. 6300. Thus, a continuous endothelium with varying levels of occluding junctions is present in those areas. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. doi: 10.1002/1878-0261.12022, De Bock, K., Georgiadou, M., Schoors, S., and Kuchnio, A. A molecular atlas of cell types and zonation in the brain vasculature. Further gene signature analysis proved the existence of proliferating ECs and tip cells, but also three new EC populations. Limitations to the novel marker gene identification should be kept in mind, as consolidating orthogonal studies confirming the in silico findings are yet to be published. According to the IMPOwer 150 (NCT02366143) study, patients from all subgroups with metastasized non-squamous NSCLC, which were previously defined by their PD-L1 expression, benefited from additional treatment with bevacizumab. Note: This only includes people who have Public Search Listings available on … Cancer Biol. Microcirculation 27:e12587. Angiogenesis 22, 355–368. First, the activation of more than 100 genes which are generally silenced during homeostasis can be observed. J. Res. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. In this situation metastases access their blood supply via co-option, meaning that tumor cells receive oxygen and nutrients from pre-existing vessels, like e.g., the hepatic sinusoids (van Dam et al., 2017). These arteries turn into their muscular counterparts, which are less elastic with the primary focus on withstanding the blood pressure. 11:591901. doi: 10.3389/fphys.2020.591901. VEGF and Notch in Tip and Stalk Cell Selection. In their study, scRNAseq of murine aorta found the existence of seven subclusters within the designated SMC population, supporting the understanding that SMCs are highly heterogeneous. The Official Whitepages. doi: 10.1038/nm1101-1194. (2009). One population showed signatures of transitioning from a postcapillary venule (PCV) to an angiogenic phenotype, whilst the other two populations were termed immature and maturing ECs (Rohlenova et al., 2020). Regen. Angiogenesis can be distinguished in two main different processes: intussusceptive microvascular growth (Ribatti and Djonov, 2012) and sprouting angiogenesis. (2018) studied the transcriptional identity of mural vessel cells such as pericytes and SMC. doi: 10.1056/NEJMoa1716948, Strasser, G. A., Kaminker, J. S., and Tessier-Lavigne, M. (2010). Nat. So ZaJac. The authors further detected an upregulation of Ehd3, which was suggested as a gene-specific marker to glomerular ECs by previous studies (George et al., 2011; Karaiskos et al., 2018). These findings indicate that neovascularization might originate in PCVs as previously predicted by morphological evidences (Folkman, 1982; Rohlenova et al., 2020). doi: 10.1016/s0002-9440(10)64 920-6, Mruk, D. D., and Cheng, C. Y. Thromb. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Write your message of sympathy today. Articles, National Autonomous University of Mexico, Mexico. Patel, J., Seppanen, E. J., Rodero, M. P., Wong, H. Y., Donovan, P., Neufeld, Z., et al. 31, 151–159. Piccone Mary J Estate. Ordinarily, constriction of the thin smooth muscle lamellae allows only 25% of the capillary bed to be perfused (Boron and Boulpaep, 2003; Drake et al., 2015). doi: 10.1038/ncb3036, Shenoy, P. S., and Bose, B. Abnormalities of Basement Membrane on Blood Vessels and Endothelial Sprouts in Tumors. doi: 10.1371/journal.pone.0017838, Gerhardt, H., Golding, M., Fruttiger, M., Ruhrberg, C., Lundkvist, A., Abramsson, A., et al. doi: 10.1073/pnas.0611206104. Sem. Rev. Bioinformatics 21, 2301–2308. One of the most common is neoangiogenesis, which is driven mainly by VEGF. The following paragraph reports on these findings. Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., et al. Therefore, CSF-1 might be a new possible target in oncology. (93 years old). Vascular heterogeneity between different organs and tissues: chart of genes differentially upregulated in endothelial cells in various tissues of the body. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Most of the liver’s blood supply comes from the portal vein (approx. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Cancer Treat Res. Pape, H.-C., Kurtz, A., and Silbernagl, S. (2014). Daneshmanesh, A. H., Hojjat-Farsangi, M., Ghaderi, A., Moshfegh, A., Hansson, L., Schultz, J., et al. doi: 10.1016/j.pharmthera.2016.11.008. Differential endothelial transcriptomics identifies semaphorin 3G as a vascular class 3 semaphorin. Physiologie. Neuro Oncol. Rev. Colak, D., Al-Harazi, O., Mustafa, O. M., Meng, F., Assiri, A. M., Dhar, D. K., et al. 1629. Perspect. 213, 286–300. (2019). (2018). 16, 931–941. (2005). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Angiogenesis: initiation and control. Cell Stem Cell 4, 263–274. Echovita offers a solidarity program that gives back the funds generated to families. doi: 10.1158/0008-5472.CAN-17-2728, Keywords: vasculature, heterogeneity, microenvironment, liver metastases, angiogenesis, vessel co-option, Citation: Fleischer JR, Jodszuweit CA, Ghadimi M, De Oliveira T and Conradi L-C (2020) Vascular Heterogeneity With a Special Focus on the Hepatic Microenvironment. Aird, W. C. (2012). Single Cell Analysis of Endothelial Cells Identified Organ-Specific Molecular Signatures and Heart-Specific Cell Populations and Molecular Features. 48, 347–356. Vascular Cellular Adhesion Molecule-1 (VCAM-1) Expression in Mice Retinal Vessels Is Affected by Both Hyperglycemia and Hyperlipidemia. Lyden, D., Hattori, K., Dias, S., Costa, C., Blaikie, P., Butros, L., et al. Cold Spring Harb. Thromb. Hence, only a summary of the process of neoangiogenesis will be addressed (for further reading see references Carmeliet, 2003; Blanco and Gerhardt, 2013; Minami et al., 2019). Besides detecting the transcriptome signature of previously described EC subpopulations, Goveia et al. They further identified that single subclusters are locally expressed, describing Pde1c and Hand2 as marker genes of SMC for the aortic arch region, whilst Hoxa7 was expressed in the descending thoracic aorta (Dobnikar et al., 2018). Caller Number Number Detail; 717-510-9856: Saverio Schueth - Paxton Church Rd, Harrisburg, Pennsylvania: 717-510-5979: Zarayah Rocafort - Saint Thomas Blvd, Harrisburg, Pennsylvania Pathological process of liver sinusoidal endothelial cells in liver diseases. Growth of tumor vasculature is not only driven by VEGF, but a dysregulated ensemble of many factors, such as angiopoietins, platelet-derived growth factor, and transforming growth factor families (Carmeliet and Jain, 2011a). 1:18. 104, 3219–3224. Rep. 10:4392. (2020). Conflicting, it has been already proven that some solid tumors and their metastases do not benefit from anti-angiogenic therapy (Hurwitz et al., 2004). (2011). West, H., McCleod, M., Hussein, M., Morabito, A., Rittmeyer, A., Conter, H. J., et al. Amongst all, sprouting angiogenesis receives most of the attention and is the prime model, on how growing tissues sustain themselves with nutrients and oxygen. It has been previously shown that one possible reason for this difference is that tumor endothelial cells are exposed to extremely high amounts of VEGF from tumor cells and tumor-associated fibroblasts (Jain, 2014). Examining murine brain vessel samples, Vanlandewijck et al. Thromb. Author Correction: Resolving genetic heterogeneity in cancer. Contrarily, they have a bigger lumen compared to arteries and store up to 80% of the total blood volume. Differentially expressed genes in different tissues. Interestingly, comparing ECs from four different murine tissues, Sabbagh et al. doi: 10.1055/s-0037-1617455, Díaz-Coránguez, M., Ramos, C., and Antonetti, D. A. Would you like to offer Marilyn A. Oldach’s loved ones a condolence message? In an effort to study heterogeneity within PCs, Vanlandewijck et al. Utilizing a pre-clinical murine model of laser-induced CNV they obtained tissue which was consecutively sequenced at single-cell resolution. 4197, Galjart, B., Nierop, P. M. H., van der Stok, E. P., van den Braak, R., Hoppener, D. J., Daelemans, S., et al. Dobnikar, L., Taylor, A. L., Chappell, J., Oldach, P., Harman, J. L., Oerton, E., et al. Physiologically, the turnover of quiescent ECs is measured in years (Bergers and Benjamin, 2003). Nevertheless, Ehd3 can be used as a glomerular EC marker gene within kidney cells. Sorting points into neighborhoods (SPIN): data analysis and visualization by ordering distance matrices. Lukowski, S. W., Patel, J., Andersen, S. B., Sim, S.-L., Wong, H. Y., Tay, J., et al. Coll. 78, 2370–2382. After toxic damage or loss of hepatic tissue, the liver enters, a still not completely understood, process that cumulates in its restorage in size, via hyperplastic growth (Mao et al., 2014). The gradual decline in expression of genes along with the projection proved that ECs are exhibiting a continuous phenotype, coined zonation (Vanlandewijck et al., 2018), rather than showing discreet phenotypes. It is important to understand the interaction between the tumor or metastases and the microenvironment, to develop new therapeutic approaches. 37, 173–187. In skeletal muscle, Ssh2, and Nrp1 were found highly expressed (Kalucka et al., 2020). (2019). (2014). Tmem100, a transmembrane protein responsible for developmental endothelial differentiation and vascular morphogenesis and regulation of nociception, was identified as a marker gene to be exclusively expressed in lung tissue (Kalucka et al., 2020). Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Sprouting angiogenesis has also been named one of the hallmarks of cancer, thus underlining, that this physiological process is highjacked in many pathologies. A., and Dvorak, H. F. (2012). Whitepages is the authority in people search, established in 1997. doi: 10.18632/oncotarget.23760, Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., and Zlokovic, B. V. (2019). (2008). 4631. Table 3. Notably, also ECs can directly contribute to hepatic regeneration, as in vivo data generated with Id-1-deficient mice show, which present reduced number of liver sinusoidal EC, demonstrated that upon hepatic damage this population releases angiocrine factors, such as Wnt2 and HGF, triggering hepatocyte proliferation and liver regeneration (Ding et al., 2010). It has been shown that hepatic stellate cells have the ability to sense hypoxia and subsequently release VEGF which further increases angiogenesis. Daneman, R., and Prat, A. Bentley, K., Mariggi, G., Gerhardt, H., and Bates, P. A. Role of PFKFB3-Driven Glycolysis in Vessel Sprouting. Sci. To achieve that, the use of hepatic portal vein embolization (PVE) has been employed since the 1990’s (Makuuchi et al., 1990). Importantly, when pseudo-time analysis was performed on lung tumor ECs that were previously collected by an affiliated author (Goveia et al., 2020), the same trajectory was found as in Rohlenovas’ (Rohlenova et al., 2020) CNV-EC samples. 1430. Michalopoulos, G. K., and DeFrances, M. C. (1997). In a study evaluating KRAS mutational status, it was observed that 6.8% of the evaluated metastatic sites differ between themselves. Vascular development and differentiation during organogenesis are driven by different aspects like cytokine activity (e.g., by VEGF, Interleukins), and the cellular microenvironment composition, including components of the extracellular matrix-like integrins (Risau, 1997). Molecular mechanisms and clinical applications of angiogenesis. (2018). The hepatic microenvironment is composed by a complex and interconnected group of highly specialized cells. Minami, T., Muramatsu, M., and Kume, T. (2019). doi: 10.1089/ten.2005.11.257, Gustavsson, C., Agardh, C.-D., Zetterqvist, A. V., Nilsson, J., Agardh, E., and Gomez, M. F. (2010). Pericytes that usually take part in vessel regulation are not only scarce in tumor-associated vessels, but also shown to be mutated, leading to vascular malformations (Morikawa et al., 2002; Bergers and Song, 2005; Viallard and Larrivée, 2017). (2019). You can add a photo to pay tribute to Marilyn A. Oldach. Proc. Alphen aan den Rijn: Wolters Kluwer. This review first wants to recapitulate microscopic features of the body’s vessels as a brief introduction to the topic of vascular heterogeneity by connecting it to familiar knowledge. Cell Stem Cell 3, 301–313. Maturing cells, which are also termed phalanx cells, overexpressed a Notch signaling signature. The same study further evaluated commonly shared markers, which are also overexpressed in different tumor ECs originating in different tissues (Rohlenova et al., 2020). Development 136, 4001–4009. Chem. Cancer Res. 1611. Farnsworth, R. H., Lackmann, M., Achen, M. G., and Stacker, S. A. The third cluster that was identified was understood to be a subcluster of the arteriolar BMECs. Intussusceptive microvascular growth in tumors. 163, 352–362. This leakiness can cause edema due to plasma extravasation which can significantly slow down blood flow as erythrocytes concentrated and interstitial hypertension increases (Jain, 2014). In the microcirculation small arterioles regulate the perfusion of the vascular bed. 42, 1149–1160. This is the mail archive of the gcc@gcc.gnu.org mailing list for the GCC project. Arterioscler. When comparing healthy murine ECs and ECs from eyes that underwent laser treatment they observed the existence of a distinct subcluster in CNV. Acad. Patterns 5, 123–127. EVPs express a stringent surface marker profile CD34+ CD45– CD31lo VEGFR2– and increased expression of VEGFR2 and CD31 when transitioning to definitive differentiated ECs (Lukowski et al., 2019). 3.7m Followers, 808 Following, 2,303 Posts - See Instagram photos and videos from Lena (@lenameyerlandrut) (2018). (2018). 8, 464–478. 2. 23, 7666–7677. (2017). Lastly, Abcc9, which was used as a marker for murine venous SMC and pericytes, was also found in a zebrafish line labeling mural cells in capillaries and veins, backing the conservation mechanism (Vanlandewijck et al., 2018). Histology : a text and atlas : with correlated cell and molecular biology, 8 Edn. Renal Thrombotic Microangiopathy in Mice with Combined Deletion of Endocytic Recycling Regulators EHD3 and EHD4. Biol. Copyright © 2021 Echovita Inc. All rights reserved. doi: 10.1038/nature09493. Res. (1998). All blood vessels can be characterized according to their function in transporting blood and nutrients (Pawlina, 2020). Nat. The afferent blood supply of the adult liver is made up mainly by the portal vein and the hepatic artery (Pawlina, 2018). Tumor angiogenesis: therapeutic implications. J. Tissue Eng. Cold Spring Harb. 36, 564–591. Besides the histopathological growth patterns other markers that indicate the response to anti-angiogenic therapy have been already described (van Dam et al., 2017; Incio et al., 2018). 2544. ALLPS PVL. Here are the tributes to Marilyn A. Oldach. Tumour heterogeneity and resistance to cancer therapies. Veins located in the lower extremities often exhibit venous valves to inhibit backflow (Welsch et al., 2014; Pawlina, 2020). 14. Alongside to Notch signaling (Blanco and Gerhardt, 2013), metabolism has shown to have important effects on angiogenesis (De Bock et al., 2013). Nature 468, 310–315. doi: 10.1038/nbt.4006, Crisan, M., Corselli, M., Chen, W. C. W., and Péault, B. doi: 10.1016/j.ccell.2014.10.006, Jambusaria, A., Hong, Z., Zhang, L., Srivastava, S., Jana, A., Toth, P. T., et al. Prepare a personalized obituary for someone you loved.. December 4, 1926 - Although this final process still remains poorly understood, recent findings suggested that TGF-β1 might be directly involved in its conclusion (Mao et al., 2014). doi: 10.1016/s0002-9440(10)63540-7. (1998). All authors revised and discussed the manuscript. Bevacizumab in advanced lung cancer: state of the art. doi: 10.1055/s-0030-1253454, Nguyen, D. X., Bos, P. D., and Massague, J. Please accept Echovita’s sincere condolences. 31, 862–77.e14. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Vascular development: from precursor cells to branched arterial and venous networks. Med. In this growth pattern, which accounts for approximately 5% of the observed patterns, also in pre-existing colorectal cancer liver metastases after chemotherapy in combination with bevacizumab, the tumor cells push the healthy liver parenchyma aside, without building a desmoplastic rim (Frentzas et al., 2016; van Dam et al., 2017). In synopsis with other sequencing data, varying levels of Ehd3 expression in the aortic EC clusters are observed (Feng et al., 2019; Lukowski et al., 2019). doi: 10.1016/j.cmet.2013.11.008, Seano, G., Chiaverina, G., Gagliardi, P. A., Di Blasio, L., Puliafito, A., Bouvard, C., et al. Impact Factor 3.367 | CiteScore 4.3More on impact ›, Mechanisms of Vessel Development: From a Primitive Draft to a Mature Vasculature (2018) went further on to examine whether murine PCs from different tissue samples show heterogeneity, by comparing them to murine lung tissue. This alteration in therapy response also echoes to the different types of growth patterns, as changes from the desmoplastic to replacement type can be observed in patients undergoing anti-angiogenic treatment (van Dam et al., 2018; Hoppener et al., 2019). A better understanding of these points is crucial to the development of new therapeutic options in the treatment of liver metastases. As discussed in “Pathological vessel heterogeneity,” vasculogenesis is seen in the embryonal development. 208, 207–223. (2018) employed a model of murine brain PCs (Crisan et al., 2008; Smyth et al., 2018; Vanlandewijck et al., 2018). Phone Number Information; 218-460-9530: Achillies Bormet - Twp Rd 3, Moose Lake, Minnesota: 218-460-4395: Sonaya Zoellner - Sandak Rd, Moose Lake, Minnesota The role of pericytes in blood-vessel formation and maintenance. Capillaries are ubiquitously found in the body, given that oxygen can only traverse 2 mm through tissue (Griffith et al., 2005). doi: 10.1152/physrev.00050.2017, Tao, Y., Wang, M., Chen, E., and Tang, H. (2017). Drug Discov. It is evident that new vessels are formed physiologically but this phenomenon is also observed in many other pathologies, including cancer (Carmeliet, 2003). doi: 10.1007/s10456-019-09661-5, George, M., Rainey, M. A., Naramura, M., Foster, K. W., Holzapfel, M. S., Willoughby, L. L., et al. Liver regeneration. Figure 1. These cells can store vitamin A and, in pathologic conditions, like chronic inflammation, are also able to transdifferentiate into myofibroblasts and further synthesize collagen (Pawlina, 2018). It has been already shown that tumor-associated macrophages release tumor-derived CSF-1 and macrophage-derived EGF through a paracrine manner, further promoting therapy resistance (Quail and Joyce, 2013). Sci. (2016), the second most prevalent metastatic growth pattern, accounting for approximately 45% of the detected growth patterns, is the replacement type (see Figure 7; Frentzas et al., 2016; van Dam et al., 2017; Galjart et al., 2019). Karaiskos et al. doi: 10.1038/nature05571. Nephrol. Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. Single-Cell Transcriptome Atlas of Murine Endothelial Cells. 18. Dvorak, H. F. (2005). doi: 10.1016/j.modgep.2004.05.004, Cleuren, A. C. A., Van Der Ent, M. A., Jiang, H., Hunker, K. L., Yee, A., Siemieniak, D. R., et al. Physiol. Therefore, the expression pattern of Vcam-1 and vWf at the opposing sides of the range, but not the middle (denoted as the capillary region), fitted to the description that they are only expressed in arteries and veins. Browse for your friends alphabetically by name. These findings indicate that the neoangiogenic process follows a conserved pattern of stages in at least two different tissue types (Goveia et al., 2020; Rohlenova et al., 2020). Sci. These cells are also considered mesenchymal stem cells and can be detected by their CD146 expression (Shenoy and Bose, 2018). Interestingly, some degree of inter-metastatic heterogeneity is observed in some patients. This finding aligns with results from another recent single-cell study (Goveia et al., 2020). Vanlandewijck et al. Papadimitrakopoulou, V., Cobo, M., Bordoni, R., Dubray-Longeras, P., Szalai, Z., Ursol, G., et al. 9, 301–310. Cnn1 was used as a marker for arterial SMC with a diameter larger than 13 μm. To accomplish their functions, ECs are highly self-organized and those receptors are of crucial importance. J. 11, 40–61. 9:4567. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Creating the main body of vascular resistance leads to their name of resistance arteries. Recollecting and supplying the blood back to the heart, venules are bigger capillaries at first, with fenestrations, allowing immune cells to trespass into the surrounding tissue (diapedesis) (see Figure 1G). 2345. The host organ microenvironment, especially the immune cells, have also been suggested to play a crucial role in in the process of metastasis (Quail and Joyce, 2013; Dagogo-Jack and Shaw, 2018). Page 2019 of 2825. Cytokine Growth Factor Rev. This suggests that an anti-angiogenic treatment can affect most types of solid tumors and their metastases (Vasudev and Reynolds, 2014; Itatani et al., 2018). Pericytes, an overlooked player in vascular pathobiology. Single-cell analysis reveals heterogeneity of high endothelial venules anddifferent regulation of genes controlling lymphocyte entry to lymph nodes. doi: 10.1161/atvbaha.110.215871, Liu, M., and Gomez, D. (2019). Dirscherl, K., Schlapfer, M., Roth Z’graggen, B., Wenger, R. H., Booy, C., Flury-Frei, R., et al. J. Bmx tyrosine kinase is specifically expressed in the endocardium and the endothelium of large arteries. doi: 10.1016/s0168-8278(02)00282-9. These vessel subtypes display a prominent membrana elastica interna that can be utilized to distinguish arteries from veins by using histochemistry stainings, such as Verhoeff’s elastica stain or more specifically resorcin-fuchsin (Puchtler and Waldrop, 1979). Surrounding the liver sinusoids we can observe Kupffer cells, which are a part of the mononuclear phagocytotic system, and are involved in the final elimination of erythrocytes and in the recycling of its fragments and ferritin (Pawlina, 2018). Normal fibroblasts instead promote the growth of healthy endothelial cells and suppress the growth of tumor cells (Quail and Joyce, 2013). Both cell populations expressed conserved markers, such as Vtn, Higd1b, S1pr3, Mcam, Ifitm1, Baiap3, and Ehd3 (Vanlandewijck et al., 2018), suggesting close relation to each other. It was recently discovered that glycolysis has a significant effect on the potency of ECs to acquire tip cell features. With the emerge of single-cell sequencing techniques in the last years, the resolution in which we can detect heterogeneity has been increased noticeably (Sabbagh et al., 2018; Vanlandewijck et al., 2018; Lukowski et al., 2019; Goveia et al., 2020; Jambusaria et al., 2020; Kalucka et al., 2020; Rohlenova et al., 2020). Also, lung, brain, pancreatic and cervical tumors present this chemotactic predilection (Yachida et al., 2010; Assoun et al., 2017; Tewari et al., 2017). Mol. (2009). doi: 10.1007/s10585-012-9500-6, Nagy, J. Those scientific insights are crucial to help us overcome the current setbacks observed in e.g., vascular regeneration and anti-angiogenic therapy. In pathological angiogenesis, large transient mother vessels are the first to form, arising from capillaries (Farnsworth et al., 2014). (2018). Tumor blood vessels show a very atypical morphology, the vessels are dilated and disorganized and are leaky (Jain, 2014; Viallard and Larrivée, 2017). Cancer Inst. JF designed the figures. Cardiovasc. Baryawno, N., Przybylski, D., Kowalczyk, M. S., Kfoury, Y., Severe, N., Gustafsson, K., et al. Dysfunctional ECs are a predictor for cardiovascular disease (Widlansky et al., 2003) but are also a relevant contributor component to other diseases, as observed in newly formed aberrant cancer vessels. 86, 767–780. Surgery 107, 521–527. A low differentiation status means that the endothelial cells are not highly specialized as are endothelial cells from hepatic sinusoids, which exhibit certain structural and functional characteristics like cytoplasmatic fenestration and a gain of differentiation markers like CD4 (Gouysse et al., 2002).