Tubes, Branches, and Pillars

HomeCirculation ResearchVol. 89, No. 8Tubes, Branches, and Pillars Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTubes, Branches, and PillarsThe Many Ways of Forming a New Vasculature Hellmut G. Augustin Hellmut G. AugustinHellmut G. Augustin From the Department of Vascular Biology & Angiogenesis Research, Tumor Biology Center, Freiburg, Germany. Originally published3 Apr 2018https://doi.org/10.1161/res.89.8.645Circulation Research. 2001;89:645–647The angiogenic cascade is getting increasingly complex. A few years ago, vasculogenesis and angiogenesis were considered as the primary mechanisms leading to the formation of new blood vessels. The original definition of vasculogenesis denotes the formation of a primary embryonic vascular network from in situ differentiating angioblastic cells.1 In contrast, angiogenesis primarily referred to the sprouting of blood vessels from preexisting vessels.1Recent advances in the identification of molecules that regulate angiogenesis and vascular remodeling have shown that the simplistic model of an invading capillary sprout is not sufficient to appreciate the whole spectrum of morphogenic events that are required to form a neovascular network (Figure 1).1–3 Undoubtedly, vascular endothelial growth factor (VEGF) acts at an early point in the hierarchical order of morphogenic events and probably fulfills all criteria to be considered as a master switch of the angiogenic cascade. In contrast, the angiopoietins and their receptor Tie-2 as well as the ephrins and their corresponding Eph receptors appear to act at a somewhat later stage of neovessel formation. These molecules orchestrate a number of related, yet functionally and molecularly not well understood, processes such as vessel assembly (network formation and formation of anastomoses), vessel maturation (recruitment of mural cells [pericytes and smooth muscle cells], and extracellular matrix assembly, pruning of the primary vascular bed), and acquisition of vessel identity (formation of arteries, capillaries, and veins)3,4 (Figure 2). Lastly, the mechanisms of organotypic differentiation of the vascular tree (continuous endothelium, discontinuous endothelium, fenestrated endothelium) are not at all understood and the first molecules that govern subpopulation-specific vascular growth and differentiation are just being uncovered.5,6Download figureDownload PowerPointFigure 1. Change of paradigm. From sprouting angiogenesis to vascular morphogenesis. Basement membrane degradation, directed endothelial cell migration, and proliferation (left) were considered as the primary mechanisms of angiogenesis. Corresponding in vitro assays have greatly helped to uncover molecules and mechanisms of angiogenesis. Today, the complexity of the sequential processes leading to the formation of a mature vascular network is increasingly recognized. These involve mechanisms of vessel assembly (network formation and formation of anastomoses), vessel maturation (pericyte recruitment, extracellular matrix assembly, pruning of neovasculature), acquisition of vessel identity (arteries, capillaries, veins), and organotypic differentiation (continuous endothelia, discontinuous endothelia, fenestrated endothelia). Yet, experimental systems to study these steps are largely missing.Download figureDownload PowerPointFigure 2. Hierarchical order of morphogenic events during embryonic and adult growth of blood vessels. The primary formation of blood vessels occurs through mechanisms of vasculogenesis (center top). Vasculogenesis refers to the formation of a vascular network from precursor cells (angioblasts). Embryonic vasculogenesis results from the in situ coalescence of mesodermal angioblastic cells to form a capillary plexus. In contrast, adult vasculogenesis is mechanistically different and is mediated by the distal recruitment of angioblastic cells from precursor cell compartments (bone marrow). The secondary level of vascular morphogenesis describes the angiogenic formation of blood vessels. Angiogenesis refers to the formation of vessels and vascular networks from preexisting vascular structures (top, outer compartment). This can occur through classical sprouting angiogenesis with formation of anastomoses (top right) or through mechanisms of nonsprouting angiogenesis (top left). Nonsprouting angiogenesis occurs through mechanisms of intussusceptive microvascular growth (IMG) focally inserting a tissue pillar or by longitudinal fold-like splitting of a vessel. Sprouting angiogenesis and intussusception contribute to an increasing complexity of a growing vascular network. The network assembles and matures, eventually allowing directional blood flow. Cellular and biomechanical factors appear to be involved in shaping vascular identity (ie, arteries, capillaries, and veins), although there is also developmental biological evidence indicating that arteriovenous fate determination may occur before the formation of arteries and veins. Lastly, microenvironmental cues (extracellular matrix, cell contacts, and organ-selective growth factors) regulate the organotypic differentiation of a neovascular tree with continuous, discontinuous, and fenestrated endothelia. In contrast to the formation and maturation of new blood vessels through vasculogenic and angiogenic mechanisms, vascular remodeling describes the adaptational reorganization of an existing mature vasculature. This may occur acutely (eg, after sudden ischemia) or as a response to chronic stimuli (eg, atherosclerotic changes of vessel wall or in response to hypertensive biomechanical forces). The term "arteriogenesis" has been coined to describe the formation of collaterals from a preexisting capillary network after sudden ischemia as it occurs after cardiac ischemia or experimentally during surgically induced hindlimb ischemia. This process describes an adaptational remodeling phenomenon and should not be confused with the developmental acquisition of vessel identity that is associated with the formation of arteries, capillaries, and veins. Likewise, vessel cooption18 describes a vascular remodeling phenomenon originating from an existing vasculature that may contribute to tumor vascularization.The function of these molecules has largely been elucidated through genetic experiments in mice ablating or overexpressing individual molecules. Yet, a detailed understanding of their molecular and functional mode of action is missing, which is primarily due to the lack of appropriate in vivo and in vitro models in which to functionally study these molecules. Most in vitro assays have very reductionist readouts such as endothelial cell chemoinvasion, migration, or proliferation. These assays have proven powerful in the early days of angiogenesis research. Yet, they are of limited use for the study of complex cellular interaction phenomena as they are associated with vessel assembly and vessel maturation. Likewise, most in vivo assays are either not quantitative or they are restricted to endpoint readouts that do not allow an appreciation of the dynamic three-dimensional spatiotemporal order of angiogenic processes, eg, in tumor models or in cardiac ischemia models. Most importantly, when it comes to studying angiogenesis in vivo, few laboratories apply three-dimensional techniques such as intravital microscopy or corrosion casting techniques to assess a neovascular bed. Instead, two-dimensional histological techniques are widely used to analyze angiogenesis in vivo. In fact, the counting of immunohistochemically stained microvessels in tissue specimens including tumors has become the gold standard to assess a neovascular bed in a given tissue.7 Clearly, this reductionist analytical approach is by no means sufficient to realistically reflect the whole spectrum of three-dimensional morphogenic events dynamically over time.It is primarily a consequence of the limited availability of appropriate experimental models and analytical tools that vascular network formation through the process of intussusception is still not widely appreciated. Intussusception or intussusceptive microvascular growth (IMG) describes the formation of a vascular network from an endothelial cell–lined vessel by focally inserting a tissue pillar or by longitudinal fold-like splitting of a vessel. As a consequence, IMG can result in complex vascular networks by a nonsprouting angiogenesis mechanism.1,2The concept of vascular network formation through IMG is not new. Originally described more than 50 years ago,8 analytical work on IMG was pioneered in the late 1980s and early 1990s by the Swiss anatomist Dr P.H. Burri.9,10 This early work has clearly shown that IMG is an important nonsprouting angiogenesis mechanism that contributes to capillary network formation independent of classical sprouting angiogenesis (Figure 2). Physiologically, IMG occurs in a number of embryonic and adult tissues, most notably during embryonic vascularization of the lungs11 as well as during the cyclic changes of the endometrial vasculature in the adult.12In two studies published in this issue of Circulation Research, Dr Patan and colleagues13,14 have shed further light into the complexity of intussusceptive microvascular growth. They have used the isolated mouse ovarian pedicle model to study IMG during wound healing–like granulation tissue formation and during growth of tumors grafted onto the ovarian pedicle. In this model, the ovarian vascular supply is surgically manipulated so that the isolated ovary is at the end of a pedicle that is supplied by the ovarian artery and the ovarian vein. This model was originally developed to perform hemodynamic studies in an experimental tumor that is supplied by a single feeding artery and a single collecting vein.15 Patan et al have used this model to characterize the intussusceptive morphogenic remodeling of the ovarian vein and artery feeding into the granulation tissue13 as well as into LS174T human colon adenocarcinoma growing in the isolated pedicle.14 A zone of several millimeters was analyzed in both models through a carefully performed rather meticulous morphological analysis of several thousands of 2-μm serial sections. Computer-aided image analysis was then applied to three dimensionally reconstruct the vascular network. The results of both studies show quite clearly that IMG can lead to complex vascular networks completely independent of sprouting angiogenesis. Furthermore, the authors' high-resolution approach demonstrates how intussusceptive vascular folds organize to establish compound loop systems resulting from tissue segmentation and intussusceptive anastomoses.As with any intriguing study, the experiments by Patan et al raise numerous additional questions. For example, what are the driving forces behind IMG? There is some evidence that the angiopoietin/Tie-2 ligand/receptor system is involved in controlling IMG.16,17 Likewise, biomechanical forces may be involved in regulating IMG. The surgical manipulation in the ovarian pedicle procedure used by Patan et al13,14 leads to significant changes in hemodynamic forces that may be involved in remodeling the preexisting ovarian vein as much as hemodynamic forces are believed to act as critical regulators of collateral formation following cardiac ischemia (arteriogenic vascular remodeling). This also raises the question of a zonal analysis of the observed intussusceptive morphogenic events, ie, does IMG occur in the center or in the periphery of the analyzed granulation tissue13 and tumors?14 Zonal analyses of vascular morphogenic processes are particularly relevant in the context of tumor angiogenesis. Microvessel counting studies usually quantitate intratumoral microvessel densities. Yet, the tumor periphery marks the invasive zone of a tumor and gives rise to metastatic cell dissemination. Thus, the equilibrium between tumor angiogenesis and remodeling of the preexisting vasculature in the tumor periphery (vessel cooption)18 may be very relevant in determining tumor fate. Lastly, and possibly most important, what is the quantitative contribution of IMG (and the other mechanisms of vessel formation) to neovascularization and particularly to tumor vascularization?It is increasingly recognized that vascular morphogenesis is a complex process driven by a number of different mechanisms that can lead to the formation of endothelial cell–lined blood vessels. Figure 2 summarizes the hierarchical order of our present understanding of hemangiogenic morphogenic events (as opposed to lymphangiogenic processes). Future work in the field of angiogenesis research will need additional tools and models to systematically analyze angiogenic processes to fully understand the complexity of the angiogenic cascade. This will also include the implementation of more sophisticated invasive and noninvasive techniques to analyze the vasculature of human tumors. The elegant, yet cumbersome experimental, approach taken by Patan et al13,14 clearly reflects our limited ability to appreciate angiogenesis as a dynamic three-dimensional process. The implementation of analytical techniques that systematically assess human tumor angiogenesis beyond the counting of microvessel densities is just at its beginning.19 At the same time, novel angiogenic factors with a narrow cell and organ selectivity are being identified as inducers and modifiers of the angiogenic cascade.5,6 Collectively, these observations indicate that the angiogenic cascade is far from being understood. Yet, a thorough understanding of the mechanisms of vascular morphogenesis will be a requisite for the rational translation of this knowledge into clinical application.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Hellmut G. Augustin, DVM, PhD, Department of Vascular Biology & Angiogenesis Research, Tumor Biology Center, Breisacher Str. 117, D-79108 Freiburg, Germany. E-mail [email protected] References 1 Risau W. Mechanisms of angiogenesis. Nature. 1997; 386: 671–674.CrossrefMedlineGoogle Scholar2 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000; 6: 389–395.CrossrefMedlineGoogle Scholar3 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000; 407: 249–257.CrossrefMedlineGoogle Scholar4 Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature. 2000; 407: 242–248.CrossrefMedlineGoogle Scholar5 LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L, Frantz G, Rangell L, DeGuzman L, Keller GA, Peale F, Gurney A, Hillan KJ, Ferrara N. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature. 2001; 412: 877–884.CrossrefMedlineGoogle Scholar6 Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y, Kitamura Y, Matsushima K, Yoshida N, Nishikawa S, Kishimoto T, Nagasawa T. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature. 1998; 393: 591–594.CrossrefMedlineGoogle Scholar7 Fox SB. Tumour angiogenesis and prognosis. Histopathology. 1997; 30: 294–301.CrossrefMedlineGoogle Scholar8 Short RHD. Alveolar epithelium in relation to growth of the lung. Philos Trans R Soc Lond B. 1950: 235: 35–87.CrossrefMedlineGoogle Scholar9 Caduff JH, Fischer LC, Burri PH. Scanning electron microscope study of the developing microvasculature in the postnatal rat lung. Anat Rec. 1986; 216: 154–164.CrossrefMedlineGoogle Scholar10 Burri PH, Tarek MR. A novel mechanism of capillary growth in the rat pulmonary microcirculation. Anat Rec. 1990; 228: 35–45.CrossrefMedlineGoogle Scholar11 Djonov V, Schmid M, Tschanz SA, Burri PH. Intussusceptive angiogenesis. Its role in embryonic vascular network formation. Circ Res. 2000; 86: 286–292.CrossrefMedlineGoogle Scholar12 Rogers PA, Lederman F, Taylor N. Endometrial microvascular growth in normal and dysfunctional states. Hum Reprod Update. 1998; 4: 503–508.CrossrefMedlineGoogle Scholar13 Patan S, Munn LL, Tanda S, Roberge S, Jain RK, Jones RC. Vascular morphogenesis and remodeling in a model of tissue repair: blood vessel formation and growth in the ovarian pedicle after ovariectomy. Circ Res. 2001; 89: 723–731.CrossrefMedlineGoogle Scholar14 Patan S, Tanda S, Roberge S, Jones RC, Jain RK, Munn LL. Vascular morphogenesis and remodeling in a human tumor xenograft: blood vessel formation and growth after ovariectomy and tumor implantation. Circ Res. 2001; 89: 732–739.CrossrefMedlineGoogle Scholar15 Gullino PM, Grantham FH. Studies on the exchange of fluids between host and tumor, I: a method for growing "tissue-isolated" tumors in laboratory animals. J Natl Acad Inst. 1961; 27: 679–693.Google Scholar16 Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995; 376: 70–74.CrossrefMedlineGoogle Scholar17 Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996; 87: 1171–1180.CrossrefMedlineGoogle Scholar18 Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 1999; 284: 1994–1998.CrossrefMedlineGoogle Scholar19 Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 2000; 60: 1388–1393.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Pasut A, Becker L, Cuypers A and Carmeliet P (2021) Endothelial cell plasticity at the single-cell level, Angiogenesis, 10.1007/s10456-021-09797-3, 24:2, (311-326), Online publication date: 1-May-2021. Arshad M, Conzelmann C, Riaz M, Noll T and G�nd�z D (2018) Inhibition of Cx43 attenuates ERK1/2 activation, enhances the expression of Cav‑1 and suppresses cell proliferation, International Journal of Molecular Medicine, 10.3892/ijmm.2018.3828 Yan H, Romero-Lopez M, Frieboes H, Hughes C and Lowengrub J Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness, IEEE Transactions on Biomedical Engineering, 10.1109/TBME.2016.2615566, (1-1) Egawa N, Lok J and Arai K (2016) Mechanisms of cellular plasticity in cerebral perivascular region New Horizons in Neurovascular Coupling: A Bridge Between Brain Circulation and Neural Plasticity, 10.1016/bs.pbr.2016.03.005, (183-200), . Macklin P, Frieboes H, Sparks J, Ghaffarizadeh A, Friedman S, Juarez E, Jonckheere E and Mumenthaler S (2016) Progress Towards Computational 3-D Multicellular Systems Biology Systems Biology of Tumor Microenvironment, 10.1007/978-3-319-42023-3_12, (225-246), . Jones R and Capen D (2013) Mechanisms of Growth of a Pulmonary Capillary Network in Adult Lung, Ultrastructural Pathology, 10.3109/01913123.2013.833561, 38:1, (34-44), Online publication date: 1-Feb-2014. Jones R, Capen D and Reid L (2014) Pulmonary Vascular Development The Lung, 10.1016/B978-0-12-799941-8.00005-5, (85-119), . De Paepe M, Chu S, Hall S, Heger N, Thanos C and Mao Q (2012) The human fetal lung Xenograft: Validation as model of microvascular remodeling in the postglandular lung, Pediatric Pulmonology, 10.1002/ppul.22617, 47:12, (1192-1203), Online publication date: 1-Dec-2012. Mamidi M, Pal R, Dey S, Bin Abdullah B, Zakaria Z, Rao M and Das A (2012) Cell therapy in critical limb ischemia: current developments and future progress, Cytotherapy, 10.3109/14653249.2012.693156, 14:8, (902-916), Online publication date: 1-Sep-2012. Ligresti G, Aplin A, Zorzi P, Morishita A and Nicosia R (2011) Macrophage-Derived Tumor Necrosis Factor-α Is an Early Component of the Molecular Cascade Leading to Angiogenesis in Response to Aortic Injury, Arteriosclerosis, Thrombosis, and Vascular Biology, 31:5, (1151-1159), Online publication date: 1-May-2011. Ward D, Cornillie P, Erkens T, Denis V, Casteleyn C, Mario V, Burvenich C, Luc V, Chris V, Peelman L and Wim V (2010) Expression and Localization of Angiogenic Growth Factors in Developing Porcine Mesonephric Glomeruli, Journal of Histochemistry & Cytochemistry, 10.1369/jhc.2010.956557, 58:12, (1045-1056), Online publication date: 1-Dec-2010. Frieboes H, Jin F, Chuang Y, Wise S, Lowengrub J and Cristini V (2010) Three-dimensional multispecies nonlinear tumor growth—II: Tumor invasion and angiogenesis, Journal of Theoretical Biology, 10.1016/j.jtbi.2010.02.036, 264:4, (1254-1278), Online publication date: 1-Jun-2010. Lowengrub J, Frieboes H, Jin F, Chuang Y, Li X, Macklin P, Wise S and Cristini V (2009) Nonlinear modelling of cancer: bridging the gap between cells and tumours, Nonlinearity, 10.1088/0951-7715/23/1/R01, 23:1, (R1-R91), Online publication date: 1-Jan-2010. Risser L, Plouraboué F, Cloetens P and Fonta C (2008) A 3D‐investigation shows that angiogenesis in primate cerebral cortex mainly occurs at capillary level, International Journal of Developmental Neuroscience, 10.1016/j.ijdevneu.2008.10.006, 27:2, (185-196), Online publication date: 1-Apr-2009. Egleton R, Brown K and Dasgupta P (2009) Angiogenic activity of nicotinic acetylcholine receptors: Implications in tobacco-related vascular diseases, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2008.10.007, 121:2, (205-223), Online publication date: 1-Feb-2009. Agliano A (2009) Angiogenesis Hemangiomas and Vascular Malformations, 10.1007/978-88-470-0569-3_1, (3-8), . Kurz H, Fehr J, Nitschke R and Burkhardt H (2008) Pericytes in the mature chorioallantoic membrane capillary plexus contain desmin and α-smooth muscle actin: relevance for non-sprouting angiogenesis, Histochemistry and Cell Biology, 10.1007/s00418-008-0478-8, 130:5, (1027-1040), Online publication date: 1-Nov-2008. Murphy G, Caplice N and Molloy M (2008) Fractalkine in rheumatoid arthritis: a review to date, Rheumatology, 10.1093/rheumatology/ken197, 47:10, (1446-1451) Kilian O, Wenisch S, Karnati S, Baumgart-Vogt E, Hild A, Fuhrmann R, Jonuleit T, Dingeldein E, Schnettler R and Franke R (2008) Observations on the microvasculature of bone defects filled with biodegradable nanoparticulate hydroxyapatite, Biomaterials, 10.1016/j.biomaterials.2008.05.003, 29:24-25, (3429-3437), Online publication date: 1-Aug-2008. Missbach-Guentner J, Dullin C, Kimmina S, Zientkowska M, Domeyer-Missbach M, Malz C, Grabbe E, Stühmer W and Alves F (2008) Morphologic Changes of Mammary Carcinomas in Mice over Time as Monitored by Flat-Panel Detector Volume Computed Tomography, Neoplasia, 10.1593/neo.08270, 10:7, (663-673), Online publication date: 1-Jul-2008. Ciccarelli M, Santulli G, Campanile A, Galasso G, Cervèro P, Altobelli G, Cimini V, Pastore L, Piscione F, Trimarco B and Iaccarino G (2009) Endothelial α 1 -adrenoceptors regulate neo-angiogenesis , British Journal of Pharmacology, 10.1038/sj.bjp.0707637, 153:5, (936-946), Online publication date: 1-Mar-2008. Krstulja M, Car A, Bonifačić D, Braut T and Kujundžić M (2008) Nasopharyngeal angiofibroma with intracellular accumulation of SPARC – a hypothesis (SPARC in nasopharyngeal angiofibroma), Medical Hypotheses, 10.1016/j.mehy.2007.06.011, 70:3, (600-604), Online publication date: 1-Jan-2008. Brey E and McIntire L (2008) Vascular Assembly in Engineered and Natural Tissues Principles of Regenerative Medicine, 10.1016/B978-012369410-2.50061-9, (1020-1037), . Cristini V, Frieboes H, Li X, Lowengrub J, Macklin P, Sanga S, Wise S and Zheng X Nonlinear Modeling and Simulation of Tumor Growth Selected Topics in Cancer Modeling, 10.1007/978-0-8176-4713-1_6, (1-69) Larrivée B, Freitas C, Trombe M, Lv X, DeLafarge B, Yuan L, Bouvrée K, Bréant C, Del Toro R, Bréchot N, Germain S, Bono F, Dol F, Claes F, Fischer C, Autiero M, Thomas J, Carmeliet P, Tessier-Lavigne M and Eichmann A (2007) Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis, Genes & Development, 10.1101/gad.437807, 21:19, (2433-2447), Online publication date: 1-Oct-2007. Downie S, Schalop L, Mazurek J, Savitch G, Lelonek G and Olson T (2006) Bilateral duplicated internal jugular veins: Case study and literature review, Clinical Anatomy, 10.1002/ca.20366, 20:3, (260-266), Online publication date: 1-Apr-2007. Frieboes H, Lowengrub J, Wise S, Zheng X, Macklin P, Bearer E and Cristini V (2007) Computer simulation of glioma growth and morphology, NeuroImage, 10.1016/j.neuroimage.2007.03.008, 37, (S59-S70), Online publication date: 1-Jan-2007. Masset A, Staszyk C and Gasse H (2006) The blood vessel system in the periodontal ligament of the equine cheek teeth – Part II: The micro-architecture and its functional implications in a constantly remodelling system, Annals of Anatomy - Anatomischer Anzeiger, 10.1016/j.aanat.2006.06.007, 188:6, (535-539), Online publication date: 1-Nov-2006. Veale D and Fearon U (2006) Inhibition of angiogenic pathways in rheumatoid arthritis: potential for therapeutic targeting, Best Practice & Research Clinical Rheumatology, 10.1016/j.berh.2006.05.004, 20:5, (941-947), Online publication date: 1-Oct-2006. Forgacs G and Newman S (2010) Biological Physics of the Developing Embryo Hirschberg R, Sachtleben M and Plendl J (2005) Electron microscopy of cultured angiogenic endothelial cells, Microscopy Research and Technique, 10.1002/jemt.20204, 67:5, (248-259), Online publication date: 1-Aug-2005. Kilian O, Alt V, Heiss C, Jonuleit T, Dingeldein E, Flesch I, Fidorra U, Wenisch S and Schnettler R (2009) New blood vessel formation and expression of VEGF receptors after implantation of platelet growth factor-enriched biodegradable nanocrystalline hydroxyapatite, Growth Factors, 10.1080/08977190500126306, 23:2, (125-133), Online publication date: 1-Jun-2005. Makanya A, Stauffer D, Ribatti D, Burri P and Djonov V (2005) Microvascular growth, development, and remodeling in the embryonic avian kidney: The interplay between sprouting and intussusceptive angiogenic mechanisms, Microscopy Research and Technique, 10.1002/jemt.20169, 66:6, (275-288), Online publication date: 15-Apr-2005. Brey E, Uriel S, Greisler H and McIntire L (2005) Therapeutic Neovascularization: Contributions from Bioengineering, Tissue Engineering, 10.1089/ten.2005.11.567, 11:3-4, (567-584), Online publication date: 1-Mar-2005. Hirschberg R and Plendl J (2005) Pododermal angiogenesis and angioadaptation in the bovine claw, Microscopy Research and Technique, 10.1002/jemt.20154, 66:2-3, (145-155), Online publication date: 1-Feb-2005. Djonov V and Makanya A New insights into intussusceptive angiogenesis Mechanisms of Angiogenesis, 10.1007/3-7643-7311-3_2, (17-33) Tozer G and Bicknell R (2004) Therapeutic targeting of the tumor vasculature, Seminars in Radiation Oncology, 10.1016/j.semradonc.2004.04.009, 14:3, (222-232), Online publication date: 1-Jul-2004. Bales G (2004) Great cardiac vein variations, Clinical Anatomy, 10.1002/ca.10248, 17:5, (436-443), Online publication date: 1-Jul-2004. Dasgupta P (2004) Somatostatin analogues: Multiple roles in cellular proliferation, neoplasia, and angiogenesis, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2004.02.002, 102:1, (61-85), Online publication date: 1-Apr-2004. Kaufmann P, Mayhew T and Charnock-Jones D (2004) Aspects of Human Fetoplacental Vasculogenesis and Angiogenesis. II. Changes During Normal Pregnancy, Placenta, 10.1016/j.placenta.2003.10.009, 25:2-3, (114-126), Online publication date: 1-Feb-2004. Charnock-Jones D, Kaufmann P and Mayhew T (2004) Aspects of Human Fetoplacental Vasculogenesis and Angiogenesis. I. Molecular Regulation, Placenta, 10.1016/j.placenta.2003.10.004, 25:2-3, (103-113), Online publication date: 1-Feb-2004. Tozer G (2003) Measuring tumour vascular response to antivascular and antiangiogenic drugs, The British Journal of Radiology, 10.1259/bjr/30165281, 76:suppl_1, (S23-S35), Online publication date: 1-Dec-2003. Michaelis U, Fisslthaler B, Medhora M, Harder D, Fleming I and Busse R (2003) Cytochrome P450 2C9‐derived epoxyeicosatrienoic acids induce angiogenesis via cross‐talk with the epidermal growth factor receptor, The FASEB Journal, 10.1096/fj.02-0640fje, 17:6, (770-772), Online publication date: 1-Apr-2003. Mouta C, Liaw L and Maciag T (2003) Angiogenesis: Cellular and Molecular Aspects of Postnatal Vessel Formation Handbook of Cell Signaling, 10.1016/B978-012124546-7/50698-7, (455-462), . Djonov V, Kurz H and Burri P (2002) Optimality in the developing vascular system: Branching remodeling by means of intussusception as an efficient adaptation mechanism, Developmental Dynamics, 10.1002/dvdy.10119, 224:4, (391-402), Online publication date: 1-Aug-2002. October 12, 2001Vol 89, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/res.89.8.645PMID: 11597985 Originally publishedApril 3, 2018 Keywordsintussusceptionangiogenesisintussusceptive microvascular growthvasculogenesisPDF download Advertisement