Lycat and cloche at the Switch Between Blood Vessel Growth and Differentiation?

Abstract

HomeCirculation ResearchVol. 102, No. 9Lycat and cloche at the Switch Between Blood Vessel Growth and Differentiation? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBLycat and cloche at the Switch Between Blood Vessel Growth and Differentiation? Sybill Patan Sybill PatanSybill Patan From the Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn. Search for more papers by this author Originally published9 May 2008https://doi.org/10.1161/CIRCRESAHA.108.176446Circulation Research. 2008;102:1005–1007The formation of the cardiovascular system starts in the mouse embryo at approximately embryonic day (E)7.0 to E7.5. The first blood vessels in the extraembryonic membranes, the major intraembryonic vessels, and the heart form by vasculogenesis, the in situ differentiation of mesodermal cells that give rise to “blood-islands.” The latter are composed of hemangioblasts, the common precursors of endothelial and blood cells. Hemangioblasts situated in the lumen of the blood islands will further differentiate into hematocytoblasts, the precursors of all 3 lineages of blood cells. In contrast, hemangioblasts lining the walls of the blood islands will give rise to angioblasts that form endothelial cells.1 Migrating angioblasts from the proximal lateral mesoderm assemble symmetrically at the lateral sides of the embryo to establish 2 preendocardial tubes. They fuse to give rise to the primordial heart.2 While vasculogenesis is still proceeding, the uniform blood islands begin to remodel to a network of large and small vessels by the process of angiogenesis, preferentially intussusceptive microvascular growth.3,4Gene expression and targeting studies have identified vascular endothelial growth factor and its 2 receptors, KDR/flk-1 and flt-1, as critical for the formation and early remodeling of the blood islands. Vascular endothelial growth factor is produced by endodermal and mesodermal cells at the onset of hemangioblast formation, whereas its receptors are expressed in the future endothelial cells lining the blood islands.5 Flk-1−/− embryos lack blood islands throughout the embryo and yolk sac.6 In flt-1−/− embryos, blood islands do not properly remodel but form large blood channels.7 Inactivation of a single vascular endothelial growth factor allele caused multiple embryonic malformations including the heart, rudimentary dorsal aortae, and a reduced number of blood cells.8,9 All deletions were lethal between days E8.5 and E11 to E12. Angiopoietin (Ang)-1, expressed by mesodermal cells, and its corresponding tie-1 and tie-2 receptors, located on the endothelium, form another important endothelial specific regulatory system that is critical for the mechanisms of intussusceptive microvascular growth.10–12Recently, the zebrafish mutation cloche has been characterized to affect blood vessel and blood cell formation at a very early stage.13 In this issue of Circulation Research, Xiong et al14 report the isolation of lysocardiolipin acyltransferase, lycat, from the deletion interval of cloche, in the attempt to determine the molecular components of the cloche gene in zebrafish. Morpholino-mediated lycat knockdown results in a strikingly similar phenotype as compared with the cloche mutation. The central embryonic vascular network is established; however, the intersegmental vessel loops are approximately one-third longer and reduced in number with largely increased intervascular spaces as compared with controls. These vessels, as well as the central large vessels, the dorsal aorta, and the axial vein, express flk-1 and tie-1 in a mosaic pattern, in the way that some endothelial cells exhibit normal levels, whereas others produce none or very low amounts. The lycat-deficient embryos lack cranial blood vessels and possess an extremely thin common endocardial–myocardial layer, comparable to the cloche mutation. Flk-1, sc1, gata1, etsrp, and fli1 act in hemangioblasts downstream of lycat, as was previously demonstrated for cloche. This establishes lycat as one of the earliest known regulators of hemangioblasts.14What does the lycat phenotype suggest concerning its function in endothelial cells, as well as in blood vessel and heart morphogenesis? For the formation of the heart, it is essential that the endocardial tube and the surrounding mesoderm that differentiates to myocardium interact. This communication is likely disturbed in the lycat mutants, and a normal heart therefore cannot form. Mice deficient of Ang-1, or its tie-2 receptor, were unable to recruit mesodermal cells to the endocardium resulting in a pathological heart morphology with a thinned myocardium that remained distant to the endocardium.10,11 It is not known presently whether Ang-1/tie-2 signaling is affected by the lycat knockdown. In their video file (available in the online data supplement to the article at http://circres.ahajournals.org), Xiong et al show impressively “endocardial” contractions that are, however, less effective, because the myocardium forms no separate thick layer.14 This suggests, that mesodermal cells are recruited and likely incorporated into the endocardium to give rise to a common 1-layered, enlarged endocardial–myocardial structure instead of forming the adjacent myocardium. Low expression levels of tie-1 could support this inclusion of mesodermal cells into the endocardium. Tie-1 was identified as a counter player of tie-2, and low tie-1 expression would thus support tie-2–mediated periendothelial recruitment. (Figure, A).10,11 Alternatively, it could be argued that the endocardium never forms. However, the supplemental video in the article by Xiong et al shows that the circulation is intact.14 This means that the “myocardium” is properly connected to the large vessels, indicating that the sinus venosus and truncus arteriosus, the endothelial in- and outflow tracts, are continuous with the myocardium. This is possible only if the endocardial tube forms a continuous layer with the vessels entering and leaving the heart, suggesting that an endocardium forms initially and surrounding cardiomyocytes invade it. Download figureDownload PowerPointFigure. Concept of blood vessel growth and differentiation. A, Expression of low levels of cloche/lycat in the endothelial layer or the endocardium (a). Recruitment of surrounding mesodermal cells based on Ang-1/tie-2 signaling to the endothelial layer or the endocardium, promotes, in the presence of low tie-1 and flk-1 expression, the incorporation of these mesodermal cells into the endothelial layer or endocardium (b) and results in expansion of the blood vessel lumen or growth of the endocardium (c). B, Expression of high levels of cloche/lycat in the endocardium or the endothelial layer (a). Recruitment of surrounding mesodermal cells based on Ang-1/tie2 signaling to the endocardium or the endothelial layer forms the myocardium or a periendothelial cell layer (b) in the presence of normal tie-1 and flk-1 expression. The periendothelial cells contribute to vessel lumen division by formation of intraluminal tissue folds and pillars (c and d). Alternately they form loop systems in the lumen of large vessels.14,15 Tissue pillars detach from the tips of intraluminal tissue folds in successive steps (1–3) involving hole formation in endothelial cells to separate the pillar, thus forming the center of a new vessel loop (transverse view, e and f). The pillar remains anchored to its fold at bottom and top (vertical view, g).14,15 Endothelial cells are white; periendothelial cells, black; collagen fiber bundles, black dots. lu indicates lumen.Correspondingly, a similar mechanism, enhanced integration of periendothelial cells into the endothelial lining, could cause the formation of elongated intersegmental vessels in the central region of the embryo. Periendothelial cells are critical for vessel lumen division to multiply vascular segments by the insertion of transluminal tissue folds that form pillars, spanning between opposite vessel walls. The analysis of Ang-1– and tie-2–deficient embryos has proven the pivotal role of periendothelial cells for the stabilization of folds and pillars and subsequently successful vessel division resulting in normal vessel growth and remodeling via intussusceptive microvascular growth.10,11 Vascular loops can form “in situ” in the wall of larger vessels in a similar way (Figure, B).15,16 The integration of periendothelial cells into the endothelial lining in the lycat knockdown will reduce the formation of transluminal tissue folds necessary for lumen division or loop systems, which explains the coarse vascular network composed of large vessel loops and big spaces between them. Some authors suggest the intersegmental vessels form by endothelial sprouting; however, a careful analysis of thin serial sections that would confirm the existence of blind ending segments was not performed.17 Indeed, such an analysis demonstrated that the perineural (intersomitic) loop plexus of mouse embryos that corresponds to the intersegmental loop system in the zebrafish is formed by in situ loop formation.11The head receives its blood vessels by expansion of the cranial central network; a contribution of migrating angioblasts has been discussed.2,18 Disturbed network expansion in the lycat and cloche knockdown based on the incorporation of periendothelial cells into the endothelial layer could explain the lack of cranial blood vessels.The detailed analysis of the vascular plexus in the chicken chorioallantoic membrane, and in mouse embryos, has demonstrated the constant existence of a periendothelial cell layer around all growing vessels.10,11,19 The periendothelial cells differentiate later to form smooth muscle cells and pericytes. As long as the network is expanding, periendothelial cells exhibit a striking similarity to endothelial cells, with which they form common intercellular junctions. Tracing periendothelial cells by analysis of serial sections has shown, at the ultrastructural level, that their extensions are frequently incorporated into the endothelial layer. These cells migrate from the surrounding mesenchyme toward vessel walls under the regulation of the Ang-1/tie-2 system and can thus readily contribute to expand the endothelial lining. Endothelial cell mitosis has only rarely been observed. Therefore, incorporation of periendothelial cells into the endothelial layer appears to be the major mechanism for the growth of vessel segments.19 The expression of differing amounts of lycat could regulate vessel wall expansion by periendothelial incorporation versus lumen division by periendothelial stabilization of transluminal tissue folds and pillars. Further investigation will deepen our insight into this possible switch that may determine cardiovascular development.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.The author thanks Max Patan for assistance with the graphical art work.Sources of FundingThe work of the author cited in this editorial was funded by the Swiss National Science Foundation, the German Research Foundation, and the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Sybill Patan, Assistant Professor, Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Ave, Box 5, Brooklyn, NY 11203-2098. References 1 Sabin FR. Origin and development of the primitive vessels of the chick and of the pig. Conrtib Embryol Carnegie Inst Publ Wash. 1917; 6: 61–124.Google Scholar2 Douglas J, Poole TJ. Endothelial cell origin and migration in embryonic heart and cranial vessel development. Anat Rec. 2005; 231: 383–395.Google Scholar3 Patan S. How is the branching of animal blood vessels implemented? In: Davies JA, ed. Branching Morphogenesis. Landes Bioscience: Georgetown, Tex; Springer: New York; 2005: 113–125.Google Scholar4 Patan S. Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. J Neuro-Onc. 2000; 50: 1–15.CrossrefMedlineGoogle Scholar5 Flamme I, Breier G, Risau W. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (flk-1) are expressed during vasculogenesis and vascular differentiation in the quail embryo. Dev Biol. 1995; 169: 699–712.CrossrefMedlineGoogle Scholar6 Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood-island formation and vasculogenesis in flk-1 deficient mice. Nature. 1995; 376: 62–66.CrossrefMedlineGoogle Scholar7 Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the flt-1 receptor tyrosine kinase in regulating the assembly of the vascular endothelium. Nature. 1995; 376: 66–70.CrossrefMedlineGoogle Scholar8 Ferrara N, Carver Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillian KJ, Moore MMW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996; 380: 439–442.CrossrefMedlineGoogle Scholar9 Carmeliet P, Ferreira V, Breier G, Poolefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996; 380: 435–439.CrossrefMedlineGoogle Scholar10 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 tie-2 receptor during embryonic angiogenesis. Cell. 1996; 87: 1171–1180.CrossrefMedlineGoogle Scholar11 Patan S. Tie-1 and tie-2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive microvascular growth. Microvasc Res. 1998; 56: 1–21.CrossrefMedlineGoogle Scholar12 Saharinen P, Kerkelä K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K. Multiple angiopoietin recombinant proteins activate the tie-1 receptor tyrosine kinase and promote its interaction with tie-2. J Cell Biol. 2005; 169: 239–243.CrossrefMedlineGoogle Scholar13 Stainier DYR, Weinstein BM, Detrich HW, Zon LI, Fishman MC. cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages. Development. 1995; 121: 3141–3150.CrossrefMedlineGoogle Scholar14 Xiong J-W, Yu Q, Zhang J, Mably JD. An acyltransferase controls the generation of hematopoietic and endothelial lineages in zebrafish. Circ Res. 2008; 102: 1057–1064.LinkGoogle Scholar15 Patan S, Munn LL, Tanda S, Roberge S, Jain RK, Jones RC. Vascular morphogenesis and remodeling in a model of tissue repair. Circ Res. 2001; 89: 723–731.CrossrefMedlineGoogle Scholar16 Patan S, Tanda S, Roberge S, Jones RC, Jain RK, Munn LL. Vascular morphogenesis and remodeling in a human tumor xenograft. Circ Res. 2001; 89: 732–739.CrossrefMedlineGoogle Scholar17 Chen E, Hermanson S, Ekker SC. Syndecan-2 is essential for angiogenic sprouting during zebrafish development. Blood. 2004; 103: 1710–1719.CrossrefMedlineGoogle Scholar18 Pardanaud L, Yassine F, Dieterlen-Lièvre F. Relationship between vasculogenesis, angiogenesis and hematopoiesis during avian ontogeny. Development. 1989; 105: 473–485.CrossrefMedlineGoogle Scholar19 Patan S, Haenni B, Burri PH. Evidence for intussusceptive capillary growth in the chicken chorio-allantoic membrane (CAM). 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Díaz-Flores L, Gutiérrez R, García M, Gayoso S, Carrasco J, Díaz-Flores L, González-Gómez M and Madrid J (2020) Intussusceptive Angiogenesis and Peg–Socket Junctions between Endothelial Cells and Smooth Muscle Cells in Early Arterial Intimal Thickening, International Journal of Molecular Sciences, 10.3390/ijms21218049, 21:21, (8049) Díaz-Flores L, Gutiérrez R, González-Gómez M, García M, Díaz-Flores L, González-Marrero I, Ávila J and Martín-Vasallo P (2021) Disproportion in Pericyte/Endothelial Cell Proliferation and Mechanisms of Intussusceptive Angiogenesis Participate in Bizarre Vessel Formation in Glioblastoma, Cells, 10.3390/cells10102625, 10:10, (2625) May 9, 2008Vol 102, Issue 9 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.108.176446PMID: 18467639 Originally publishedMay 9, 2008 Keywordsintussusceptive microvascular growthvasculogenesisangiogenesislycatclochePDF download Advertisement