Semin Thromb Hemost 2010; 36(3): 227-235
DOI: 10.1055/s-0030-1253446
© Thieme Medical Publishers

Development of the Endothelium: An Emphasis on Heterogeneity

Laura A. Dyer1 , Cam Patterson1
  • 1McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina
Further Information

Publication History

Publication Date:
20 May 2010 (online)

ABSTRACT

The endothelium is composed of specialized epithelial cells that line the vasculature, the lymph vessels, and the heart. These endothelial cells are characterized by their stratification and are connected via intercellular junctions that confer specific permeability. Although all endothelium acts as a barrier, considerable heterogeneity exists among different organs and even within vessels. During development, the endothelial cells are specified before they migrate to their final destination, and then they commit to an arterial or venous fate. From the venous endothelial cell population, a subset of cells is further specified as lymphatic endothelium. The endothelium can be highly permeable, as in the lymph vessels, or impenetrable, as in the blood-brain barrier. These differences arise during development and are orchestrated through a series of signaling pathways. This review details how endothelial cells arise and are directed to their specific fate, specifically targeting what differentiates endothelial populations.

REFERENCES

  • 1 Streit A, Lee K J, Woo I, Roberts C, Jessell T M, Stern C D. Chordin regulates primitive streak development and the stability of induced neural cells, but is not sufficient for neural induction in the chick embryo.  Development. 1998;  125(3) 507-519
  • 2 Park C, Afrikanova I, Chung Y S et al.. A hierarchical order of factors in the generation of FLK1- and SCL-expressing hematopoietic and endothelial progenitors from embryonic stem cells.  Development. 2004;  131(11) 2749-2762
  • 3 Pearson S, Sroczynska P, Lacaud G, Kouskoff V. The stepwise specification of embryonic stem cells to hematopoietic fate is driven by sequential exposure to Bmp4, activin A, bFGF and VEGF.  Development. 2008;  135(8) 1525-1535
  • 4 Huber T L, Zhou Y, Mead P E, Zon L I. Cooperative effects of growth factors involved in the induction of hematopoietic mesoderm.  Blood. 1998;  92(11) 4128-4137
  • 5 Karabagli H, Karabagli P, Ladher R K, Schoenwolf G C. Comparison of the expression patterns of several fibroblast growth factors during chick gastrulation and neurulation.  Anat Embryol (Berl). 2002;  205(5–6) 365-370
  • 6 Mitrani E, Ziv T, Thomsen G, Shimoni Y, Melton D A, Bril A. Activin can induce the formation of axial structures and is expressed in the hypoblast of the chick.  Cell. 1990;  63(3) 495-501
  • 7 Azar Y, Eyal-Giladi H. Marginal zone cells—the primitive streak-inducing component of the primary hypoblast in the chick.  J Embryol Exp Morphol. 1979;  52 79-88
  • 8 Chapman S C, Schubert F R, Schoenwolf G C, Lumsden A. Analysis of spatial and temporal gene expression patterns in blastula and gastrula stage chick embryos.  Dev Biol. 2002;  245(1) 187-199
  • 9 Marom K, Levy V, Pillemer G, Fainsod A. Temporal analysis of the early BMP functions identifies distinct anti-organizer and mesoderm patterning phases.  Dev Biol. 2005;  282(2) 442-454
  • 10 Flamme I, Risau W. Induction of vasculogenesis and hematopoiesis in vitro.  Development. 1992;  116(2) 435-439
  • 11 Nishikawa S I, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H. Progressive lineage analysis by cell sorting and culture identifies FLK1 + VE-cadherin + cells at a diverging point of endothelial and hemopoietic lineages.  Development. 1998;  125(9) 1747-1757
  • 12 Faloon P, Arentson E, Kazarov A et al.. Basic fibroblast growth factor positively regulates hematopoietic development.  Development. 2000;  127(9) 1931-1941
  • 13 Kessel J, Fabian B C. Graded morphogenetic patterns during the development of the extraembryonic blood system and coelom of the chick blastoderm: a scanning electron microscope and light microscope study.  Am J Anat. 1985;  173 99-112
  • 14 Minko K, Bollerot K, Drevon C, Hallais M F, Jaffredo T. From mesoderm to blood islands: patterns of key molecules during yolk sac erythropoiesis.  Gene Expr Patterns. 2003;  3(3) 261-272
  • 15 Shalaby F, Rossant J, Yamaguchi T P et al.. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.  Nature. 1995;  376(6535) 62-66
  • 16 Ferrara N, Heinsohn H, Walder C E, Bunting S, Thomas G R. The regulation of blood vessel growth by vascular endothelial growth factor.  Ann N Y Acad Sci. 1995;  752 246-256
  • 17 Belaoussoff M, Farrington S M, Baron M H. Hematopoietic induction and respecification of A-P identity by visceral endoderm signaling in the mouse embryo.  Development. 1998;  125(24) 5009-5018
  • 18 Baron M H. Molecular regulation of embryonic hematopoiesis and vascular development: a novel pathway.  J Hematother Stem Cell Res. 2001;  10(5) 587-594
  • 19 Dyer M A, Farrington S M, Mohn D, Munday J R, Baron M H. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo.  Development. 2001;  128(10) 1717-1730
  • 20 Gonzalez-Crussi F. Vasculogenesis in the chick embryo. An ultrastructural study.  Am J Anat. 1971;  130(4) 441-460
  • 21 Liao W, Ho C Y, Yan Y L, Postlethwait J, Stainier D Y. Hhex and scl function in parallel to regulate early endothelial and blood differentiation in zebrafish.  Development. 2000;  127(20) 4303-4313
  • 22 Crompton M R, Bartlett T J, MacGregor A D et al.. Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells.  Nucleic Acids Res. 1992;  20(21) 5661-5667
  • 23 Sumanas S, Lin S. Ets1-related protein is a key regulator of vasculogenesis in zebrafish.  PLoS Biol. 2006;  4(1) e10
  • 24 Zhong T P, Childs S, Leu J P, Fishman M C. Gridlock signalling pathway fashions the first embryonic artery.  Nature. 2001;  414(6860) 216-220
  • 25 Torres-Vázquez J, Gitler A D, Fraser S D Van N Pham et al. Semaphorin-plexin signaling guides patterning of the developing vasculature.  Dev Cell. 2004;  7(1) 117-123
  • 26 Gebb S, Stevens T. On lung endothelial cell heterogeneity.  Microvasc Res. 2004;  68(1) 1-12
  • 27 Adamo L, Naveiras O, Wenzel P L et al.. Biomechanical forces promote embryonic haematopoiesis.  Nature. 2009;  459(7250) 1131-1135
  • 28 Lee J S, Yu Q, Shin J T et al.. Klf2 is an essential regulator of vascular hemodynamic forces in vivo.  Dev Cell. 2006;  11(6) 845-857
  • 29 Dai G, Kaazempur-Mofrad M R, Natarajan S et al.. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature.  Proc Natl Acad Sci U S A. 2004;  101(41) 14871-14876
  • 30 Garin G, Berk B C. Flow-mediated signaling modulates endothelial cell phenotype.  Endothelium. 2006;  13(6) 375-384
  • 31 Conklin B S, Vito R P, Chen C. Effect of low shear stress on permeability and occludin expression in porcine artery endothelial cells.  World J Surg. 2007;  31(4) 733-743
  • 32 Lawson N D, Vogel A M, Weinstein B M. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation.  Dev Cell. 2002;  3(1) 127-136
  • 33 Lanner F, Sohl M, Farnebo F. Functional arterial and venous fate is determined by graded VEGF signaling and notch status during embryonic stem cell differentiation.  Arterioscler Thromb Vasc Biol. 2007;  27(3) 487-493
  • 34 Seo S, Fujita H, Nakano A, Kang M, Duarte A, Kume T. The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development.  Dev Biol. 2006;  294(2) 458-470
  • 35 Hayashi H, Kume T. Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells.  PLoS One. 2008;  3(6) e2401
  • 36 Lee S W, Moskowitz M A, Sims J R. Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts.  Int J Mol Med. 2007;  19(3) 445-451
  • 37 Krishnan V, Pereira F A, Qiu Y et al.. Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase.  Science. 1997;  278(5345) 1947-1950
  • 38 You L R, Lin F J, Lee C T, DeMayo F J, Tsai M J, Tsai S Y. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity.  Nature. 2005;  435(7038) 98-104
  • 39 Shaut C A, Keene D R, Sorensen L K, Li D Y, Stadler H S. HOXA13 Is essential for placental vascular patterning and labyrinth endothelial specification.  PLoS Genet. 2008;  4(5) e1000073
  • 40 Lawson N D, Scheer N, Pham V N et al.. Notch signaling is required for arterial-venous differentiation during embryonic vascular development.  Development. 2001;  128(19) 3675-3683
  • 41 Füller T, Korff T, Kilian A, Dandekar G, Augustin H G. Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells.  J Cell Sci. 2003;  116(Pt 12) 2461-2470
  • 42 François M, Caprini A, Hosking B et al.. Sox18 induces development of the lymphatic vasculature in mice.  Nature. 2008;  456(7222) 643-647
  • 43 Wigle J T, Oliver G. Prox1 function is required for the development of the murine lymphatic system.  Cell. 1999;  98(6) 769-778
  • 44 Hong Y K, Harvey N, Noh Y H et al.. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate.  Dev Dyn. 2002;  225(3) 351-357
  • 45 Wigle J T, Harvey N, Detmar M et al.. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype.  EMBO J. 2002;  21(7) 1505-1513
  • 46 Shin D, Anderson D J. Isolation of arterial-specific genes by subtractive hybridization reveals molecular heterogeneity among arterial endothelial cells.  Dev Dyn. 2005;  233(4) 1589-1604
  • 47 Kubo H, Cao R, Brakenhielm E, Mäkinen T, Cao Y, Alitalo K. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea.  Proc Natl Acad Sci U S A. 2002;  99(13) 8868-8873
  • 48 Chang L K, Garcia-Cardeña G, Farnebo F et al.. Dose-dependent response of FGF-2 for lymphangiogenesis.  Proc Natl Acad Sci U S A. 2004;  101(32) 11658-11663
  • 49 Hogan B M, Bos F L, Bussmann J et al.. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting.  Nat Genet. 2009;  41(4) 396-398
  • 50 Maisonpierre P C, Suri C, Jones P F et al.. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.  Science. 1997;  277(5322) 55-60
  • 51 Mäkinen T, Norrmén C, Petrova T V. Molecular mechanisms of lymphatic vascular development.  Cell Mol Life Sci. 2007;  64(15) 1915-1929
  • 52 Cueni L N, Detmar M. Galectin-8 interacts with podoplanin and modulates lymphatic endothelial cell functions.  Exp Cell Res. 2009;  315(10) 1715-1723
  • 53 Levy Y, Arbel-Goren R, Hadari Y R et al.. Galectin-8 functions as a matricellular modulator of cell adhesion.  J Biol Chem. 2001;  276(33) 31285-31295
  • 54 Benjamin L E, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF.  Development. 1998;  125(9) 1591-1598
  • 55 Blose S H, Chacko S. In vitro behavior of guinea pig arterial and venous endothelial cells.  Dev Growth Differ. 1975;  17(2) 153-165
  • 56 Rensen S S, Niessen P M, van Deursen J M et al.. Smoothelin-B deficiency results in reduced arterial contractility, hypertension, and cardiac hypertrophy in mice.  Circulation. 2008;  118(8) 828-836
  • 57 Zhang J, Burridge K A, Friedman M H. In vivo differences between endothelial transcriptional profiles of coronary and iliac arteries revealed by microarray analysis.  Am J Physiol Heart Circ Physiol. 2008;  295(4) H1556-H1561
  • 58 le Noble F, Moyon D, Pardanaud L et al.. Flow regulates arterial-venous differentiation in the chick embryo yolk sac.  Development. 2004;  131(2) 361-375
  • 59 Moyon D, Pardanaud L, Yuan L, Bréant C, Eichmann A. Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo.  Development. 2001;  128(17) 3359-3370
  • 60 Othman-Hassan K, Patel K, Papoutsi M, Rodriguez-Niedenführ M, Christ B, Wilting J. Arterial identity of endothelial cells is controlled by local cues.  Dev Biol. 2001;  237(2) 398-409
  • 61 dela Paz N G, D'Amore P A. Arterial versus venous endothelial cells.  Cell Tissue Res. 2009;  335(1) 5-16
  • 62 Chi J T, Chang H Y, Haraldsen G et al.. Endothelial cell diversity revealed by global expression profiling.  Proc Natl Acad Sci U S A. 2003;  100(19) 10623-10628
  • 63 Prasain N, Stevens T. The actin cytoskeleton in endothelial cell phenotypes.  Microvasc Res. 2009;  77(1) 53-63
  • 64 Maby-El Hajjami H, Petrova T V. Developmental and pathological lymphangiogenesis: from models to human disease.  Histochem Cell Biol. 2008;  130(6) 1063-1078
  • 65 Baluk P, Fuxe J, Hashizume H et al.. Functionally specialized junctions between endothelial cells of lymphatic vessels.  J Exp Med. 2007;  204(10) 2349-2362
  • 66 Saharinen P, Tammela T, Karkkainen M J, Alitalo K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation.  Trends Immunol. 2004;  25(7) 387-395
  • 67 Drake C J, Fleming P A. Vasculogenesis in the day 6.5 to 9.5 mouse embryo.  Blood. 2000;  95(5) 1671-1679
  • 68 Wei Y, Mikawa T. Fate diversity of primitive streak cells during heart field formation in ovo.  Dev Dyn. 2000;  219(4) 505-513
  • 69 Motoike T, Markham D W, Rossant J, Sato T N. Evidence for novel fate of Flk1 + progenitor: contribution to muscle lineage.  Genesis. 2003;  35(3) 153-159
  • 70 Saga Y, Kitajima S, Miyagawa-Tomita S. Mesp1 expression is the earliest sign of cardiovascular development.  Trends Cardiovasc Med. 2000;  10(8) 345-352
  • 71 Misfeldt A M, Boyle S C, Tompkins K L, Bautch V L, Labosky P A, Baldwin H S. Endocardial cells are a distinct endothelial lineage derived from Flk1 + multipotent cardiovascular progenitors.  Dev Biol. 2009;  333(1) 78-89
  • 72 Barnett J V, Desgrosellier J S. Early events in valvulogenesis: a signaling perspective.  Birth Defects Res C Embryo Today. 2003;  69(1) 58-72
  • 73 Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development.  Nature. 1995;  378(6555) 386-390
  • 74 Ballermann B J. Glomerular endothelial cell differentiation.  Kidney Int. 2005;  67(5) 1668-1671
  • 75 Braet F, Wisse E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review.  Comp Hepatol. 2002;  1(1) 1
  • 76 Wolburg H, Wolburg-Buchholz K, Kraus J et al.. Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme.  Acta Neuropathol. 2003;  105(6) 586-592
  • 77 Liebner S, Corada M, Bangsow T et al.. Wnt/beta-catenin signaling controls development of the blood-brain barrier.  J Cell Biol. 2008;  183(3) 409-417
  • 78 Abbott N J, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier.  Nat Rev Neurosci. 2006;  7(1) 41-53
  • 79 Tousoulis D, Charakida M, Stefanadis C. Endothelial function and inflammation in coronary artery disease.  Postgrad Med J. 2008;  84(993) 368-371
  • 80 Wang H H, Kung C I, Tseng Y Y et al.. Activation of endothelial cells to pathological status by down-regulation of connexin43.  Cardiovasc Res. 2008;  79(3) 509-518
  • 81 Bergan J J, Schmid-Schönbein G W, Smith P D, Nicolaides A N, Boisseau M R, Eklof B. Chronic venous disease.  N Engl J Med. 2006;  355(5) 488-498
  • 82 Meissner M H, Moneta G, Burnand K et al.. The hemodynamics and diagnosis of venous disease.  J Vasc Surg. 2007;  46(suppl S) 4S-24S
  • 83 Wynd S, Melrose W D, Durrheim D N, Carron J, Gyapong M. Understanding the community impact of lymphatic filariasis: a review of the sociocultural literature.  Bull World Health Organ. 2007;  85(6) 493-498
  • 84 Rockson S G. The unique biology of lymphatic edema.  Lymphat Res Biol. 2009;  7(2) 97-100
  • 85 Jurisic G, Detmar M. Lymphatic endothelium in health and disease.  Cell Tissue Res. 2009;  335(1) 97-108
  • 86 de la Torre J C. Vascular basis of Alzheimer's pathogenesis.  Ann N Y Acad Sci. 2002;  977 196-215
  • 87 Buée L, Hof P R, Delacourte A. Brain microvascular changes in Alzheimer's disease and other dementias.  Ann N Y Acad Sci. 1997;  826 7-24
  • 88 Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease.  Nat Rev Neurosci. 2004;  5(5) 347-360
  • 89 Jellinger K A. Alzheimer disease and cerebrovascular pathology: an update.  J Neural Transm. 2002;  109(5-6) 813-836
  • 90 Kalaria R N. The role of cerebral ischemia in Alzheimer's disease.  Neurobiol Aging. 2000;  21(2) 321-330

Cam PattersonM.D. 

McAllister Heart Institute, University of North Carolina

Chapel Hill, NC 27599-7525

Email: cpatters@med.unc.edu

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