An anteroposterior wave of vascular inhibitor downregulation signals aortae fusion along the embryonic midline axis

Paracrine signals, both positive and negative, regulate the positioning and remodeling of embryonic blood vessels. In the embryos of mammals and birds, the first major remodeling event is the fusion of bilateral dorsal aortae at the midline to form the dorsal aorta. Although the original bilaterality of the dorsal aortae occurs as the result of inhibitory factors (antagonists of BMP signaling) secreted from the midline by the notochord, it is unknown how fusion is later signaled. Here, we report that dorsal aortae fusion is tightly regulated by a change in signaling by the notochord along the anteroposterior axis. During aortae fusion, the notochord ceases to exert its negative influence on vessel formation. This is achieved by a transcriptional downregulation of negative regulators while positive regulators are maintained at pre-fusion levels. In particular, Chordin, the most abundant BMP antagonist expressed in the notochord prior to fusion, undergoes a dramatic downregulation in an anterior to posterior wave. With inhibitory signals diminished and sustained expression of the positive factors SHH and VEGF at the midline, fusion of the dorsal aortae is signaled. These results demonstrate a novel mechanism by which major modifications of the vascular pattern can occur through modulation of vascular inhibitors without changes in the levels of positive vascular regulators.

[1]  A. Navis,et al.  A series of normal stages in the development of the chick embryo. 1951. , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[2]  Michael S. Becker,et al.  Beta1 integrin establishes endothelial cell polarity and arteriolar lumen formation via a Par3-dependent mechanism. , 2010, Developmental cell.

[3]  A. Bogdanov,et al.  In vitro and In vivo imaging of antivasculogenesis induced by Noggin protein expression in human venous endothelial cells , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  L. Ellis,et al.  Role of Class 3 Semaphorins and Their Receptors in Tumor Growth and Angiogenesis , 2009, Clinical Cancer Research.

[5]  E. Dejana,et al.  The molecular basis of vascular lumen formation in the developing mouse aorta. , 2009, Developmental cell.

[6]  H. Kleinman,et al.  The endothelial cell tube formation assay on basement membrane turns 20: state of the science and the art , 2009, Angiogenesis.

[7]  T. Mikawa,et al.  Notochord-derived BMP antagonists inhibit endothelial cell generation and network formation. , 2009, Developmental biology.

[8]  J. Haigh Role of VEGF in organogenesis , 2008, Organogenesis.

[9]  T. Yatskievych,et al.  Non-canonical Wnt signaling through Wnt5a/b and a novel Wnt11 gene, Wnt11b, regulates cell migration during avian gastrulation. , 2008, Developmental biology.

[10]  M. Grim,et al.  Sonic hedgehog is required for the assembly and remodeling of branchial arch blood vessels , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  C. O'brien,et al.  Chordin-like 1, a bone morphogenetic protein-4 antagonist, is upregulated by hypoxia in human retinal pericytes and plays a role in regulating angiogenesis , 2008, Molecular vision.

[12]  K. Miyazono,et al.  BMPs promote proliferation and migration of endothelial cells via stimulation of VEGF-A/VEGFR2 and angiopoietin-1/Tie2 signalling. , 2008, Journal of biochemistry.

[13]  T. Mikawa,et al.  Induction of proepicardial marker gene expression by the liver bud , 2007, Development.

[14]  Ruijin Huang,et al.  FGFs, Wnts and BMPs mediate induction of VEGFR-2 (Quek-1) expression during avian somite development. , 2007, Developmental biology.

[15]  T. Mikawa,et al.  Enhanced sensitivity and stability in two‐color in situ hybridization by means of a novel chromagenic substrate combination , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[16]  P. Krieg,et al.  Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. , 2006, Developmental biology.

[17]  T. Nagase,et al.  Defects in Aortic Fusion and Craniofacial Vasculature in the Holoprosencephalic Mouse Embryo under Inhibition of Sonic Hedgehog Signaling , 2006, The Journal of craniofacial surgery.

[18]  D. Huylebroeck,et al.  The novel Smad-interacting protein Smicl regulates Chordin expression in the Xenopus embryo , 2005, Development.

[19]  Ruijin Huang,et al.  BMP4 and noggin control embryonic blood vessel formation by antagonistic regulation of VEGFR-2 (Quek1) expression. , 2005, Developmental biology.

[20]  Thomas M. Jessell,et al.  Semaphorin 3E and Plexin-D1 Control Vascular Pattern Independently of Neuropilins , 2005, Science.

[21]  S. Vokes,et al.  Hedgehog signaling is essential for endothelial tube formation during vasculogenesis , 2004, Development.

[22]  S. Kishi,et al.  Crucial role of activin a in tubulogenesis of endothelial cells induced by vascular endothelial growth factor. , 2004, Endocrinology.

[23]  T. Mikawa,et al.  Negative regulation of midline vascular development by the notochord. , 2004, Developmental cell.

[24]  M. Tessier-Lavigne,et al.  Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function , 2003, Nature.

[25]  T. Mikawa,et al.  Optic cup morphogenesis requires pre-lens ectoderm but not lens differentiation. , 2003, Developmental biology.

[26]  A. Bikfalvi,et al.  Regulation of vascular development by fibroblast growth factors , 2003, Cell and Tissue Research.

[27]  B. Weinstein,et al.  sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. , 2002, Developmental cell.

[28]  A. Nagy,et al.  Insufficient VEGFA activity in yolk sac endoderm compromises haematopoietic and endothelial differentiation. , 2002, Development.

[29]  M. Goumans,et al.  Balancing the activation state of the endothelium via two distinct TGF‐β type I receptors , 2002, The EMBO journal.

[30]  Takayuki Asahara,et al.  The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors , 2001, Nature Medicine.

[31]  M. Dyer,et al.  Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. , 2001, Development.

[32]  S. Chapman,et al.  Improved method for chick whole‐embryo culture using a filter paper carrier , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[33]  C. Tickle,et al.  Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development. , 2000, Development.

[34]  C. McPherson,et al.  Expression and regulation of type I BMP receptors during early avian sympathetic ganglion development. , 2000, Developmental biology.

[35]  P. Donahoe,et al.  Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  P. Krieg,et al.  Endoderm patterning by the notochord: development of the hypochord in Xenopus. , 2000, Development.

[37]  A. Streit,et al.  Mesoderm patterning and somite formation during node regression: differential effects of chordin and noggin , 1999, Mechanisms of Development.

[38]  S. Gory-Fauré,et al.  Role of vascular endothelial-cadherin in vascular morphogenesis. , 1999, Development.

[39]  B. Weinstein What guides early embryonic blood vessel formation? , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[40]  J. Clarke,et al.  Differential patterning of ventral midline cells by axial mesoderm is regulated by BMP7 and chordin. , 1999, Development.

[41]  Y. Takahashi,et al.  Somitogenesis controlled by Noggin. , 1998, Developmental biology.

[42]  P. Krieg,et al.  VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. , 1998, Development.

[43]  A. McMahon,et al.  Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. , 1998, Genes & development.

[44]  T. Jessell,et al.  Chordin regulates primitive streak development and the stability of induced neural cells, but is not sufficient for neural induction in the chick embryo. , 1998, Development.

[45]  A. Lassar,et al.  Regulation of dorsal somitic cell fates: BMPs and Noggin control the timing and pattern of myogenic regulator expression. , 1998, Genes & development.

[46]  J. Kondo,et al.  Inhibition of DNA synthesis and tube morphogenesis of cultured vascular endothelial cells by chondromodulin‐I , 1997, FEBS letters.

[47]  Thomas N. Sato,et al.  Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. , 1997, Science.

[48]  N. Ueno,et al.  Mesodermal subdivision along the mediolateral axis in chicken controlled by different concentrations of BMP-4. , 1997, Development.

[49]  J. Cooke,et al.  Chick noggin is expressed in the organizer and neural plate during axial development, but offers no evidence of involvement in primary axis formation. , 1997, The International journal of developmental biology.

[50]  A. Lassar,et al.  A role for bone morphogenetic proteins in the induction of cardiac myogenesis. , 1997, Genes & development.

[51]  Pamela F. Jones,et al.  Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis , 1996, Cell.

[52]  Pamela F. Jones,et al.  Isolation of Angiopoietin-1, a Ligand for the TIE2 Receptor, by Secretion-Trap Expression Cloning , 1996, Cell.

[53]  J. Kondo,et al.  A Novel Growth-Promoting Factor Derived from Fetal Bovine Cartilage, Chondromodulin II , 1996, The Journal of Biological Chemistry.

[54]  C. Tabin,et al.  Regulation of patched by sonic hedgehog in the developing neural tube. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[56]  C. Little,et al.  Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[57]  D. Connolly,et al.  Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. , 1989, The Journal of clinical investigation.

[58]  H. Kleinman,et al.  Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures , 1988, The Journal of cell biology.

[59]  F. Dieterlen‐Lièvre,et al.  Vasculogenesis in the early quail blastodisc as studied with a monoclonal antibody recognizing endothelial cells. , 1987, Development.

[60]  S. Schwartz,et al.  Inhibition of endothelial regeneration by type-beta transforming growth factor from platelets. , 1986, Science.

[61]  H. Dvorak,et al.  Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. , 1983, Science.

[62]  V. Hamburger,et al.  A series of normal stages in the development of the chick embryo , 1951, Journal of morphology.

[63]  V. Bautch,et al.  Blood vessel patterning at the embryonic midline. , 2004, Current topics in developmental biology.

[64]  T. J. Poole,et al.  The role of FGF and VEGF in angioblast induction and migration during vascular development , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[65]  H. Arnold,et al.  BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos , 1998, Mechanisms of Development.

[66]  D. Gospodarowicz Humoral control of cell proliferation: the role of fibroblast growth factor in regeneration, angiogenesis, wound healing, and neoplastic growth. , 1976, Progress in clinical and biological research.