*601667	Links
ANGIOPOIETIN 1; ANGPT1

Alternative titles; symbols

ANG1

Gene map locus 8q22

TEXT

CLONING

TIE2 (TEK; 600221) is a receptor-like tyrosine kinase expressed almost exclusively in endothelial cells and early hematopoietic cells and required for the normal development of vascular structures during embryogenesis. Davis et al. (1996) identified a secreted ligand for TIE2, termed angiopoietin-1, using a novel expression cloning technique that involved intracellular trapping and protection of the ligand in COS cells. The human gene encodes a 498-amino acid polypeptide with predicted coiled-coil and fibrinogen-like domains. The structure of angiopoietin-1 differs from that of known angiogenic factors or other ligands for receptor tyrosine kinases. Although angiopoietin-1 bound and induced the tyrosine phosphorylation of TIE2, it did not directly promote the growth of cultured endothelial cells. However, its expression and close proximity to developing blood vessels implicated angiopoietin-1 in endothelial developmental processes. See also angiopoietin-2 (601922).

GENE FUNCTION

Folkman and D'Amore (1996) pointed out that vascular abnormality in both mice and humans is defined by a receptor-ligand system on the vascular endothelial cell. An apparent defect in vascular remodeling can result from an activating mutation of the receptor (Vikkula et al., 1996), from the absence of the ligand (Suri et al., 1996), or from a deficiency of the TIE2 receptor itself (Sato et al., 1995). However, while each situation reveals a general abnormality in vascular remodeling, there may be subtle but important differences.

To explore the possibility that VEGF (192240) and angiopoietins collaborate during tumor angiogenesis, Holash et al. (1999) analyzed several different murine and human tumor models. The apparent association of tumor vessel regression, apoptosis, and disruption of endothelial cell interactions with support cells in rat C6 gliomas raised the possibility that blockade of the stabilizing action of Ang1 might be contributing to tumor vessel regression. Consistent with this possibility, Holash et al. (1999) noted that angiopoietin-1 was antiapoptotic for cultured endothelial cells and expression of its antagonist angiopoietin-2 was induced in the endothelium of co-opted tumor vessels before their regression. Diffuse angiopoietin-1 expression in human tumors resembled that seen in the rat model. Holash et al. (1999) suggested that a subset of tumors rapidly co-opts existing host vessels to form an initially well vascularized tumor mass. Perhaps as part of a host defense mechanism there is widespread regression of these initially co-opted vessels, leading to a secondarily avascular tumor and a massive tumor cell loss. However, the remaining tumor is ultimately rescued by robust angiogenesis at the tumor margin.

Loughna and Sato (2001) showed that the combinatorial function of angiopoietin-1 and the orphan receptor TIE1 (600222) is critical for the development of the right-hand side venous system but is dispensable for the left-hand side venous system. This finding revealed the existence of a distinct genetic program for the establishment of the right-hand side and left-hand side vascular networks well before the network asymmetry becomes morphologically discernible.

Geva et al. (2002) investigated VEGFA, ANGPT1, and ANGPT2 transcript profiles, and the protein products that they encode, in placentas from normotensive pregnancies throughout pregnancy. Quantitative real-time PCR analysis demonstrated that VEGFA and ANGPT1 mRNA increased in a linear pattern by 2.5% (not significant) and 2.8%/week (P = 0.034), respectively, whereas ANGPT2 decreased logarithmically by 3.5%/week (P = 0.0003). ANGPT2 mRNA was 400- and 100-fold higher than that of ANGPT1 and VEGFA, respectively, in the first trimester and declined to 20-fold and 7-fold in the third. In situ hybridization and immunohistochemical studies revealed that VEGFA was localized in cyto- and syncytiotrophoblast and perivascular cells, whereas ANGPT1 and ANGPT2 were only in syncytiotrophoblast and perivascular cells in the immature intermediate villi during the first and second trimesters, and mature intermediate and terminal villi during the third trimester. The authors concluded that these molecules may play important roles in placental biology and chorionic villus vascular development and remodeling in an autocrine/paracrine manner.

Interaction of hematopoietic stem cells (HSCs) with their particular microenvironments, known as stem cell niches, is critical for adult hematopoiesis in bone marrow. Arai et al. (2004) demonstrated that HSCs expressing the receptor tyrosine kinase TIE2 are quiescent and antiapoptotic and comprise a side population of HSCs that adhere to osteoblasts in the bone marrow niche. The interaction of TIE2 with its ligand, ANG1, induced cobblestone formation of HSCs in vitro and maintained in vivo long-term repopulating activity of HSCs. Furthermore, ANG1 enhanced the ability of HSCs to become quiescent and induced adhesion to bone, resulting in protection of the HSC compartment from myelosuppressive stress. These data suggested that the TIE2/ANG1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the bone marrow niche.

GENE STRUCTURE

Ward et al. (2001) determined that the ANGPT1 gene contains 9 exons and spans 48.3 kb. Exons 1 to 5 encode the N terminus, the coiled-coil domain, and part of the hinge region, and exons 5 to 9 encode the remainder of the hinge region, the fibrinogen (see 134820)-like domain, and the C terminus.

MAPPING

By FISH and radiation hybrid analysis, Cheung et al. (1998) mapped the ANGPT1 gene to 8q22.3-q23. Using radiation hybrid analysis and FISH, Grosios et al. (1999) also mapped the ANGPT1 gene to chromosome 8q22.3-q23. By FISH, Valenzuela et al. (1999) mapped the ANGPT1 gene to 8q22 in a region that shows homology of synteny to mouse chromosome 15, where they mapped the mouse Angpt1 gene. However, by indirect in situ PCR and FISH, Marziliano et al. (1999) mapped the Angpt1 gene in the mouse to chromosome 9E2.

ANIMAL MODEL

Suri et al. (1996) showed that mice engineered to lack angiopoietin-1 display angiogenic defects reminiscent of those previously seen in mice lacking Tie2, demonstrating that angiopoietin-1 is a primary physiologic ligand for Tie2 and that it has critical in vivo angiogenic actions that are distinct from vascular endothelial growth factor (VEGF; 192240) and that are not reflected in the classic in vitro assays used to characterize VEGF. They concluded that angiopoietin-1 appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.

Targeted gene inactivation studies in mice show that vascular endothelial growth factor is necessary for the early stages of vascular development and that angiopoietin-1 is required for the later stages of vascular remodeling. Suri et al. (1998) showed that transgenic overexpression of angiopoietin-1 in the skin of mice produces larger, more numerous, and more highly branched vessels. These results raised the possibility that angiopoietins can be used, alone or in combination with VEGF, to promote therapeutic angiogenesis.

Thurston et al. (1999) compared transgenic mice overexpressing either Vegf or Ang1 in the skin. Vegf-induced blood vessels were leaky, whereas those induced by Ang1 were not. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and Vegf had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Thurston et al. (1999) concluded that ANG1, therefore, may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEFG and, in combination with VEGF, for promoting growth of nonleaky vessels.

SEE ALSO

Hanahan (1997)

REFERENCES

1. Arai, F.; Hirao, A.; Ohmura, M.; Sato, H.; Matsuoka, S.; Takubo, K.; Ito, K.; Koh, G. Y.; Suda, T. :

Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118: 149-161, 2004.
PubMed ID : 15260986

2. Cheung, A. H.; Stewart, R. J.; Marsden, P. A. :

Endothelial Tie2/Tek ligands angiopoietin-1 (ANGPT1) and angiopoietin-2 (ANGPT2): regional localization of the human genes to 8q22.3-q23 and 8p23. Genomics 48: 389-391, 1998.
PubMed ID : 9545648

3. Davis, S.; Aldrich, T. H.; Jones, P. F.; Acheson, A.; Compton, D. L.; Jain, V.; Ryan, T. E.; Bruno, J.; Radziejewski, C.; Maisonpierre, P. C.; Yancopoulos, G. D. :

Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87: 1161-1169, 1996.
PubMed ID : 8980223

4. Folkman, J.; D'Amore, P. A. :

Blood vessel formation: what is its molecular basis? Cell 87: 1153-1155, 1996.
PubMed ID : 8980221

5. Geva, E.; Ginzinger, D. G.; Zaloudek, C. J.; Moore, D. H.; Byrne, A.; Jaffe, R. B. :

Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J. Clin. Encodr. Metab. 87: 4213-4224, 2002.

6. Grosios, K.; Leek, J. P.; Markham, A. F.; Yancopoulos, G. D.; Jones, P. F. :

Assignment of ANGPT4, ANGPT1, and ANGPT2 encoding Angiopoietins 4, 1 and 2 to human chromosome bands 20p13, 8q22.3-q23 and 8p23.1, respectively, by in situ hybridization and radiation hybrid mapping. Cytogenet. Cell Genet. 84: 118-120, 1999.
PubMed ID : 10343124

7. Hanahan, D. :

Signaling vascular morphogenesis and maintenance. Science 277: 48-50, 1997.
PubMed ID : 9229772

8. Holash, J.; Maisonpierre, P. C.; Compton, D.; Boland, P.; Alexander, C. R.; Zagzag, D.; Yancopoulos, G. D.; Wiegand, S. J. :

Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284: 1994-1998, 1999.
PubMed ID : 10373119

9. Loughna, S.; Sato, T. N. :

A combinatorial role of angiopoietin-1 and orphan receptor TIE1 pathways in establishing vascular polarity during angiogenesis. Molec. Cell 7: 233-239, 2001.
PubMed ID : 11172728

10. Marziliano, N.; Crovella, S.; Audero, E.; Pecile, V.; Bussolino, F.; Amoroso, A.; Garagna, S. :

Genetic mapping of the mouse homologue of the human angiopoietin-1 gene (Agpt) to mouse chromosome 9E2 by in situ hybridization. Cytogenet. Cell Genet. 87: 199-200, 1999.
PubMed ID : 10702667

11. Sato, T. N.; 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 376: 70-73, 1995.
PubMed ID : 7596437

12. Suri, C.; Jones, P. F.; Patan, S.; Bartunkova, S.; Maisonpierre, P. C.; Davis, S.; Sato, T. N.; Yancopoulos, G. D. :

Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87: 1171-1180, 1996.
PubMed ID : 8980224

13. Suri, C.; McClain, J.; Thurston, G.; McDonald, D. M.; Zhou, H.; Oldmixon, E. H.; Sato, T. N.; Yancopoulos, G. D. :

Increased vascularization in mice overexpressing angiopoietin-1. Science 282: 468-471, 1998.
PubMed ID : 9774272

14. Thurston, G.; Suri, C.; Smith, K.; McClain, J.; Sato, T. N.; Yancopoulos, G. D.; McDonald, D. M. :

Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286: 2511-2514, 1999.
PubMed ID : 10617467

15. Valenzuela, D. M.; Griffiths, J. A.; Rojas, J.; Aldrich, T. H.; Jones, P. F.; Zhou, H.; McClain, J.; Copeland, N. G.; Gilbert, D. J.; Jenkins, N. A.; Huang, T.; Papadopoulos, N.; Maisonpierre, P. C.; Davis, S.; Yancopoulos, G. D. :

Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc. Nat. Acad. Sci. 96: 1904-1909, 1999.
PubMed ID : 10051567

16. Vikkula, M.; Boon, L. M.; Carraway, K. L., III; Calvert, J. T.; Diamonti, A. J.; Goumnerov, B.; Pasyk, K. A.; Marchuk, D. A.; Warman, M. L.; Cantley, L. C.; Mulliken, J. B.; Olsen, B. R. :

Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87: 1181-1190, 1996.
PubMed ID : 8980225

17. Ward, E. G.; Grosios, K.; Markham, A. F.; Jones, P. F. :

Genomic structures of the human angiopoietins show polymorphism in angiopoietin-2. Cytogenet. Cell Genet. 94: 147-154, 2001.
PubMed ID : 11856872

CONTRIBUTORS

Patricia A. Hartz - updated : 8/23/2005
Stylianos E. Antonarakis - updated : 8/17/2004
John A. Phillips, III - updated : 12/16/2002
Carol A. Bocchini - updated : 2/15/2001
Stylianos E. Antonarakis - updated : 1/31/2001
Ada Hamosh - updated : 12/27/1999
Ada Hamosh - updated : 6/17/1999
Victor A. McKusick - updated : 3/23/1999
Carol A. Bocchini - updated : 3/8/1999
Victor A. McKusick - updated : 10/14/1998

CREATION DATE

Victor A. McKusick : 2/6/1997

EDIT HISTORY

mgross : 8/23/2005
mgross : 8/23/2005
mgross : 8/17/2004
alopez : 12/16/2002
alopez : 12/16/2002
carol : 2/15/2001
mgross : 1/31/2001
alopez : 12/27/1999
carol : 10/21/1999
alopez : 6/17/1999
alopez : 6/17/1999
alopez : 6/17/1999
mgross : 4/7/1999
mgross : 4/5/1999
terry : 3/23/1999
carol : 3/11/1999
terry : 3/9/1999
carol : 3/8/1999
terry : 10/14/1998
mark : 7/9/1997
terry : 7/9/1997
mark : 4/9/1997
terry : 2/7/1997
terry : 2/6/1997
terry : 2/6/1997
mark : 2/6/1997

Copyright © 1966-2007 Johns Hopkins University