© 2001 American Heart Association, Inc.
Editorials |
Transcriptional Regulation of Vascular Development
From The University of Texas Southwestern Medical Center at Dallas, Dallas, Tex.
Correspondence to Thomas N. Sato, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, NB11.200, Dallas, TX 75390-8573. E-mail island1005{at}aol.com
Key Words: vascular development\b • angiogenesis • Tie2 gene • gene expression
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Introduction |
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 Top Introduction References |
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Formation of the vascular system is a landmark event during development. Normal development and function of virtually all organs rely on the feeding and gas exchanges mediated by the vascular system. Although the establishment of the vascular system requires a complex developmental process involving multiple cell types, the initial formation of the rudimentary vascular network is primarily accomplished by a single cell type, endothelial cells.
Endothelial cells originate from an embryonic mesoderm
during the initial phase of the vascular
development.1 However, very
little is known regarding the control mechanisms underlying the
specification of endothelial cells. The overview of the endothelial
cell specification during development is shown in the
Figure
.
A subset of mesodermal cells differentiates to a bipotential stem cell
called a hemangioblast, which differentiates to either hematopoietic or
endothelial cell lineages. Endothelial cells then assemble together to
form a rudimentary vascular network, referred to as the primary
capillary plexus.1 The
primary capillary plexus is characterized by its uniform and relatively
simple network pattern consisting of a honeycomb-like vessel branching
pattern. However, it has recently become evident that the primary
capillary plexus is made of at least two distinct types of endothelial
cells: arterial and venous endothelial
cells.2 3 An
arterial endothelial cell type is characterized by its specific
expression of ephrin-B2 and a venous type expresses specifically
EphB4.2 3 Although
we know the presence of these two types of endothelial cells at this
initial stage of the vessel formation, an origin of the arterial and
venous endothelial types remains unknown. It is possible that there are
already two types of progenitor cells that are committed to either
arterial or venous types as hemangioblasts differentiate to endothelial
lineages (dotted arrow line in the
Figure).
Alternatively, they originate from differentiated endothelial cells
(solid arrow line in the
Figure).
In the latter scenario, it would be interesting to consider the
possibility that all of the initial population of the differentiated
endothelial cells may represent only one type, such as venous type,
from which the other type (in this case, arterial) is derived. In such
a case, the venous type could be generated as a consequence of a
default pathway of endothelial lineage differentiation, and the
generation of arterial type could require inductive
signals.
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The problem of cell type differentiation has been a classic subject and extensively studied in other fields of biology such as immunology and neurobiology.4 In these fields, varieties of cell types are defined by their combinatorial expression of the specific markers. Identification and the systematic classification of such specific markers have led to significant advances in our understanding of the molecular mechanisms underlying the origin of cell type heterogeneity in immune and neural systems. However, the origin of endothelial cells and the generation of the diverse endothelial types have been the subject of molecular studies during only the last few years. One of the bottlenecks in this area has been the lack of systematic dissection of the expression patterns of specific markers in the various endothelial cell populations. Classification of endothelial cell types based on specific expression of such markers could be expected to lead directly to analysis of mechanisms underlying their origin and subtype differentiation.
The study of Dube et al5 in this issue of Circulation Research is an example of this type of investigative approach. The authors are trying to assess whether the problem of endothelial origin can be determined by transcriptional regulation. Tie2/Tek is one of the markers expressed primarily in endothelial lineages.6 7 8 9 It is undetectable in this hemangioblast population, but it is expressed in further differentiated endothelial cells. Therefore, authors have studied the transcriptional regulation of the Tie2 gene in an effort to understand transcriptional mechanisms underlying the specification of endothelial cells. Previously, cis-acting elements in both promoter and enhancer regions of the Tie2 gene that are critical for its endothelial-specific expression were defined.10 11 ELF-1 was identified as one of the Ets transcription factors that shows expression in endothelial cells. Furthermore, ELF-1 binds to one of the cis-acting sequences in the Tie2 promoter that is essential for its endothelial-specific expression. It was also shown that the endothelial nuclear extract contains ELF-1 that binds to the same cis-acting sequences in vitro. In addition, ELF-1 can transactivate the reporter expression mediated via the Tie2 promoter in cultured cells. Interestingly, ELF-1 can also transactivate the endothelial-specific promoter derived from another endothelial-specific gene, Tie1. On the basis of this evidence, Dube et al5 suggest that ELF-1 controls the expression of endothelial-specific marker genes such as Tie1 and Tie2. Although the data presented are correlative, ELF-1 should be added to the list of potentially important transcription factors in vascular development. Some key future investigations could include (1) specific perturbation of ELF-1 function in developing embryos to show that ELF-1, in fact, is directly involved in the regulation of Tie1 and Tie2 gene expression during vascular development; (2) precise determination of the temporal and spatial ELF-1 expression pattern during endothelial differentiation; and (3) examination as to whether induction of ELF-1 in endothelial precursor cells leads to Tie1 and Tie2 expression.
As suggested based on the presence of multiple cis-acting sequences within the Tie2 gene mediating endothelial-specific expression, it is likely that the combinatorial functions of many transcription factors present in developing endothelial cells are required for Tie2 gene expression.10 11 12 The clever use of increasing genomic information and further characterization of ELF-1 and other known and novel transcription factors could be expected to contribute to new understanding of how endothelial specification is regulated at the transcriptional level. Further identification and systematic classification of markers in endothelial cell subtypes should help discern the molecular mechanisms underlying the generation of these diverse classes of endothelial cells during vascular development.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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2. Gerety SS, Wang HU, Chen ZF, Anderson DJ. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell. 1999;4:403–414.[Medline] [Order article via Infotrieve]
3. Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell. 1998;93:741–753.[Medline] [Order article via Infotrieve]
4. Anderson DJ. The neural crest cell lineage problem: neuropoiesis? Neuron. 1989;3:1–12.[Medline] [Order article via Infotrieve]
5.
Dube A, Thai S,
Gaspar J, Rudders S, Libermann TA, Iruela-Arispe L, Oettgen P. ELF-1 is
a transcriptional regulator of the Tie2 gene during vascular
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6. Maisonpierre PC, Goldfarb M, Yancopoulos GD, Gao G. Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. Oncogene. 1993;8:1631–1637.[Medline] [Order article via Infotrieve]
7. Dumont DJ, Gradwohl GJ, Fong G-H, Auerbach R, Breitman ML. The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene. 1993;8:1293–1301.[Medline] [Order article via Infotrieve]
8.
Sato TN, Qin Y,
Kozak CA, Audus KL. Tie-1 and
tie-2 define another class of
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9. Schnurch H, Risau W. Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development. 1993;119:957–968.[Abstract]
10. Schlaeger TM, Qin Y, Fujiwara Y, Magram J, Sato TN. Vascular endothelial cell lineage-specific promoter in transgenic mice. Development. 1995;121:1089–1098.[Abstract]
11.
Schlaeger TM,
Bartunkova S, Lawitts JA, Teichmann G, Risau W, Deutch U, Sato TN.
Uniform vascular-endothelial-cell-specific gene expression in both
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12. Fadel BM, Boutet SC, Quertermous T. Functional analysis of the endothelial cell-specific Tie2/Tek promoter identifies unique protein-binding elements. Biochem J. 1998;330(pt 1):335–343.
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