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Genes critical to vasculogenesis as defined by systematic analysis of vascular defects in knockout mice.

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Mouse House
THE ANATOMICAL RECORD PART A 286A:875– 884 (2005)
Genes Critical to Vasculogenesis as
Defined by Systematic Analysis of
Vascular Defects in Knockout Mice
W. SCOTT ARGRAVES* AND CHRISTOPHER J. DRAKE
Department of Cell Biology and Anatomy, Medical University of South Carolina,
Charleston, South Carolina
ABSTRACT
To identify genes important to the process of vasculogenesis, we evaluated embryonic vascular anomalies from 100 mouse knockout studies
using a novel meta-analysis approach. By applying this method, termed
approach for ranking of embryonic vascular anomalies (AREVA), rank
scores were calculated for each knockout based on the occurrence of vascular defects during periods of vasculogenesis in specific embryonic regions.
As a result, 12 genes (fibronectin, VEGFR-1/Flt-1, VEGFR-2/Flk-1, alpha 5
integrin, Tek/Tie2, VE-cadherin, VEGFA, connexin 45, ShcA, cytochrome
P450 reductase, CD148/DEP-1, and EphrinB2) were determined to play
critical roles in vasculogenesis. Functional categorization of these genes
revealed the fundamental importance of VEGF signaling since 10 of the 12
genes (fibronectin, VEGFR-1/Flt-1, VEGFR-2/Flk-1, alpha 5 integrin, VEcadherin, VEGFA, ShcA, cytochrome P450 reductase, CD148/DEP-1, and
EphrinB2) relate to this pathway. Furthermore, the findings highlight a
potential network for regulating VEGF signaling involving integration of
fibronectin, EphrinB2, Tie2, and connexin 45 signaling pathways via the
ShcA/Ras/Raf/Mek/Erk cascade. In addition to retrospective application of
AREVA as done herein, AREVA can be used prospectively to determine the
relevancy to vasculogenesis of newly inactivated genes.
©
2005 Wiley-Liss, Inc.
Key words: angioblast; endothelial cell; fibronectin; ShcA;
vasculogenesis
Gene deletion studies in mice have led to the identification
of numerous genes that are critical to embryonic blood vessel
formation. In virtually all of these studies, embryonic vascular defects have been attributed to either aberrant angiogenesis, failed remodeling of primary vascular networks, or impaired mural cell investment. Only three genes, VEGFR-2/
Flk-1, fibronectin, and cytochrome P450 reductase/Cpr, have
emerged from such studies as being critical to vasculogenesis
(Fong et al., 1995; Shalaby et al., 1995; Yang et al., 2000), the
process by which endothelial progenitors (angioblasts) assemble and form endothelial tubes. Undoubtedly, there are
more genes that are critical to the process of vasculogenesis.
There are many reasons why targeted gene deletion has
not led to identification of more vasculogenesis genes. A
major reason is that vasculogenesis is generally assessed in
mutant vertebrate embryos at a single stage despite the fact
that the process of vasculogenesis is initiated in the embryo
at different places and times. The first blood vessels of the
mouse begin to form in the yolk sac at 6 – 6.5 dpc (Drake and
Fleming, 2000). Later in development (i.e., 7–7.5 dpc), vas©
2005 WILEY-LISS, INC.
culogenesis is initiated within the embryo proper, with blood
vessels appearing in the following order: endocardium, primary vascular networks lateral to the midline, paired dorsal
aortae, head and cardinal vessels. It is of central importance
Grant sponsor: National Institutes of Health; Grant number:
HL57375, HL61873, and HL52813.
*Correspondence to: W. Scott Argraves, Department of Cell
Biology and Anatomy, Medical University of South Carolina,
173 Ashley Avenue, Charleston, SC 29425. Fax: 843-792-0664.
E-mail: argraves@musc.edu
Christopher J. Drake, Department of Cell Biology and Anatomy, Medical University of South Carolina, 173 Ashley Avenue,
Charleston, SC 29425. Fax: 843-792-0664.
E-mail: drakec@musc.edu
Received 19 May 2005; Accepted 21 June 2005
DOI 10.1002/ar.a.20232
Published online 21 August 2005 in Wiley InterScience
(www.interscience.wiley.com).
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ARGRAVES AND DRAKE
to understand that nascent blood vessels in one region of a
mutant embryo can appear abnormal while those in regions
that were initiated at a later stage are normal. This is exemplified by embryos deficient in VE-cadherin, in which
blood vessels of the yolk sac are abnormal at 8.5 dpc,
whereas the dorsal aortae at this stage appear normal
(Crosby et al., 2005). However, by 9.5 dpc, the dorsal aortae
of VE-cadherin nulls are morphologically abnormal as well.
Accordingly, assessment of the role of a given gene in vasculogenesis can benefit from a systematic evaluation of the
spatial and temporal effects of gene ablation on embryonic
blood vessel formation.
Here we describe a method for scoring a gene’s importance to vasculogenesis based on spatiotemporal vascular
defects occurring in response to its inactivation. Using
this approach, we retrospectively evaluated embryonic
vascular anomalies in numerous mouse knockout studies
and ranked the targeted genes according to their importance in vasculogenesis. Based on this analysis, a novel set
of genes was identified as being critical to vasculogenesis.
MATERIALS AND METHODS
Approach for Ranking of Embryonic Vascular
Anomalies (AREVA)
We have developed a method for assessing the importance
of a gene to the process of vasculogenesis based on phenotypic analysis of embryos deficient in the expression of the
given gene. The method is referred to as the approach for
ranking of embryonic vascular anomalies (AREVA) and is
designed to tabulate a numeric score for a gene based on the
developmental stage at which mutant embryos display vascular defects at three specific sites of vasculogenesis. The
three embryonic sites include the yolk sac, endocardium, and
paired dorsal aortae. At each site, blood vessel formation is
assessed at three stages of development (i.e., 6 – 6.5, 7–7.5,
and 8 – 8.5 for yolk sac vessels and 7–7.5, 8 – 8.5, and 9 –9.5
dpc for the endocardium and dorsal aortae). The ranges of
development were chosen as they represent periods in which
angioblasts assemble to form nascent blood vessels within
each site (Drake and Fleming, 2000; Crosby et al., 2005). The
endpoints for each period represent the stage at which angioblast populations in each vasculogenic region are no
longer present, having been converted into endothelial cells
(Drake and Fleming, 2000).
Measures of vascular abnormality include gross morphological anomalies such as absence, enlargement, or
reduced diameter of blood vessels and failure of capillarylike networks to be remodeled into larger-caliber blood
vessels. For assessment of the earliest events in vasculogenesis, morphological aspects of the process including
angioblast aggregation and primary capillary-like network formation need to be evaluated. One means to accomplish this is to perform immunofluorescent microscopic examination using antibodies that detect
angioblasts and early endothelial cells. For example, angioblasts can be detected as SCL/Tal-1 and Flk-1 double
positive cells; early endothelial cells can be detected as
either Flk-1 and PECAM-1 double positive cells or SCL/
Tal-1 and PECAM-1 double positive as previously described (Drake and Fleming, 2000; Argraves et al., 2002).
A template of procedures for examination of the earlystage mouse vasculature, including embryo dissection and
whole-mount immunolabeling, has been described elsewhere (Drake and Fleming, 2000; Crosby et al., 2005).
The AREVA scoring algorithm is weighted such that vascular defects at each of the sites receive positive scores,
whereas normal blood vessels at given sites receive negative
scores. The scores for vascular defects are further weighted
such that early stage defects receive higher scores than later
stage defects. For example, at 6 – 6.5 dpc, abnormal vessels
in the yolk sac receive a 3 and normal vessels receive a ⫺3.
At 7–7.5 dpc, abnormal vessels in the yolk sac receive a 2 and
normal vessels receive a ⫺2. At 8 – 8.5 dpc, abnormal vessels
in the yolk sac receive a 1 and normal vessels receive a ⫺1.
Since the endocardium and dorsal aortae initiate formation
later than the yolk sac vessels, their scoring period ranges
from 7 to 9.5 dpc. At 7–7.5 dpc, abnormal vessels in the
endocardium and dorsal aortae receive a 3 and normal vessels receive a ⫺3. At 8 – 8.5 dpc, abnormal vessels in the
endocardium and dorsal aortae receive a 2 and normal vessels receive a ⫺2. At 9 –9.5 dpc, abnormal vessels in the
endocardium and dorsal aortae receive a 1 and normal vessels receive a ⫺1. Given that this is a retrospective analysis,
some sites of vascular development and/or developmental
stages are not reported and therefore cannot receive a normal or abnormal score. Under these circumstances, the
stages receive a score of 0.
By evaluating blood vessel morphology at each of the
three sites and assigning scores for each developmental
stage, an average score can be attained for each site and
an overall average score obtained for all three sites combined. Based on average combined scores, genes can be
ranked. An overall average score of zero is the boundary
between genes that are considered important in vasculogenesis (those scoring ⬎ 0) and genes likely not having
critical roles in vasculogenesis (those scoring ⱕ 0).
RESULTS
Compilation of Genes Associated With
Vascular Defects
We have reviewed papers describing gene knockouts
that produce embryonic lethality attributable to vascular
defects. As a result, a set of 79 single gene deletions and 5
double gene deletions were identified (Table 1). Through
compilation of embryonic vascular phenotypes described
in these studies, it became apparent that yolk sac blood
vessels, dorsal aorta, and endocardium were most often
evaluated. Of the 100 knockout studies listed in Table 1,
28 reported vascular phenotypes in each of the three sites
and 11 reported phenotypes in only two of the three sites.
Meta-Analysis of Knockout Studies
Using AREVA
AREVA analysis was performed on those gene knockout
studies in which embryonic vascular phenotypes were reported in at least two of the three key sites. As a result, the
vascular phenotype of embryos from 12 gene deletion studies
attained an average score greater than 0 (Table 2). The
genes in these studies can be considered as having potentially critical roles to the process of vasculogenesis. The
genes assigned to this category included (listed in rank order
from highest to lowest AREVA score): fibronectin, VEGFR1/Flt-1, VEGFR-2/Flk-1, alpha 5 integrin, Tek/Tie2, VE-cadherin, VEGFA, connexin 45, ShcA, cytochrome P450 reductase, CD148/DEP-1, and EphrinB2 (Table 2).
The relative rank of individual genes in the group of 12
can be only tentatively assigned since there is insufficient
information in most of the knockout studies. For example,
GENES WITH CRITICAL ROLES IN VASCULOGENESIS
877
TABLE 1. Compilation of genes that when deleted cause embryonic lethality with associated vascular defects
1
The genes listed in this table are ordered according to the stage in development at which lethality occurs in embryos deficient in the expression
of the indicated gene. Several genes (i.e., ERK5, Tissue Factor, Notch 1 and Endoglin) are each listed more than once in the table due to the fact
that stage of lethality differs between separate reports. When two genes are listed together, (i.e., Neuropilin/ Nrp 1&2, Hey 1&2, Notch 1&4,
Presenilin 1&2 and ld 1&3) the phenotype indicated corresponds to that of the double knockout. (⫹/⫺), indicates the phenotype described was in
embryos heterozygous for the targeted gene deletion.
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ARGRAVES AND DRAKE
TABLE 2. AREVA evaluation of embryonic vascular anomalies resulting from
targeted deletion of murine genes
1
Of the 100 knockout studies listed in the previous table, Table I, only those in which information was reported for at least two of the three
key sites of vasculogenesis were subjected to AREVA analysis and listed in this Table.
2
When the status of blood vessels at a given sites/stage was not reported in the knockout study, a score of zero was assigned.
Red shading indicates that there was a report of abnormality at the indicated site and stage.
Blue shading indicates that the vasculature was a reported to be normal at the indicated site and stage. Yellow shading highlights those genes
whose AREVA scores are greater than zero, thus defining them as critical to vasculogenesis. (⫹/⫺), indicates the phenotype described was
in embryos heterozygous for the targeted gene deletion. Apostrophes indicate that more than one report of the targeted deletion of the gene
exists and that vascular phenotypes are different.
the status of blood vessels in embryos earlier than 8.0 dpc
was not reported for any of the genes in this category. Furthermore, for one of the knockout studies in this group,
connexin 45, embryonic vascular defects were only reported
in two of the three sites of vasculogenesis. It is also important to note that in addition to the 12 genes whose AREVA
score placed them in the category of genes being critical to
vasculogenesis, there are several genes whose AREVA
scores might increase if additional analysis of knockout mice
were performed, particularly those gene knockouts that lead
to lethality during periods of peak vasculogenesis (i.e., 8.5–
9.5 dpc). Included in this group are single gene knockouts for
Tal1/SCL and Notch 1 as well as double gene knockouts for
presenilin-1 and -2 and neuropilin-1 and -2. While the early
embryonic lethality that occurs in these knockouts may not
have a vascular origin, it is of interest that the genes are
related to the VEGF-signaling pathway. For example, Tal1/
SCL expression is promoted by VEGF (Giles et al., 2005) and
neuropilin-1 and -2 are both VEGF receptors. Furthermore,
Notch 1 and presenilin-1 and -2 are key components of Notch
GENES WITH CRITICAL ROLES IN VASCULOGENESIS
signaling, which downregulates expression of VEGFR2/
Flk-1 (Taylor, 2002).
DISCUSSION
Many of the Genes Scored as Critical for
Vasculogenesis Are Implicated in VEGF
Signaling
Upon examination of genes assigned as having critical
roles in vasculogenesis, it is evident that the majority of
the genes (10 of 12) are related to the VEGF signaling
pathway. These genes include fibronectin, VEGFR-1/Flt-1,
VEGFR-2/Flk-1, alpha 5 integrin subunit, VE-cadherin,
VEGFA, cytochrome P450 reductase, ShcA, CD148/DEP-1,
and EphrinB2 (Table 2). For the most part, genes in this
group can be categorized as either positive or negative
regulators of the VEGF signaling pathway. For example,
the genes Flt-1, CD148/DEP-1, VE-cadherin, and EphrinB2 are negative regulators in that Flt-1 is a decoy
receptor for VEGF, CD148/DEP-1 suppresses VEGF signaling by dephosphorylating Flk-1 (Grazia Lampugnani
et al., 2003), VE-cadherin inhibits VEGFR-2/Flk-1 phosphorylation (Grazia Lampugnani et al., 2003), and EphrinB2 inhibits VEGF-induced Ras/mitogen-activated protein kinase activation (Kim et al., 2002).
By contrast, fibronectin, alpha 5 integrin subunit, Flk-1,
VEGFA, cytochrome P450 reductase, and ShcA gene products have been implicated as being positive VEGF regulators. For example, fibronectin has been shown to promote VEGF-induced differentiation of peripheral bloodderived endothelial progenitors to endothelial cells
(Wijelath et al., 2004). Fibronectin expression is also augmented in response to VEGF signaling (Kazi et al., 2004).
Since the alpha 5 integrin is a subunit of the fibronectinbinding receptor, ␣5␤1, it is reasonable to conclude that
alpha 5 integrin, like fibronectin, is also a positive regulator of VEGF signaling. Cytochrome P450 reductase promotes the expression of both VEGF and Flk-1, possibly via
its regulatory effects on retinol/retinoic acid metabolism
and consequences on RXR/RAR transcriptional activation
(Otto et al., 2003). The adaptor protein ShcA, a substrate
for many tyrosine kinases, including VEGFR-3/Flt4
(Fournier et al., 1999), is phosphorylated in response to
VEGF stimuli (Kroll and Waltenberger, 1997). Furthermore, ShcA physically associates with VE-cadherin in a
VEGF-dependent manner (Zanetti et al., 2002). The significance of the ShcA-VE-cadherin association remains to
be established, but it may result in suppression of ShcA
phosphorylation leading to reduced VEGF signal transmission through the MAP kinase pathway.
Targeted Deletion of Some VasculogenesisCritical Genes Results in an Augmentation of
VEGF Expression and Formation of Sinusoidal
Blood Vessels
Of the 12 genes assigned to be important to vasculogenesis, 8 genes (fibronectin, VEGFR-1/Flt-1, connexin 45,
VEGFA, Tek/Tie2, ShcA, CD148/DEP-1, and EphrinB2)
when deleted lead to the formation of sinusoidal blood
vessels in the yolk sac (Dumont et al., 1994; Sato et al.,
1995; Carmeliet et al., 1996a; Ferrara et al., 1996; George
et al., 1997; Adams et al., 1999; Fong et al., 1999; Kruger
et al., 2000; Lai and Pawson, 2000; Gerety and Anderson,
2002; Takahashi et al., 2003; Gale et al., 2004; Krebs et
al., 2004). Such anomalies are consistent with VEGF-
879
mediated vascular hyperfusion, a phenomenon in which
capillary-sized vessels are replaced by larger sinusoidal
vessels in response to augmentation of VEGF levels either
as a result of exogenous VEGF administration (Drake and
Little, 1995; Argraves et al., 2002), transgenic VEGF overexpression (Benjamin and Keshet, 1997; Zeng et al., 1998;
Dor et al., 2002; Eremina et al., 2003), or in response to
hypoxia (Kotch et al., 1999). Of the 8 genes that displayed
vascular hyperfusion when deleted, VEGF levels were
only evaluated in Flt-1 and CD148/DEP-1 deletion mutants (Fong et al., 1999; Takahashi et al., 2003). In each of
these mutants, VEGF levels were significantly increased.
Increased VEGF expression is an expected outcome in
Flt-1 and CD148/DEP-1 nulls considering that VEGF
transcription is promoted by VEGF (Vega-Diaz et al.,
2001) and both proteins are negative regulators of VEGF
receptor signaling. It remains to be established whether
any of the remaining knockouts that exhibit hyperfusion
also have augmented levels of VEGF.
Targeted Deletion of Candidate Vasculogenesis
Genes Results in Cardiac Abnormalities
Eleven of the 12 genes (fibronectin, Flt-1, Flk1, connexin
45, VE-cadherin, VEGF-A, Tek/TIE-2, cytochrome P450
reductase, ShcA, CD148/DEP-1, and EphrinB2), assigned
to be important to vasculogenesis, when deleted lead to
defects of the endocardium (Table 2). Defective development of the endocardium can be expected to lead to impaired cardiac function, which in turn may have consequences to extracardiac vascular development. For
example, impaired cardiac function could result in insufficient oxygenation (hypoxia) of extracardiac embryonic
tissues leading to increased VEGF expression (Maltepe
and Simon, 1998). Among the 11 gene knockouts displaying endocardial defects, a subset may exhibit extracardiac
anomalies in vasculogenesis attributable to hypoxia-induced VEGF expression. However, since the mouse heart
begins to contract at 8.5 dpc, cardiac insufficiency cannot
influence vasculogenesis that has preceded this stage in
sites such as the yolk sac and dorsal aortae, which are
formed by 8.5 dpc. Thus, in knockouts of fibronectin, Flt-1,
Flk1, connexin 45, and VE-cadherin genes, in which cardiac defects are evident between 8 and 8.5 dpc (George et
al., 1993; Carmeliet et al., 1999; Gory-Faure et al., 1999;
Kruger et al., 2000; Crosby et al., 2005), abnormalities in
the yolk sac vessels that are apparent at this same period
were not the result of cardiac insufficiency.
ShcA/Ras/Raf/Mek/Erk Pathway Integrates
VEGF Signaling With Additional Signaling
Cascades
When the 12 vasculogenesis-critical genes are considered with respect to their involvement in canonical signaling pathways, an integrated network centering on the
ShcA/Ras/Raf/Mek/Erk pathway becomes apparent (Fig.
1). Simply described, the integrated network has at its
hub the ShcA/Ras/Raf/Mek/Erk pathway with links to fibronectin-␣5␤1 integrin, angiopoietin-Tie2, EphrinB2/
Eph, and Connexin 45 signaling pathways. The adaptor
protein ShcA, which promotes Grb2/Sos/Ras-dependent
Erk activation, appears to be a central node in the network given that 7 of the 12 vasculogenesis genes (i.e.,
fibronectin, VEGFA, VEGFR-2/Flk-1, VEGFR-1/Flt-1, VEcadherin, integrin alpha 5, and Tek/Tie2) have functional
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ARGRAVES AND DRAKE
Fig. 1. Schematic model depicting the 12 vasculogenesis-critical genes in the context of canonical
signaling pathways. Genes highlighted in red are those genes categorized by AREVA (Table 2) as playing
critical roles in vasculogenesis.
relationships that involve ShcA. For example, ShcA interacts with the fibronectin receptor (␣5␤1) via the integrin
alpha 5 subunit (Wary et al., 1996; Mauro et al., 1999),
and fibroblasts from ShcA-deficient mice display defective
spreading when plated on fibronectin (Lai and Pawson,
2000). Similarly, ShcA also interacts with the tyrosine
kinase receptor, Tie2, and mediates angiopoietin-1-induced chemotaxis and sprouting in endothelial cells (Audero et al., 2004). Finally, ShcA also interacts with
VEGFR-2 (Zanetti et al., 2002) and VEGF stimulation
results in the phosphorylation of the 46, 52, and 66 kDa
isoforms of ShcA and the induction of Shc-Grb2 complex
formation (Seetharam et al., 1995; Kroll and Waltenberger, 1997). Additionally, Shc binds to the carboxyterminal domain of VE-cadherin and this interaction
exerts a negative effect on Shc phosphorylation by
VEGFR-2/Flk-1 (Zanetti et al., 2002).
Three of the 12 vasculogenesis critical genes, EphrinB2, Tek/Tie2, and connexin 45, can regulate components of the Ras/mitogen-activated protein kinase-signaling pathway down stream from ShcA. The Tek/Tie-2
ligand, angiopoietin-1, can increase both Erk1/2 and
p38 phosphorylation in endothelial cells (Kim et al.,
2002; Harfouche et al., 2003). By contrast, the EphB
ligand, EphrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogen-activated protein kinase
pathway in endothelial cells (Kim et al., 2002). Finally,
the gap junction protein connexin 45 is required for
optimal activation of signal transduction through Erk
(Stains and Civitelli, 2005). Taken together, the bulk of
the genes identified as critical to vasculogenesis can be
integrated into a network of modulators of the ShcA/
Ras/Raf/Mek/Erk cascade, a principal pathway for
transmitting VEGF-stimulated signal transduction.
GENES WITH CRITICAL ROLES IN VASCULOGENESIS
ACKNOWLEDGMENTS
The authors thank Paul A. Fleming, Cynthia K. Gittinger, and Dr. Jeremy Barth (Medical University of
South Carolina, Charleston, SC) for their assistance with
the preparation of this article.
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