© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Altered apoptosis pattern during pharyngeal arch artery remodelling is associated with aortic arch malformations in Tgfβ2 knock-out mice
aDepartment of Anatomy and Embryology, Leiden University Medical Centre, P.O. Box 9602, 2300 RC Leiden, The Netherlands
bDepartment of Chemistry and Microbiology, University of Cincinnati, Cincinnati, OH, USA
acgitten{at}lumc.nl
* Corresponding author. Tel.: +31-71-527-6691/6660; fax: +31-71-527-6680.
Received 18 December 2001; accepted 13 June 2002
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Objective: The morphogenetic process underlying the remodelling of the embryonic mammalian pharyngeal arch artery system is unknown. Within this process, the right sixth, carotid ducts and the distal part of the dorsal aorta (right
-segment) regress. In order to unravel the underlying mechanism we studied the role of apoptosis in the normal regression of pharyngeal arch artery segments and in a mouse model that develops aortic arch malformations. Methods: Normal remodelling was studied in wild-type Swiss (CPBS) and altered remodelling in the Tgfβ2–/– compared to the Tgfβ2+/+ (Swiss/Bl6) strain using immunohistochemistry and morphometric analysis. Results: During normal remodelling, apoptosis occurs in the mesenchyme surrounding pharyngeal arch arteries before regression starts. With the onset of regression, apoptosis spreads from the mesenchyme to the media. Morphometric evaluation confirms the increase in apoptosis in the actin-positive media of the disappearing segments. In Tgfβ2–/–, aberrant apoptosis was found in both fourth arch arteries, whereas the right dorsal aorta lacks apoptosis associated with normal regression. Fourth arch hypoplasia is the main arch abnormality. In the most severe case, the fourth arch is interrupted and the right dorsal aorta -segment persists, giving rise to aortic arch interruption type-B and an aberrant right subclavian artery. Conclusions: We have shown for the first time that specific vascular apoptosis patterns accompany normal regression and that the incidence of apoptosis is selectively altered in the case of arch artery abnormalities in Tgfβ2 knock-out mice.
KEYWORDS Apoptosis; Arteries; Congenital defects; Developmental biology; Growth factors
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The morphogenetic processes underlying pharyngeal arch artery (PAA) remodelling from the symmetrical configuration towards the unilateral left-sided aortic arch have not been fully unravelled. The early embryonic mammalian system consists of five paired arch arteries, numbered I to VI from cranial to caudal. The fifth artery is considered to be rudimentary or absent [1]. Congdons schematic time scale models, representing a general overview of the origin, persistence and regression of specific PAA segments, can be regarded as the foundation for the descriptions used today [2].
Several mechanisms have been postulated to play a role in the remodelling process. Hemodynamic factors, especially flow reduction, are considered to regulate the regression of specific PAA segments [3,4]. The same counts for morphogenetic factors. The arterial wall of the fourth arches exclusively expresses the deformed paralogous group of Hox genes (Hox4A–D) [5], whereas the sixth arch specifically expresses Hox5B in the surrounding mesenchyme [6]. Also, the cellular composition of the PAA, especially neural crest cell (NCC) derived smooth muscle cells (SMC) [7], can contribute, as NCC disturbance resulted in PAA abnormalities [8,9].
We decided to take a novel approach and studied the presence of vascular apoptosis during PAA remodelling. Apoptosis is associated with both normal and defective cardiogenesis [10,11], but data on apoptosis and PAA remodelling are lacking [12,13].
We evaluated vascular apoptosis under normal and abnormal conditions using wild-type (CPBS Leiden) and Tgfβ2 mutant mice (Swiss/Bl6), which present aortic arch abnormalities and intra-cardiac defects [14,15].
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1 Immunohistochemical procedures
Wild-type Swiss CPBS Leiden mice were used to study normal remodelling. Altered PAA remodelling was studied using Tgfβ2 mutant mice, which are derived from succeeding F-generations of Tgfβ2 129/Ola male chimeras bred to Swiss/Bl6 females [14].
Pregnant mice were killed by cervical dislocation. Detection of the vaginal plug was designated as day E0.5 of development. The procedures conform to the Guide for the Care and Use of Laboratory Animals published by the NIH.
Twenty-four wild-type Swiss CPBS Leiden embryos were analysed for normal PAA remodelling. For abnormal PAA development, 32 Tgfβ2–/– and 16 Tgfβ2+/+ littermates were used. Developmental day E11.0–18.0 embryos were fixed in 4% paraformaldehyde/phosphate-buffered saline (0.1 mol/l, pH 7.2), dehydrated in graded ethanol, transferred to 100% xylene and embedded in paraffin.
Consecutive transverse sections (5 µm) were stained with Mayer’s hematoxylin (HE), the primary mouse antibody against alpha-smooth muscle actin (-SM-actin: 1A4/M851; Dako, Denmark), or used for TdT-mediated dUTP-X nick end labeling (TUNEL; Boehringer, Mannheim, Germany). Both -SM-actin and TUNEL protocols have been described elsewhere [11,16]. Apoptotic cells, as determined by cell shrinkage, chromatin condensation and DNA fragmentation, were studied in parallel HE- and TUNEL-stained sections. The sections were studied by light microscopy.
2.2 Incidence of apoptosis and morphometry
To describe apoptosis in regressing segments during PAA remodelling, a morphometric analysis was used, as general approaches using, for example, CASPASE-3 are not applicable because separate segments cannot be isolated for biochemical evaluation [17].
The PAA system was divided into segments, as outlined in Fig. 1. Dorsal aorta (DAo) segmentation in the -, β- and 
-segments was defined by their boundaries. The proximal boundary of the β-segment is marked by the sixth and fourth arches; the latter can be recognised by its weaker -SM-actin staining [16]. The distal boundary of the β-segment is delineated by the subclavian artery. The -segment is proximally bordered by the subclavian artery and distally by the fusion point with the other DAo. The right sixth arch artery was defined as the vessel connecting the pulmonary trunk to the right DAo. At the stages studied the pulmonary arteries connected directly to the pulmonary trunk.
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To analyse the difference in apoptosis between the right (regressing) and left (persisting) segment of the sixth arch artery and the dorsal aorta
-segment, respectively, the number of apoptotic cells per -SM-actin-positive vessel wall volume (apoptose incidence: apoptotic cells/mm3) of each segment was estimated. Apoptotic cells, determined by cell shrinkage and chromatin condensation, were scored in HE-stained sections. Only apoptotic cells located in the vessel wall of the segments were counted; apoptosis in the mesenchymal compartment surrounding the vessels was only described quantitatively as objective boundaries were lacking. The volume of the vessel wall was estimated by the method proposed by Cavalieri [18]. Between 12 and 23 (depending on developmental stage) -SM-actin-stained sections, taken systematically at equal distances, were used to determine the vessel wall volume of the segments as described by Bouman et al. [19]. The apoptotic cells were counted in the adjacent HE-stained slides. At all stages the selected sections enclosed the complete vascular segments of the PAA system, and the counting analysis was repeated three times.
As PAA remodelling is tightly regulated, a landmark for vascular development was introduced that was more applicable than the time point of conception or somite stages. The ratio between the vessel wall volume of the right regressing and the left persisting artery was used as the landmark of vascular remodelling. For analysis of normal PAA remodelling, -SM-actin and HE sections of nine E12.0–14.0 (distribution: 2x E12.0, 2x E12.5, 2x E13.0, 1x E13.5 and 2x E14.0) wild-type Swiss CPBS Leiden embryos were used. To outline the difference in apoptosis between the regressing and the persisting segments during remodelling, the ratio of apoptosis incidence was plotted versus the ratio of vessel wall volume.
To estimate the number of apoptotic cells per vessel wall volume of different PAA segments under abnormal circumstances, four E14.5 embryos of both Tgfβ2–/– and Tgfβ2+/+ genotypes were analysed morphometrically as described above. The mean apoptosis incidence and standard deviation of each segment was obtained for all embryos analysed. To analyse the apoptosis incidence per segment between Tgfβ2–/– and Tgfβ2+/+ embryonic mice, a Mann–Whitney test with a P-value of 0.05 was used.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1 Remodelling of the normal pharyngeal arch artery system
At developmental day 11.5 the PAA system (Fig. 1a) consisted of a left and right third (III), fourth (IV) and sixth (VI) arch artery, connecting both continuous DAo with the ventrally located aortic sac. The latter had separated into an ascending aorta and pulmonary trunk around E12.0 (Fig. 1a and b). Between E11.5 and E14.0 the arterial system had developed towards the mature left-sided configuration, due to regression of the right-sided sixth arch artery (R-VI), the right DAo
-segment (R-), and both the left and right carotid duct (L/R-) (Figs. 1a–d, 2 and 3
).
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The vascular segments revealed a comparable regression process, showing a progressive decline of lumen diameter, accompanied by a reduction of vessel wall thickness of the right segment as compared to the left (Figs. 2 and 3
). The regression resulted in the formation of an -SM-actin-positive strand (Figs. 2g and 3e) that soon became interrupted at its midpoint. Finally, the proximal and distal ends disappeared completely. Despite the morphologic resemblance, the regression of the R-VI progressed faster than the R- segment
3.2 Location and incidence of apoptosis during remodelling
At E10.5, before the start of regression, there is no marked apoptosis in the mesenchyme surrounding the vascular segments. As early as E11.5, apoptotic cells, found in both the TUNEL- and HE-stained sections, were preferentially located in the mesenchyme surrounding the vascular segments that will regress (Figs. 2d and 3b). Between E12.0 and E14.0 the localisation and number of apoptotic cells changed for the regressing segments, i.e. spreading from the surrounding mesenchyme (Figs. 2c,d and 3a,b) towards the outer border of the -SM-actin-positive media (Figs. 2e,f and 3c,d) and eventually into the media. At the strand stage of regression (Figs. 2g,h and 3e,f), only a non-luminised -SM-actin-positive cord of cells was seen as a remnant of the former vessel.
Both TUNEL- and HE-stained sections gave comparable results for the morphometric analysis; for merely practical reasons, HE sections were applied. The difference between the triple countings was negligible (data not shown). Morphometrical analysis of the apoptotic cells located in the media (apoptosis incidence) of the regressing R- and R-VI segment in E12.0–14.0 embryos revealed a substantial increase as compared to the left counter part (Fig. 4). This difference was greatest during the end stage of remodelling and is comparable to the stage at which the regressing vessel segments were remodelled into an -SM-actin-positive strand without a continuous lumen (see Figs. 2g,h and 3e,f).
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) and R-VI (
) regression in nine E12.0–14.0 mouse embryos, given as the ratio right/left apoptosis incidence versus the ratio right/left vessel wall volume (in percentage). The increased apoptosis incidence parallels the enhanced decline of vessel volume at the final stage of regression. Three embryos for each segment were analysed at this stage.The timing and apoptosis patterning of PAA remodelling was comparable between wild-type CPBS Leiden and Tgfβ2+/+ (data not shown).
3.3 Influence of Tgfβ2 depletion on PAA remodelling and apoptosis patterning
PAA abnormalities were found in 24 of 32 (75%) Tgfβ2–/– mouse embryos. Intra-cardiac malformations, consisting of outflow tract and inflow tract septation abnormalities, were encountered in all embryos from E13.5 and no isolated PAA malformations were observed in this group. Within the time window E12.0–15.5, Tgfβ2–/– mice had developed a spectrum of PAA anomalies ranging from aortic arch hypoplasia to interruption. Before E12.0 (E11.0–11.5) no vascular differences were found between Tgfβ2+/+ and Tgfβ2–/– mice. At E12.0–13.0 and E13.5–14.5, two of six and eight of 10 embryos, respectively, had developed tubular hypoplasia of the proximal aortic arch and/or the more distally located fourth arch artery segments (Fig. 5). Additionally, a substantial delay of R- regression was found in both E12.0–13.0 cases and in one E13.5–14.5 embryo (shown schematically in Fig. 6, panels 1 and 2), as shown by the lack of apoptotic cells normally found in the media of this segment. The other embryos (4/6 and 2/10) had developed mild vascular hypoplasia. A marked number of apoptotic cells was found, predominantly within the mesenchyme and media at the basis of the fourth arch artery segment (Fig. 5c and d). This eccentric patterning of apoptosis was never observed in Tgfβ2+/+ littermates (Fig. 5a and b). Noteworthy is the increased condensation of the mesenchyme surrounding the trachea and oesophagus, seen in the Tgfβ2–/– phenotype (Fig. 5c).
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To substantiate our findings, four Tgfβ2–/– E14.5 mice with a variable degree of tubular hypoplasia of the aortic arch were analysed morphometrically for their PAA apoptosis incidence. The measurements confirmed a higher apoptosis incidence for all PAA segments, being most marked for the fourth arch arteries and the proximal aortic arch as compared to four Tgfβ2+/+ embryos (Fig. 7). Of the PAA segments, only the R-IV and L-IV arch arteries revealed a significantly higher apoptosis incidence (both P=0.029) for the Tgfβ2–/– mice (Fig. 7). All other segments, with the exception of the proximal part of the aortic arch (P=0.057), were far above P=0.05. The apoptosis patterning characteristic for the normal regression of the R-
, with a spread from the surrounding mesenchyme to the media, was absent in all cases in which the R- persisted (not shown).
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At E15.5, three of six embryos had developed double aortic arch interruption (L- and R-IV) and persistence of R-
, resulting in a type-B aortic arch interruption accompanied by an aberrant right subclavian artery (Fig. 6c and d). One embryo still possessed extremely thin remnants of the former L- and R-IV pharyngeal arch (Fig. 6a and b). All three E15.5 embryos with a R- and L-IV arch artery interruption showed a left-sided system. Regression of the R-VI segment had taken place normally in all cases. The remaining three E15.5 embryos revealed a variable degree of hypoplasia of the fourth arch artery segment. All six E16.0–18.0 embryos showed vascular hypoplasia at comparable locations as described for younger embryos. No PAA-associated apoptosis could be discerned at these stages.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The formation of the aortic arch and its tributaries from the paired PAA system has been described for mammals [1,2,16] and avian embryos [7,20]. We have shown for the first time that apoptosis accompanies normal PAA remodelling and that alterations in this process coincide with PAA malformations. It should be kept in mind that PAA remodelling also depends on the proliferation, migration and differentiation of multiple cell types (e.g. NCC, endothelial and mesenchymal cells), which are not addressed in this study.
4.1 Normal pharyngeal arch artery remodelling and apoptosis
The development of the mammalian PAA system into the left-sided aortic arch configuration requires a tightly regulated remodelling process involving regression of various segments. The presence of mesenchymal and media-located apoptosis, predominantly in specific right-sided segments, associated with the development of the left-sided aortic arch system is evident. Intriguing is the spreading of apoptosis with the onset of regression from the mesenchyme towards the media at the final stages of regression. Accompanying regression, we find apoptosis in the surrounding mesenchyme and in the media. This outer mesenchymal area has been referred to as an important cellular source for investment of mesenchymal cells to the media [21]. The morphometrically evaluated spatio-temporal apoptosis incidence is considerable as several pharyngeal arch arteries present different progressions of the remodelling process; e.g. the R-VI being slightly faster than R-. The sequence of events starts at the midpoint of the vessel and extends in the proximal and distal direction during vessel regression.
The time in which apoptotic cells can be detected is limited, and is often associated with the execution phase of apoptosis [13,22], which is 6 h for TUNEL-positive cells in vitro [22]. Moreover, there is in vivo apoptotic clearance, which in E11.0–13.0 mouse embryos takes 15–30 min [23,24]. Besides apoptosis, mitosis is a key factor in cell dynamics. A small percentage of the total cell population of an embryo is in G1 and cell division for one cell typically requires 8–16 h [25,26]. We regard vascular regression to occur when apoptosis is not counterbalanced by mitosis. The limited detection time of apoptotic cells implies that, during the period of one cell cycle, 16–64 times more cells can be removed by apoptosis than added by mitosis. Therefore, it is reasonable to assume that even a small number of apoptotic cells can account for the regression of a vessel.
In general, apoptosis during development is considered to be a mechanism by which superfluous cells are removed. The mechanism driving differential apoptosis patterns during PAA remodelling still remains elusive. So far, a relation between apoptosis and vascular development has only been reported for the development of the embryonic endothelial network [27]. For normal intra-cardiac development, specifically the endocardial outflow tract and atrio-ventricular cushions, numerous reports exist on spatio-temporal apoptosis patterning, as reviewed by Poelmann et al. [13]. Apoptosis-related knockout models, e.g. Caspase-8 and Fadd [28], manifest cardiac abnormalities, underlining a functional relationship between apoptosis and cardiovascular development.
Potential inductive and regulatory mechanisms of PAA apoptosis could be flow-regulated, as found in programmed capillary regression [3]. The relation between endothelial-mediated signals and PAA regression remains to be discovered. With regard to the right-sided dominance in PAA remodelling, we considered a relation with genes that orchestrate left/right asymmetry. Left/right patterning genes, such as Nodal, Lefty, and Sonic Hedgehog, are promising candidates [29], but no link with apoptosis has been proven. Several transcription factors, MSX2 in particular, do correlate with apoptosis and patterning, however they reflect an anterior–posterior rather than left–right asymmetry [30].
Cellular heterogeneity of the PAA system might contribute to the remodelling differences found. The most appealing example of cellular heterogeneity is the NCC-derived SMC composition of the PAA system, revealing strong boundaries between the pharyngeal arch arteries (fourth and sixth) and the dorsal aorta [7,31]. An in vitro study by Topouzis and Majesky showed a difference in growth, apoptosis and differentiation between NCC and mesodermally derived SMCs [32].
There is also heterogeneity within the NCC-derived PAA as exemplified by the fourth arch artery, revealing a poor -SM-actin and elastin make-up [16], and extended NCC-related CX43 expression [33] as compared to the adjacent segments, but clear data that link these morphologic differences to a higher susceptibility for malformations is lacking.
4.2 Tgfβ2 depletion and aortic arch remodelling
PAA development is hampered by Tgfβ2 depletion, giving rise to fourth arch artery and right dorsal aorta -segment anomalies. All other segments, i.e. the R-VI and both -segments, regress normally. The onset of these vascular defects can be observed before intra-cardiac defects are detectable [14]. This difference in Tgfβ2 dependency is surprising, as TGFβ ligands have been reported to influence the cellular behaviour of virtually all cellular participants of vascular development. Striking is the opposite effect on the fourth arch and the R- segment, inducing regression of the former and persistence of the latter. Both events correlated with an aberrant vascular apoptosis incidence, being enhanced for the fourth and reduced for the R-.
This differential effect could be related to the vascular composition, being predominantly NCC (fourth) or mesodermally (R-) derived. In this context, TGFβ has been reported to exert opposite effects on the cellular fate of SMC precursors, stimulating the proliferation and differentiation of NCC-SMC derivatives and inhibiting non-NCC-related SMCs [32,34]. A relation between TGFβ2 and SMC apoptosis is lacking. Intriguing is the overlap between the eccentric apoptosis patterning found during abnormal fourth arch remodelling and the signet ring-shaped discontinuous -SM-actin expression as described by Bergwerff [16].
Future research will have to elucidate if TGFβ2 acts upon PAA remodelling in an instructive (differentiation) and/or selective (apoptosis) order.
4.3 Relation to clinically and experimentally reported aortic arch malformations
Kutsche and Van Mierop [35] associated aortic arch interruptions with the anomalous origin of the right subclavian artery. Their clinical study showed that 14/21 aortic arch interruption type-B (AAI-B) cases were associated with an aberrant right subclavian artery (ARSA). Almost 50% of these patients carry a deletion of chromosome 22q11 [36], a genetic disorder that can give rise to the DiGeorge and Velocardiofacial syndrome.
The AAI-B/ARSA and aortic arch hypoplasia found in our Tgfβ2–/– mice resulted from abnormal pharyngeal arch remodelling of the R- and fourth arch arteries between E11.5 and E15.5. The coincidence of these anomalies with a changed apoptosis pattern might point towards an apoptosis-related process in the aetiology of aortic arch defects.
Interruption and fourth arch artery hypoplasia are not restricted to the Tgfβ2 knock-out model, as they were also present in mesenchyme fork head-1 (Mfh-1) [37], endothelin converting enzyme-1 (Ece-1), endothelin-A receptor (EtA) [38] and human 22q11 deletion syndrome homologous Df1 knockout mice [39]. Future research will have to elucidate the downstream cellular and genetic targets of TGFβ2 during cardiovascular development.
In conclusion, asymmetric PAA remodelling coincides with a highly spatio-temporal apoptosis pattern. Alterations in this pattern are associated with PAA anomalies as exemplified by the Tgfβ2 mutant, giving rise to fourth arch artery and R--related defects comparable to aortic arch interruptions (type-B) and aberrant right subclavian arteries in men. The involvement of apoptosis in normal and abnormal PAA development provides a new focus in the research field of vascular development and in understanding the aetiology of PAA anomalies.
Time for primary review 22 days.
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Acknowledgements |
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This research was supported by NIH grants HL58511 and HD26471 and Netherlands Heart Foundation grant NHS46.014. The authors would like to thank Ron Slagter of Inter Medics and Jan Lens for the graphics and layout.
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References |
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|
TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
|---|
- DeRuiter M.C., Gittenberger-de Groot A.C., Poelmann R.E. The special status of the pulmonary arch artery in the branchial arch system of the rat. Anat Embryol (1989) 179:319–325.[CrossRef][Medline]
- Congdon E.D. Transformation of the aortic arch system during the development of the human embryo. Carnegie Inst Contr Embryol (1922) 14:47–110.
- Meeson A., Palmer M., Calfon M., Lang R. A relationship between apoptosis and flow during programmed capillary regression is revealed by vital analysis. Development (1996) 122:3929–3938.[Abstract]
- Moene R.J., Gittenberger-de Groot A.C., Oppenheimer-Dekker A., Bartelings M.M. Anatomic characteristics of ventricular septal defect associated with coarctation of the aorta. Am J Cardiol (1987) 59:952–955.[CrossRef][Web of Science][Medline]
- Krumlauf R. Hox genes and pattern formation in the branchial region of the vertebrate head. Trends Genet (1993) 9:106–112.[CrossRef][Web of Science][Medline]
- Kuratani S.C., Wall N.A. Expression of Hox 2.1 protein in restricted populations of neural crest cells and pharyngeal ectoderm. Dev Dyn (1992) 195:15–28.[Web of Science][Medline]
- Bergwerff M., Verberne M.E., DeRuiter M.C., Poelmann R.E., Gittenberger-de Groot A.C. Neural crest cell contribution to the developing circulatory system. Implications for vascular morphology? Circ Res (1998) 82:221–231.
[Abstract/Free Full Text] - Bergwerff M., DeRuiter M.C., Gittenberger-de Groot A.C. Comparative anatomy and ontogeny of the ductus arteriosus, a vascular outsider. Anat Embryol (1999) 200:559–571.[CrossRef][Medline]
- Kirby M.L., Hunt P., Wallis K., Thorogood P. Abnormal patterning of the aortic arch arteries does not evoke cardiac malformations. Dev Dyn (1997) 208:34–47.[CrossRef][Web of Science][Medline]
- Poelmann R.E., Mikawa T., Gittenberger-de Groot A.C. Neural crest cells in outflow tract septation of the embryonic chicken heart: differentiation and apoptosis. Dev Dyn (1998) 212:373–384.[CrossRef][Web of Science][Medline]
- Poelmann R.E., Gittenberger-de Groot A.C. A subpopulation of apoptosis-prone cardiac neural crest cells targets to the venous pole: multiple functions in heart development? Dev Biol (1999) 207:271–286.[CrossRef][Web of Science][Medline]
- van den Hoff M.J.B., Van den Eijnde S.M., Virágh S., Moorman A.F.M. Programmed cell death in the developing heart. Cardiovasc Res (2000) 45:603–620.
[Free Full Text] - Poelmann R.E., Molin D., Wisse L.J., Gittenberger-de Groot A.C. Apoptosis in cardiac development. Cell Tissue Res (2000) 301:43–52.[CrossRef][Web of Science][Medline]
- Sanford L.P., Ormsby I., Gittenberger-de Groot A.C., et al. TGFβ2 knockout mice have multiple developmental defects that are non-overlapping with other TGFβ knockout phenotypes. Development (1997) 124:2659–2670.[Abstract]
- Bartram U., Molin D.G.M., Wisse L.J., et al. Circulation. (2001) 2745–2752.
- Bergwerff M., DeRuiter M.C., Hall S., Poelmann R.E., Gittenberger-de Groot A.C. Unique vascular morphology of the fourth aortic arches: possible implications for pathogenesis of type-B aortic arch interruption and anomalous right subclavian artery. Cardiovasc Res (1999) 44:185–196.
[Abstract/Free Full Text] - Watanabe M., Choudhry A., Berlan M., et al. Developmental remodelling and shortening of the cardiac outflow tract involves myocyte programmed cell death. Development (1999) 125:3809–3820.[Web of Science]
- Gundersen H.J., Jensen E.B. The efficiency of systematic sampling in stereology and its prediction. J Microsc (1987) 147:229–263.[Medline]
- Bouman H.G.A., Broekhuizen M.L.A., Baasten A.M.J., Gittenberger-de Groot A.C., Wenink A.C.G. Stereological study of stage 34 chicken hearts with looping disturbances after retinoic acid treatment: disturbed growth of myocardium and atrioventricular cushion tissue. Anat Rec (1997) 248:242–250.[CrossRef][Medline]
- DeRuiter M.C., Gittenberger-de Groot A.C., Poelmann R.E., van Iperen L., Mentink M.M.T. Development of the pharyngeal arch system related to the pulmonary and bronchial vessels in the avian embryo. Circulation (1993) 87:1306–1319.
[Abstract/Free Full Text] - Thayer J.M., Meyers K., Giachelli C.M., Schwartz S.M. Formation of the arterial media during vascular development. Cell Mol Biol Res (1995) 41:251–262.[Web of Science][Medline]
- Kockx M.M. Apoptosis in the atherosclerotic plaque. Quantitative and qualitative aspects. Arterioscler Thromb Vasc Biol (1998) 18:1519–1522.
[Abstract/Free Full Text] - Van den Eijnde S.M., Boshart L., Reutelingsperger C.P.M., De Zeeuw C.I., Vermeij-Keers C. Phosphatidyl serine plasma membrane asymmetry in vivo: a pancellular phenomenon which alters during apoptosis. Cell Death Differ (1997) 4:311–316.[CrossRef][Web of Science][Medline]
- Van den Eijnde S.M., Luijsterberg A.J.M., Boshart L., et al. In situ detection of apoptosis during embryogenesis with annexin V: from whole mount to ultrastructure. Cytometry (1997) 29:313–320.[CrossRef][Web of Science][Medline]
- Goedbloed J.F. The embryonic and postnatal growth of the rat and mouse. Acta Anat (1974) 87:209–247.[Web of Science][Medline]
- Poelmann R.E. Differential mitosis and degeneration patterns in relation to the alterations in the shape of the embryonic ectoderm of early postimplantation mouse embryos. J Embryol Exp Morphol (1980) 55:33–51.[Web of Science][Medline]
- Pollmann M.J., Naumovski L., Gibbons G.H. Endothelial cell apoptosis in capillary network remodeling. J Cell Physiol (1999) 178:359–370.[CrossRef][Web of Science][Medline]
- Vaux D.L., Korsmeyer S.J. Cell death in development. Cell (1999) 96:245–254.[CrossRef][Web of Science][Medline]
- Capdevila J., Vogan K.J., Tabin C.J., Belmonte J.C.I. Mechanisms of left–right determination in vertebrates. Cell (2000) 101:9–21.[CrossRef][Web of Science][Medline]
- Lumsden A., Graham A. Death in the neural crest: implications for pattern formation. Semin Cell Dev Biol (1996) 7:169–174.[CrossRef][Web of Science]
- Jiang X., Rowitch D.H., Soriano P., McMahon A.P., Sucov H.M. Fate of the mammalian cardiac neural crest. Development (2000) 127:1607–1616.[Abstract]
- Topouzis S., Majesky M.W. Smooth muscle lineage diversity in the chick embryo. Two types of aortic smooth muscle cell differ in growth and receptor-mediated transcriptional responses to transforming growth factor-β. Dev Biol (1996) 178:430–445.[CrossRef][Web of Science][Medline]
- Waldo K.L., Lo C.W., Kirby M.L. Connexin 43 expression reflects neural crest patterns during cardiovascular development. Dev Biol (1999) 208:307–323.[CrossRef][Web of Science][Medline]
- Garcia-Castro M., Bronner-Fraser M. Induction and differentiation of the neural crest. Curr Opin Cell Biol (1999) 11:695–698.[CrossRef][Web of Science][Medline]
- Kutsche L.M., van Mierop L.H.S. Cervical origin of the right subclavian artery in aortic arch interruption: pathogenesis and significance. Am J Cardiol (1984) 53:892–895.[CrossRef][Web of Science][Medline]
- Lewin M.B., Lindsay E.A., Jurecic V., et al. A genetic etiology for interruption of the aortic arch type B. Am J Cardiol (1997) 80:493–497.[CrossRef][Web of Science][Medline]
- Iida K., Koseki H., Kakinuma H., et al. Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development (1997) 124:4627–4638.[Abstract]
- Yanagisawa H., Hammer R.E., Richardson J.A., et al. Role of endothelin-1/endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice. J Clin Invest (1998) 102:22–33.[Web of Science][Medline]
- Lindsay E.A., Botta A., Jurecic V., et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature (1999) 401:379–383.[CrossRef][Medline]
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 K. Niessen, Y. Fu, L. Chang, P. A. Hoodless, D. McFadden, and A. Karsan Slug is a direct Notch target required for initiation of cardiac cushion cellularization J. Cell Biol., July 28, 2008; 182(2): 315 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Todorovic, D. Frendewey, D. E. Gutstein, Y. Chen, L. Freyer, E. Finnegan, F. Liu, A. Murphy, D. Valenzuela, G. Yancopoulos, et al. Long form of latent TGF-{beta} binding protein 1 (Ltbp1L) is essential for cardiac outflow tract septation and remodeling Development, October 15, 2007; 134(20): 3723 - 3732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M.S. van den Akker, D. G.M. Molin, P. P.W.M. Peters, S. Maas, L. J. Wisse, R. van Brempt, C. J. van Munsteren, M. M. Bartelings, R. E. Poelmann, P. Carmeliet, et al. Tetralogy of Fallot and Alterations in Vascular Endothelial Growth Factor-A Signaling and Notch Signaling in Mouse Embryos Solely Expressing the VEGF120 Isoform Circ. Res., March 30, 2007; 100(6): 842 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhang, F. Cerrato, H. Xu, F. Vitelli, M. Morishima, J. Vincentz, Y. Furuta, L. Ma, J. F. Martin, A. Baldini, et al. Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development Development, December 1, 2005; 132(23): 5307 - 5315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. B. Keller Developmental structure-function insights from Tbx5del/+ mouse model of Holt-Oram syndrome Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H975 - H976. [Full Text] [PDF]
|
|
|
|
|
|
D. G.M. Molin, R. E. Poelmann, M. C. DeRuiter, M. Azhar, T. Doetschman, and A. C. Gittenberger-de Groot Transforming Growth Factor {beta}-SMAD2 Signaling Regulates Aortic Arch Innervation and Development Circ. Res., November 26, 2004; 95(11): 1109 - 1117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Boot, R. P.M. Steegers-Theunissen, R. E. Poelmann, L. van Iperen, and A. C. Gittenberger-de Groot Cardiac outflow tract malformations in chick embryos exposed to homocysteine Cardiovasc Res, November 1, 2004; 64(2): 365 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Kaartinen, M. Dudas, A. Nagy, S. Sridurongrit, M. M. Lu, and J. A. Epstein Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells Development, July 15, 2004; 131(14): 3481 - 3490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Boot, R. P.M. Steegers-Theunissen, R. E. Poelmann, L. van Iperen, and A. C. Gittenberger-de Groot Homocysteine Induces Endothelial Cell Detachment and Vessel Wall Thickening During Chick Embryonic Development Circ. Res., March 5, 2004; 94(4): 542 - 549. [Abstract] [Full Text] [PDF]
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