Published online before print November 4, 2004, doi: 10.1161/01.RES.0000150047.16909.ab
© 2004 American Heart Association, Inc.
Integrative Physiology |
Transforming Growth Factor ß–SMAD2 Signaling Regulates Aortic Arch Innervation and Development
From the Department of Anatomy and Embryology (D.G.M.M., R.E.P., M.C.D., A.C.G.-d.G.) Leiden University Medical Center, Leiden, the Netherlands; and the Department of Molecular Genetics, Biochemistry and Microbiology (M.A., T.D.), University of Cincinnati, College of Medicine, Cincinnati, Ohio.
Correspondence to Prof A.C. Gittenberger-de Groot, Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9602, 2300 RC Leiden, The Netherlands. E-mail acgitten{at}lumc.nl
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Abstract |
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Aortic arch interruptions in humans and animal models are mainly caused by aberrant development of the fourth pharyngeal arch artery. Little is known about the maturation of this vessel during normal and abnormal development, which is the subject of this study. Tgfß2 knockout mice that present with fourth artery defects have been associated with defective neural crest cell migration. In this study, we concentrated on pharyngeal arch artery development during developmental days 12.5 to 18.5, focusing on neural crest cell migration using a Wnt1-Cre by R26R neural crest cell reporter mouse. Fourth arch artery maturation was studied with antibodies directed against smooth muscle
-actin and neural NCAM-1 and RMO-270. For diminished transforming growth factor ß (TGF-ß) signaling, SMAD2 and fibronectin have been analyzed. Neural crest migration and differentiation into smooth muscle cells is unaltered in mutants, regardless of the cardiovascular defect found; however, innervation of the fourth arch artery is affected. Absent staining for nuclear SMAD2, NCAM-1, and RMO-270 in the fourth artery in mutant coincides with severe defects of this segment. Likewise, fibronectin expression is diminished in these cases. From these data we conclude the following: (1) neural crest cell migration is not a common denominator in cardiovascular defects of Tgfß2–/– mice; (2) fourth arch artery maturation is a complex process involving innervation; and (3) TGF-ß2 depletion diminishes SMAD2-signaling in the fourth arch artery and coincides with reduced vascular NCAM-1 expression and neural innervation of this artery. We hypothesize that disturbed maturation of the fourth pharyngeal arch artery, and especially abrogated vascular innervation, will result in fourth arch interruptions.
Key Words: vascular innervation • neural crest • NCAM • SMAD • embryo
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Introduction |
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The paired fourth pharyngeal arches (PAAs) develop during embryogenesis into the proximal part of the right subclavian artery and the distal part of the aortic arch located between the left common carotid artery and the descending aorta (designated segment-B).1,2 Fourth PAA defects are frequently encountered in congenital cardiovascular diseases, including DiGeorge3,4 and tetralogy of Fallot,5 but also in several mouse models (eg, ET-1/ET-A, MFH-1, VEGF120/120).6–8 We have previously shown that the left and right fourth PAAs are interrupted in transforming growth factor ß2 (Tgfß2) knockout mice and, as a consequence, give rise to aortic arch interruption type-B and aberrant right-subclavian artery, respectively.1,9
Tgfß2–/– mice develop fourth PAA interruptions, whereas Tgfß1 and Tgfß3 mutants do not develop these defects.10,11 This difference is remarkable because TGF-ß1 to -ß3 belong to the same group of the TGF-ß superfamily with comparable effects on cell proliferation, differentiation and cell death when applied in vitro.10,11 Although the discrepancy between in vitro and in vivo indicates redundancy between the ligands, local activation or temporal-spatial variation in ligand and receptor expression can apply for the difference found as well. We have previously shown that vascular endothelium expresses Tgfß1, whereas Tgfß2 and, to a lesser extent, Tgfß3 are expressed by smooth muscle cells (SMCs) of the great arteries without any clear preference for the fourth PAA.12
From a morphological perspective, the fourth PAA is an unique vascular segment of the developing aortic arch, reflecting a reduced number of SM--actin–positive cells in the media as compared with other arteries.2 Connexin-43, a gap junction protein predominantly found in migrating neural crest cells (NCCs), remains prominently present in the fourth PAA during development, whereas the proximal part of the aortic arch and third and sixth PAAs have lost expression.13 Interestingly, this morphologically special part of the fourth arch artery shows apparent innervation of afferent sensory neurons suggested to be related to baro- and chemoreceptor function.2,14
SMCs constituting the wall of the PAAs are NCC derived.13,15 Their migration, homing, and differentiation into SMCs are essential for PAA development13,15 and are supposed to depend on TGF-ß,16,17 but no clear distinction for the function of TGF-ß1 to -ß3 has been made. Besides recruitment and differentiation of NCCs, TGF-ßs enhance the expression of SMC-specific proteins (eg, SM--actin, SM22, SM-MHC, h(1)-calponin) and matrix proteins (eg, fibronectin [FN], collagen, elastin).18,19 In these processes, intracellular signaling via SMAD2/3 can handle the signal transduction.10,18
In this study, we have focused on the development of the fourth PAA in normal and Wnt1-Cre by R26 (NCC-reporter) Tgfß2 wild-type and knockout mice. Migration is analyzed in NCC reporter mice because Tgfß2 knockout mice develop aortic arch interruptions and common arterial trunk and show absent myocardialization of the aorticopulmonary septum, all of which are potentially related to NCC defects.1,9 TGF-ß–SMAD2 signaling and FN expression, which is important for NCC migration,20 have been analyzed to discriminate for differences in signaling between Tgfß2+/+ and Tgfß2–/– mice.
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Materials and Methods |
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Embryonic Materials and Immunohistochemical Procedures
Tgfß2 wild-type (+/+) and knockout (–/–) fetuses of embryonic day (E) 13.5 to 18.0 were obtained from the animal facilities of the Leiden University Medical Center and processed as previously described.1,9 The procedures conform to the Guide for the Care and Use of Laboratory Animals published by the NIH. Briefly, fetuses were fixed in 4% paraformaldehyde/PBS (0.1mol/L, pH7.2), dehydrated in graded ethanol, transferred to 100% xylene, and embedded in paraffin. Consecutive transverse sections (5 µm) were serially mounted on glass slides and were subjected to standard immunohistochemical procedures.1,9 Sections were incubated overnight with the primary antibodies for
-SM-actin diluted 1:3000 (-SM-actin: 1A4/M851; Dako, Denmark); SMAD2 diluted 1:200 (clone S-20/SC-6200; Santa Cruz Biotechnology);21 RMO-270 diluted 1:400 (anti-neurofilament protein; kindly provided by Dr J.Q. Trojanowski, Philadelphia, Penn);22 NCAM-1 diluted 1:2000 (anti–NCAM-1; kindly provided by Dr S. Hoffman, Charleston, SC) or FN diluted 1:5000 Dako, Denmark). TUNEL, according to the protocol of the manufacturer (Roche), was used to detect apoptotic cells.23 All sections were analyzed using standard microscopic optics.
NCC Analysis in TGF-ß2 Wild-Type and Knockout Mice
The fate of NCCs in Tgfß2 wild-type and knockout mice was analyzed by crossing Tgfß2-heterozygous mice24 with the NCC-specific Wnt1Cre by R26R mouse line.25 This mouse line is NCC-specific and permanently marks NCCs within the neural tube before they start to migrate. Harvested mutant and wild-type Wnt1Cre by R26R by Tgfß2 fetuses were dissected in PBS, fixed by immersion in 0.2% glutaraldehyde for 30 minutes, soaked in 10% sucrose/PBS for 30 minutes at 4°C, incubated in 2 mmol/L MgCl2, 30% sucrose/50% OCT/PBS (Tissue Tek; Sakura Finetek Europe) at 4°C for 2 hours, and, finally, frozen in OCT. Sections were cut at 20-µm thickness, mounted on gelatin-coated slides, fixed in 0.2% glutaraldehyde for 10 minutes, and rinsed twice in 2 mmol/L MgCl2/PBS. For 5-bromo-4-chloro-3-indolyl ß-D-galactoside (X-Gal) staining, sections were incubated in detergent rinse solution (0.005% Nonidet P-40 and 0.01% sodium deoxycholate/PBS) for 10 minutes at 4°C, and were next stained with 0.4% X-Gal staining solution (5 mmol/L potassium ferricyanide/potassium ferrocyanide, 2 mmol/L MgCl2/PBS) overnight at room temperature, and counterstained with Eosin and Nuclear Fast Red.
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Results |
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In mammals, the mature left-sided aortic arch developed from an almost symmetrical and segmented vascular configuration containing the paired third, fourth, and sixth PAAs by selective regression of specific segments. All PAAs are maintained in the mature configuration (schematic outline, Figure 1a), with the exception of both sixth, of which the right regresses and the left (ductus arteriosus) closes after birth. The third PAAs give rise to the right/left common carotid artery, the right fourth constitutes the proximal part of the right subclavian artery, and the left fourth composes the distal part of the aortic arch located between the left common carotid artery and the descending aorta. In Tgfß2–/– mice, disturbed development of these segments resulted in PAA defects (see Figures 1d, 1g, 5e, and 5j).
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Aortic Arch Interruption Coincides With Severe Cardiac Outflow Tract Defects
Tgfß2–/– mice showed fourth PAA defects ranging from hypoplasia (Figure 4g and 4h) to an atretic nonluminal strand (Figures 1d through 1f and 4j and 4k) and complete interruption (Figures 1g through 1i and 5e through 5l). These defects became apparent after E12.5 and interruptions were found from E14.5.
Extreme hypoplasia, atresia, and interruption of the fourth artery were found in 9 Tgfß2 mutants and coincided with severe cardiac outflow tract malformations as common arterial trunk and double outlet of the right ventricle (Table) with a large subarterial or subaortic ventricular septal defect. All cases with severe outflow tract and PAA anomalies presented a considerably reduced caliber of the ascending aorta as compared with the pulmonary trunk.
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In Tgfß2–/– mice, fourth PAA defects could occur as left-sided defects (6 of 9 cases) (Figure 1d and 1g) or in combination with interruption of the right fourth (4 of 9 cases). The latter always involved aberrant persistence of the most distal part of the right dorsal aorta (R- segment) and when combined gives rise to an aberrant subclavian artery (Figure 5e and 5j). This configuration is predominantly found in cases with common arterial trunk (Table). Another group of anomalies presented a cervical aortic arch, which showed aberrant interruption of the left fourth PAA and persistence of the dorsal aorta 
-segment. In one E16.5 Tgfß2–/– fetus, a preliminary stage of aortic arch interruption type-C had developed, reflecting the combination of interruption of the left fourth artery, an atretic left-common carotid artery (third PAA), and an aberrant persisting left dorsal aorta -segment (Figure 5e).
NCCs Populate the Arch Arteries and Outflow Tract in Tgfß2-Mutants
NCCs in E14.5 to 17.5 Wnt1Cre by R26R (NCC reporter) Tgfß2–/– mice populated the media of the third, fourth, and sixth PAAs and outflow tract; nevertheless, NCCs were more abundant in the mesenchyme surrounding these structures as compared with wild types (Figures 1 and 2).
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In cases with fourth PAA atresia (Figure 1d through 1f) and interruption (Figure 1g through 1i), a high number of NCCs were found in areas where apoptotic cells were present (Figure 1j and 1k). The border between the distal part of the aortic arch and the dorsal aorta in normal fetuses will become the site of interruption (compare Figure 1b and 1c with 1e and 1f and 1h and 1i). In wild-type mice, this NCC-populated border of the left fourth arch artery connects cranially with the aortic arch at the level where the carotid artery splits of and caudally with the ductus arteriosus (see Figure 1a)
NCCs in Tgfß2 mutants with a subaortic ventricular septal defect (Figure 2f) still populated the aortopulmonary septum and valvular tissue. In the case of a common arterial trunk (Figure 2g), intense X-Gal blue staining was present in the endocardial ridges of the remaining cushion tissue, the semilunar valves, and condensed mesenchyme.
Distinct Vascular Morphology of the Fourth Pharyngeal Arch Artery
All PAAs and their derivatives received NCCs. Therefore, a sharp boundary was seen between the distal part of the fourth arch artery and the dorsal aorta (Figures 1b, 1c, 3a, and 3b). The fourth PAA was different compared with the adjacent vasculature. The media of this artery were negative for smooth muscle -actin (1A4) (Figure 3c and 3d) and positive for neurofilament protein (RMO-270) (Figure 3e and 3f). The neural marker NCAM-1 was highly expressed in the fourth PAA (Figure 3g, 3h, and 3k) overlapping with the distinct 1A4 and RMO-270 expression (compare Figure 3d, 3f, and 3h). The sixth PAA and -segment showed weak and diffuse NCAM-1 expression in their media and were RMO-270 negative (not shown). These three markers demarcated the left and right fourth PAA during all stages of development studied (E12.5 to 18.5).
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Neural Markers Are Differently Expressed in Tgfß2+/+ and Tgfß2–/– Mice
The vessel wall of the fourth PAAs showed prominent expression of the neural markers RMO-270 and NCAM-1. At E12.5, NCAM-1 was strongly expressed in the adventitia in close proximity to the vagal and recurrent nerve of wild-type and mutant fetuses (not shown). During the next 2 days the expression in the wild type extended into the media (Figures 3g, 3h, 3k, 4a, and 5a) overlapping the SM--actin–negative region (compare Figure 3g and 3h with 3c and 3d).
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Tgfß2–/– fetuses with fourth PAA defects showed a different NCAM-1 (Figures 4g, 4j, 5c, 5f, and 5k) and RMO-270 pattern (Figure 5i and 5l). In contrast to the extension of NCAM-1 expression toward the tunica media in wild types, the expression in these mutants remained limited to the adventitia (Figure 4g and 4j). In two cases with interruption, a small region of the caudal part of the remnant, in close proximity of the ductus arteriosus, expressed NCAM-1 (Figure 5c, 5h, and 5k); however, no RMO-270 staining was found within the remnants (Figure 5i and 5l).
In Tgfß2–/– mice with common arterial trunk, the epicardium covering the common outflow tract showed an abnormally high NCAM-1 expression and randomly distributed NCAM-1–positive ganglia over the complete orifice level (Figure 2h), whereas in wild type the expression was restricted to the coronary arterial orifice level (not shown). The expression of SM--actin in the vasculature of Tgfß2–/– mice did not differ considerably from wild-type mice (not shown). FN, an extracellular matrix molecule, highly expressed in the vascular wall of the aortic arch in Tgfß+/+ mice (Figure 6a), was severely reduced in Tgfß2–/– cases with aortic arch interruptions (Figure 6b and 6c), whereas the ductus arteriosus in the same mutants did show expression (Figure 6d).
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The temporal-spatial NCAM-1 (Figure 4d), RMO-270, and FN patterning (not shown) for mutant fetuses without a cardiovascular phenotype was comparable to wild types (Figure 4a).
SMAD2 Expression in the Fourth PAA of Tgfß2+/+ and Tgfß2–/– Mice
To study TGF-ß2 signal transduction, nuclear localization of SMAD2 was analyzed (Figure 3l). In wild-type fetuses the media of the fourth PAA showed a high number of cells with SMAD2-positive nuclei (Figures 3i, 3j, 3l, 4b, and 4c). This region overlapped with the morphologically distinct fourth artery region described above (see Figure 3) including the NCAM-1–positive part (Figures 3g, 3h, 3k, and 4a). No comparable SMAD2-positive nuclei were found in the third and sixth PAAs nor in the dorsal aorta -segment (not shown).
Tgfß2–/– mice with extreme aortic arch hypoplasia, atresia, and interruption showed no SMAD2-positive nuclei in the media of the fourth artery or its remnants (Figure 4h, 4i, 4k, and 4l). The adventitia of the affected fourth arteries in these mutant still presented cells with SMAD2-positive nuclei (Figure 4h, 4i, 4k, and 4l) and overlapped with regions that expressed NCAM-1 (Figure 4g and 4j). Tgfß2 mutants without cardiovascular defects revealed normal SMAD2 signaling (compare Figure 4b with 4e and 4c with 4f).
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Discussion |
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It has been reported by our group that Tgfß2 plays an important role in cardiovascular development and is essential for normal fourth PAA development.1 In the present study, we show that a high degree of TGF-ß2–specific SMAD2 signaling goes concomitant with vascular innervation of the fourth arch artery.
NCC Migration and Differentiation into SMC Are Unaffected in Tgfß2 Mutants
The reported resemblance between cardiovascular defects (ie, common arterial trunk and fourth interruption) present in NCC-ablated chicken embryos (review5) and in Tgfß2 mutant mice led us1,9 to postulate an important role for TGF-ß2 in NCC migration and homing.26 Our present data show that NCCs populate the expected cardiovascular targets in NCC reporter Tgfß2–/– mice. These findings exclude abrogated migration as the main cause of vascular hypoplasia, fourth PAA, and outflow tract defects in Tgfß2 mutants.
The genes and mechanisms directing tunica media development (arteriogenesis) are largely unknown. Within this process, NCCs are recruited from the surrounding mesenchyme and condense into SMCs around the endothelial.15,27 This process is essential for stabilization of this endothelium tube and development of muscular PAAs.15,27 The presence of NCCs in the mesenchyme surrounding the aortic arch and fourth artery of affected Tgfß2 mutants implies that NCC recruitment is affected. Because the high number of NCCs in the mesenchyme surrounding the vessels of mutants resembles the situation normally seen in younger fetuses we conclude that NCC recruitment is delayed. Our observations underline a role for Tgfß2 in NCC homing, as has been suggested before.11,26 Although a structural function of NCCs in cardiovascular development has been proven25 strong arguments exist for a mechanistic function as well.5,13,15,23 This assumption is supported by the development of cardiovascular defects in animal models (eg, retinoic acid receptor28 and PAX329 knockout mice), which were originally linked to NCC-migration defects. The malformations must now be considered to result from disturbed interaction between NCCs and their target organs,28,29 which might apply for Tgfß2–/– mice as well.
With respect to SMC development, TGF-ßs can induce differentiation of splanchnic mesoderm13,19 and NCCs16,17 into SMCs and are involved in the expression of SMC-specific proteins (eg, SM--actin, SM22, SM-MHC, h(1)-calponin).18,30 Early SMC differentiation seems unaffected in Tgfß2 mutants, implying that TGF-ß2 is not essential for this process.
Aberrant Neural Innervation Coincides With Fourth PAA Defects
In Tgfß2 mutants, interruption of the fourth PAA gives rise to aortic arch interruptions and an aberrant subclavian artery or a combination of both anomalies (this report).1,9 The fourth arch artery reflects a morphogenetically distinct vascular segment, showing specific expression of neural (ie, RMO-270, NCAM-1) and SMC expression markers (this report).2
The mechanisms underlying fourth PAA innervation are unknown but probably rely on interactions of cytokines including brain-derived neurotrophic factor14 and TGF-ß.31,32 The role of TGF-ßs in NCC differentiation, survival, and maturation have been proven.16,18,31 Our results in Tgfß2–/– mice show a function of TGF-ß2 in vascular innervation. We demonstrated for the fourth artery, a correlation between the presence of TGF-ß2–SMAD2 signaling and the expression of NCAM-1 and innervation, as shown by RMO-270, a neurofilament subunit marker highly expressed in the perikarya and axon.22
NCAM-1 is a cell-recognition molecule of the IG superfamily, which effects NCC-migration, axon pathfinding, neural fasciculation, and neural differentiation.32,33 NCAM-1 expression has been reported to diminish after NCCs have ceased migration.34 In this report, we show that NCAM-1 becomes prominently expressed in the media of the fourth PAA during development, which coincides with innervation by RMO-270–positive axons. Within this context, NCAM-1 can be regarded as a morphogenetic factor required for differentiation (ie, innervation) of the fourth arch artery. Interestingly, NCAM-1 is positively regulated by TGF-ß,31–33 and the effect of NCAM-1 on neurite extension is dose dependent,35 ascribing a critical function to TGF-ß in innervation. The lack of NCAM-1 expression and absent innervation in the affected fourth arch vessel wall of Tgfß2–/– mice underscores this relation.
Disturbed fourth PAA innervation might be contemplated in other (transgenic) animals as well. Fourth arch artery defects are described in mutant mice including Et-1/Et-A,6 Vegf120/120, and Vegf188/1888 and Sema3C.36 Interestingly, these targeted genes function in both vascular and neural development, often influencing the maturation, survival, and/or patterning of both neural and vascular structures.
SMAD-Signaling Is Critical for Fourth PAA Development
TGF-ß1 to -ß3 intracellular signaling is transduced by cytoplasmic SMAD2 or -3. On activation SMAD2/3 are translocated by SMAD4 to the nucleus, modulating transcription of TGF-ß–responsive genes (ie, FN, NCAM-1).10
SMAD2 signaling is marked in the vessel wall of the fourth PAA as illustrated by SMAD2-postive nuclei. The reason for SMAD2 signaling in the media of this vessel segment remains elusive. Specific expression of TGF-ß receptors (ie, betaglycan), low cellular content of inhibitor SMAD6/7 or high cellular expression of cotranscription factors (ie, forkhead activin signal transducer-1) could relate to the differences in signaling found that need further investigation.
In Tgfß2 knockout mice with outflow tract defects, we find no SMAD2-positive nuclei and absent NCAM-1 expression in the affected vessel wall of the fourth arch artery, whereas in mutants without any anomalies expression is comparable to the wild type. This striking difference between phenotypically normal and abnormal mutants implies that additional factors are involved in SMAD2 signaling. Regarding the redundancy in function among TGF-ß1, -ß2, and -ß310,11 when applied in vitro and the endothelial expression of Tgfß1,12 we speculate that depletion of endothelial TGF-ß1 enhances the penetrance of the vascular defects in Tgfß2–/– mice. We exclude a substantial function for TGF-ß3 as its expression in the aortic arch is low.12 Furthermore, fourth PAA defects are not encountered in Tgfß3–/– mice and the additional contribution of Tgfß3 knockout in Tgfß2–/– mice is negligible.11
SMAD3-signaling might be involved in the development of the fourth PAA, however, considering Smad3–/– mice develop normally,37 we expect SMAD3 to have a redundant function in cardiovascular development. In contrast to the report of Flanders et al,21 the use of the SMAD3 antibody was not successful in our hands, prohibiting conclusions in our study. SMAD-independent signaling10,11 might also be involved in aortic arch development. Although our data do not exclude involvement of these signaling pathways it can be concluded that they are insufficient to prevent fourth PAA defects in Tgfß2–/– mice.
It is generally accepted that severe outflow tract defects can compromise blood flow through the aortic arch.38 The expression of Tgfß1 is shear stress responsive and positively related to increased flow and is capable to adjust SMC differentiation of the aortic arch.39 We hypothesize that reduced shear stress is a common denominator in the development of vascular anomalies in Tgfß2 mutants and causes downregulation of TGF-ß1. Within this proposition, the blood flow of unaffected Tgfß2 knockouts is sufficient to keep Tgfß1 expression at a level appropriate for SMAD2 signaling to outrun the threshold required to inhibit SMC apoptosis40 and to retain NCAM-1 expression adequate for innervation.35 For affected mutants, SMAD2 signaling in the fourth PAA will be too low to induce NCAM-1 expression and to inhibit SMC apoptosis.
In this study, we have shown that TGF-ß2 signaling is involved in fourth arch artery development. Future research will be necessary to unravel the mechanisms involved in differentiation of this vascular segment.
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Acknowledgments |
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We thank Jan Lens and Ron Slagter (InterMedics) for assistance with the graphics and layout and Lambertus Wisse for technical assistance. Special gratitude goes to Henry Sucov for kindly providing us with the Wnt1Cre by R26R Tgfß2 mouse sections (shown in Figures 1 through 3).
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Footnotes |
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Original received July 2, 2004; revision received September 30, 2004; accepted October 27, 2004.
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References |
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