© 2001 American Heart Association, Inc.
Brief Reviews |
Cell Lineages and Tissue Boundaries in Cardiac Arterial and Venous Poles
Developmental Patterns, Animal Models, and Implications for Congenital Vascular Diseases
From the Department of Biomedical Sciences (S.A., S.S.) and the National Research Council Center of Muscle Biology (S.A., S.S.), Padua, Italy.
Correspondence to Dr Simonetta Ausoni, Department of Biomedical Sciences, University of Padua, Viale G. Colombo, 3, I-35121 Padua, Italy. E-mail ausoni{at}civ.bio.unipd.it
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Abstract |
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 Top Abstract IntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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Abstract—Multiple cell populations with different embryological histories are involved in the morphogenesis of the cardiac arterial and venous poles as well as in the correct alignment and connection of the developing vessels with the cardiac chambers. Formation of the aorta and the pulmonary trunk is a complicated process orchestrated via a specific sequence of highly integrated spatiotemporal events of cell proliferation, migration, differentiation, and apoptosis. The peculiar susceptibility of this intricate cell network to be altered explains the frequency of congenital cardiovascular diseases of the arterial and venous poles. We review this topic from the "vascular point of view," putting major emphasis on (1) the existence of different cell lineages from which smooth muscle cells of the aorticopulmonary trunk can be derived, (2) the establishment of cell/tissue boundaries in the cardiovascular connecting regions, and (3) the animal models that can mimic human congenital defects of the arterial and venous poles of the heart.
Key Words: congenital cardiovascular diseases • tissue boundaries • outflow tract • inflow tract • animal models
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Introduction |
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TopAbstractIntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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Ahigh percentage of cardiovascular congenital malformations arise from an abnormal development of the great vessels and an improper alignment with the heart.1 2 3 Many of the cardiovascular defects that reach clinical observation are due to an abnormal development of the arterial pole, in particular, aortic arches, aorta, and pulmonary trunk. Abnormalities induced in the venous pole, on the other hand, can mostly be embryonically lethal, as supported by experimental observations in animal models,4 and are likely to be largely underestimated.
Previous reports in the field have dealt mostly with chamber specification, general heart morphogenesis, and cardiac looping. Instead, this report will discuss cell lineages and cell-signaling pathways in normal and abnormal development of the arterial and venous great vessels, inasmuch as this approach can provide more detailed information on the cell fate within the morphogenetic plan.
In the developing cardiovascular system, cell movements and the establishment of boundaries between the heart and the vessels are responsible for casting the outflow tract (OFT) and the inflow tract (IFT) of the heart, and this is why they represent the main topic of the present review. Development of the coronary vessels, derived from the proepicardium by a unique vasculogenetic process,5 6 7 will not be discussed because it has no primary impact on the arterial pole formation.
Pursuant to the aims mentioned above, we will highlight the following aspects: (1) Which cell lineages contribute to the formation of the arterial and venous poles of the heart? (2) How do vascular cells achieve their final identity and position with respect to cardiac cells? (3) What is the role of different cell lineages in the establishment of connections and boundaries? (4) Which "signals" control cell organization temporally and spatially? (5) Which experimental cardiovascular malformations arise from perturbations of these processes?
In the present review, we will present an updated list of animal models carrying defects of either the arterial or venous pole or both. The rapid generation of these models, thanks to the advances in gene-targeting techniques, are now allowing us to probe deeply into the molecular bases of congenital cardiovascular defects in humans and to underscore unexpected similarities and overlaps in the molecular pathways that control cardiac and vascular development.
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A Snapshot of Cardiovascular Development |
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TopAbstractIntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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In the developing embryo, the arterial pole consists of an OFT connected to the aortic arch arteries,8 and the venous pole consists of an IFT connected to the vitelline veins. The OFT has an aortic sac (proximal to the aorta) and a conotruncus (proximal to the ventricle). The IFT has a sinus venosus (proximal to the cardinal veins) and a sinuatrial region (proximal to the atria). The OFT and the IFT are transient embryological regions that undergo profound remodeling during development and result in the formation of cardiac as well as vascular distinct structures. This is why, whenever appropriate, we prefer to use the terms arterial pole and venous pole to indicate the outlet and inlet of the heart instead of OFT and IFT. Formation of the arterial and venous poles in the embryo is a complex morphogenetic event whose detailed analysis is beyond the scope of the present review. Nonetheless, we have summarized the main embryological stages in Figure 1
to help the reader visualize the complicated
processes.
Figure 1 illustrates the initial differentiation of vascular
and cardiac lineages in the cardiogenic area
(Figure 1A), the progressive septation of the OFT into the
aorta and the pulmonary trunk due to migration of neural crest
cells
(Figure 1B and 1C), the alignment of the great vessels and
the cardiac chambers
(Figure 1D), and the remodeling of the vitelline veins,
umbilical veins, and cardinal veins so that finally all venous blood
enters the right atrium via the superior and inferior caval
veins
(Figure 1C and 1D). For a detailed embryological
analysis, we refer to previous
articles.3 9 10 11
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Cell Lineages in the Cardiac Arterial and Venous Pole |
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TopAbstractIntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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Endothelial and Endocardial Lineages
The arterial pole contains endocardial cells of the OFT and endothelial cells of the aortic sac and aortic arches. These distinct cell lineages are, at least in the adult, structurally and functionally distinct in terms of tissue permeability, cell-cell contact, and cell communication with adjacent compartments.12 13 Endothelial precursors of mesodermal origin initiate vasculogenesis and promote the recruitment of surrounding mesenchymal cells to form the definitive smooth muscle cells (SMCs) and fibroblasts of the vascular wall.14 15 Vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFR-1, VEGFR-2, VEGFR-3, and neuropilins), angiopoietins and their Tie receptors, platelet-derived growth factor, transforming growth factor-ß (TGF-ß), and the ephrin-Eph receptor system are essential for vasculogenesis and remodeling (see reviews 16,17) and act as carefully orchestrated players in terms of time, space, and dose effect. Unlike the endothelial cells of the aortic sac, endocardial cells of the OFT form 2 endocardial cushions through an epithelial-to-mesenchymal transition.18 These cushions are essential in forming the aorticopulmonary septum, as demonstrated by the absence of an aorticopulmonary septum in null mice lacking proper endocardial ridges, such as the Sox-4 mutants (see below).19
SMC Lineage From Different Compartments
The great vessels connected to the heart contain SMCs
with largely diverse embryological origin. Their mesenchymal progenitor
cells may be recruited from local and distant sources
(Figure 2), among which there are the neural crest cells.
Neural crest cells migrate from the neural folds to the pharyngeal
arches. Here, they separate each arch artery and aortic sac from the
pharyngeal ectoderm and condense against the lumen to generate its
smooth muscle
wall.20 21 22
A subpopulation of neural crest cells invades the OFT and the base of
the heart, thus forming the aorticopulmonary septum,
pulmonary infundibulum, aortic vestibule, and separation of the
great vessels from the right and left
ventricles.23 This explains
why ablation of cardiac neural crest cells in the chick embryos leads
to a wide variety of malformations, including common trunk and
ventricular septal defects
(VSDs).24 25 There
is no significant neural crest cell contribution to the formation of
the venous pole, even though neural crest–derived SMCs are present
in the tunica media of the anterior cardinal
veins26 and defects of the
venous pole after ablation of cardiac neural crest cells have been
described.27 The properties
of the cardiac neural crest cells are quite unique, allowing them to
differentiate into SMCs, initiate elastogenesis in the aorta and
pulmonary trunk,28
and control tissue remodeling of the forming vessels. It is likely,
therefore, that they represent a specific subpopulation with
partially restricted developmental options, as suggested by grafting
experiments in which replacement of cardiac neural crest cells by
cranial neural crest cells failed to support
cardiovascular
development.29 Cardiac neural
crest cells are functionally linked by gap junctions, and gap junction
communications are associated with SMC
differentiation.30
Furthermore, neural crest cells are responsive to TGF-ß in
vitro,31 and TGF-ß and
BMP-2 and -3 instructively promote SMC
differentiation.32
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There is at least one more major source of mesenchymal cells that differentiate into SMCs. This is the local mesoderm that contributes to the muscular wall of the ascending aorta and to the pulmonary trunk but not to the aortic arch arteries.33 Distribution of SMCs of mesodermal origin in the aorticopulmonary septum is not clear, because differences in OFT septation have been found in mice and in chicks.34
Recent reports indicate the
endocardium,9 the
mesothelium,35 and the
myocardium36 as
other possible sources of vascular SMCs, but these contributions, if
any, remain speculative and will require further investigation. The
fourth possible SMC origin is the endothelium.
Endothelial cells transdifferentiate into SMCs and
migrate into the media and adventitia in the chick dorsal
aorta.37 Whether
endothelial cell transdifferentiation contributes to
form the tunica media of other vessels has yet to be investigated. SMC
origin from endothelial cells can also be explained
differently. Endothelial precursors share a common
progenitor, the hemangioblast, with the hemopoietic stem cells (see
Figure 1A
). The intimate relationship between hemopoietic
and vascular cells is exemplified by the common expression of the CD34
cell surface
glycoproteins,38
by the presence of CD34+ cells in the mouse
para-aortic mesenchyme,39 and
by the absence of hemopoietic and endothelial cells in
the zebra fish mutant
cloche.40
Intra-aortic hemopoietic cells can be derived from
endothelial
cells41 and play a role in
postnatal
angiogenesis.42 43 44
Whether hemopoietic stem cells also participate in prenatal
vasculogenesis is a tempting speculation, but this is still under
debate. In conclusion, the mesenchymal SMC progenitor in the
arterial pole originates from multiple differentiation
pathways. After the mesenchymal cells become associated with the
endothelium, a coordinated differentiation program is
activated, and smooth muscle–specific contractile and
cytoskeletal proteins are
synthesized.45 This process
is likely to involve the majority of cells, but it is also formally
possible that a minor population of mesenchymal cells persists as a
reservoir, with intermediate characteristics of SMC
precursors.46 Ubiquitous or
widely expressed transcription factors, such as serum response
factor47 48 49
and Sp-1/Sp-3,50 play a role
in the smooth muscle–specific gene transcription. A
Kruppel-like factor and the BTEB2 protein are required to
activate the smooth muscle lineage marker, the SM22 gene,
through a TGF-ß control
element.51 However, the
molecular details of a functional smooth muscle–specific transcription
complex remain to be elucidated.
Cardiac Lineage
Septation of the OFT ends with the formation of an
outlet septum that separates the 2 great arteries and allows the aorta
and the pulmonary artery to drain into the left and right
ventricle, respectively. Initially, this septum is a mesenchymal
structure originating from the OFT endocardial ridges, but later in
development, it becomes muscular through an ingrowth of a newly formed
myocardium into the mesenchymal endocardial
cushions.52 53
Impaired myocardialization results in the persistence of an embryonic
outlet septum and can lead to a variety of congenital heart diseases,
ranging from VSD to double-outlet right ventricle (DORV). There is much
evidence to indicate that myocardialization is under multiple control
signals from the aortic sac
mesenchyme52 and from the
neural crest
cells.30 52 53
Myocardialization proceeds in the venous pole, too. Here, it is not limited to the heart, but extends up to the forming caval veins and pulmonary veins. In fact, myocardial cells largely contribute to the tunica media of these vessels in rodents54 and, to a lesser extent, in humans. In transgenic mice expressing the LacZ reporter gene under the control of the cardiac troponin I promoter,55 we observed that cardiac cells in the pulmonary veins never go beyond well-defined boundaries that correspond to the third bifurcation and never spread to colonize the pulmonary arteries.56 It is likely, therefore, that endothelial cells and/or SMCs of the veins release "signals" to recruit and set the position of the myocardial cells.
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Morphological, Cellular, and Molecular Boundaries in the Arterial and Venous Pole |
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TopAbstractIntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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Formation of the great vessels at the arterial and venous pole involves multiple cell types that rearrange themselves at the correct space in the body to realize a precise morphogenetic plan. The existence of a prepattern on which the heart and the great vessels are built is suggested by much evidence, most of which pertains to the heart more than to vessel formation. Strict boundaries for Hox gene expression exist in the pharyngeal arches,57 58 but nothing similar has ever been demonstrated in other vessels. So far, the Hairy-related family members HRT1, HRT2, and HRT3 are the only genes that exhibit distinct expression patterns in the vascular system, with strict boundaries along the anterior-posterior axis.59 In zebra fish, the grid-lock mutation for the grl gene, which encodes a Hairy-type basic helix-loop-helix protein, selectively perturbs assembly of the aorta, suggesting that identity of this vessel is determined before the onset of circulation.60 This is in agreement with the idea that the embryonic circulatory plan is genetically established.
To create strict boundaries between the heart and specific vascular segments, integrated cellular and molecular events are required; these include the following: specific cell-cell and cell-matrix adhesion and cell migration, proliferation, differentiation, and apoptosis. In this respect, neural crest cells may be fundamental because their migration follows a precise colonization territory. In the chick, there is a strict boundary between the aortic arches, ascending aorta, and pulmonary trunk invested by neural crest cells on one side and descending aorta and pulmonary arteries that are completely devoid of neural crest cells on the other side.9 20 34
Our hypothesis is that neural crest cells perform 2
functions: (1) they colonize and demarcate the territory where the
vasculature will develop (instructive role), and (2) they provide an
abundant population of SMC precursors for vascular remodeling
(structural role). Interestingly, ablation of neural crest cells
indicates that a threshold level of cells is critically important for
proper septation and tissue
remodeling.26 Another
essential event to guarantee OFT septation is the interplay between
endocardial cushions and neural crest cells. In this respect,
endothelin-mediated signaling seems to be of great importance. Targeted
inactivation of
endothelin-1,61 endothelin
receptor A,62 and
endothelin-converting
enzyme-163 in mice causes
abnormal aortic arches, poor development of the endocardial cushions,
DORV, and VSD (see
Table)
similar to the DiGeorge syndrome in humans. Endothelin-1–mediated
signals from endocardial and endothelial cells may be
relayed to neural crest cells by classic binding to endothelin type A
and B receptors. It is interesting that the transcription factors
goosecoid,61 d-HAND, and
msx1,64 are downregulated in
mice lacking the endothelin-mediated pathway and that dHAND and msx1
are required for the development of the aortic arches and OFT septation
(see below).
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What is the significance of boundaries in the embryo, and
how are they formed? Tissue boundaries and, hence, morphogenetic
patterning are likely to be the result of a combined effect of
endogenous and exogenous "driving cues" and
"positional cues"
(Figure 3). The former impose the correct spatiotemporal
migration to cells that may or may not be intrinsically determined for
movement; the latter establish and maintain the correct topographic
patterns by restricting cell and tissue intermingling. This process can
result from a series of molecular events involving cell-cell and/or
cell-matrix contact-mediated guidance in a short range. The nervous
system, in which guidance signals direct axon formation along defined
patterns to establish the neuronal connection network, is paradigmatic.
It is noteworthy that some of the molecular cues that guide neural
crest cell migration and stabilization of neural patterns play a role
in vasculogenesis and angiogenesis, too. Three major groups of
molecules can be involved in these processes: (1) diffusible molecules,
such as semaphorins65 and
netrins,66 (2) membrane-bound
proteins, such as the ephrins-Eph receptor
system,16 17 67 68
and (3) extracellular matrix proteins. The semaphorin Sema3A is able to
inhibit endothelial cell motility, capillary formation,
and sprouting by competing with VEGF for the neuropilin-1
coreceptor.65 Other
molecules, such as netrins, act as either a chemoattractant or
chemorepellent in the nervous system, and netrin-1 transcripts are also
present in the developing cardiovascular
system.66 Ephrins and Eph
receptors, initially discovered in the nervous system, may mediate
cell-cell adhesion or deadhesion, restricting the cellular
intermingling and thus establishing and maintaining the appropriate
tissue
boundary.16 17 67 68
Recent data indicate that the ephrin-Eph receptors can trigger a local
depolymerization of the cytoskeleton, leading to
the collapse of filopodia and, hence, producing a direct control over
cell migration.69 In
addition, ephrin B2, initially restricted to
endothelial cells in the embryo, is also later
expressed in the surrounding
SMCs.16 Finally, in the
nervous system, the ephrin-Eph receptor system displays complementary
gradients that overlap those of the fate mapping. This may occur in the
establishment of cardiovascular boundaries, too.
Ephrins also regulate surface density of integrins
Vß3 and 5ß1,
which are known to have a
role70 in early
vasculogenesis.
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Cell adhesion and extracellular matrix are likely to be involved in setting boundaries between 2 neighboring tissues. For example, in the OFT extracellular matrix components, such as fibronectin, elastin, and laminin, collagens I and VI have a specific temporal and spatial distribution,71 and versican, a cell adhesion molecule, seems to play a nonpermissive role in cell movements.72 Lack of versican in the hdf mouse mutants72 and lack of hyaluronan synthase-273 in the embryo results in severe cardiovascular defects for impaired endocardial cushion formation. Possible consequences in septation of the OFT cannot be observed in these mutants because of early death in the littermate.
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Cell Lineage and Tissue Boundary Defects in Animal Models |
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TopAbstractIntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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Many mouse mutants that reproduce aspects of human congenital cardiovascular defects are currently being generated. These animal models provide an exciting instrument for identifying the factors involved in cardiac morphogenesis and are extremely powerful in establishing the relationship between a genetic defect and its functional consequences in vivo. Animal models with defects in the cardiac arterial and venous pole are listed in the Table
,
where associated references can be
found.19 25 27 61 62 63 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 In this section, we will mainly focus on animal models with abnormal development of the arterial pole. Abnormalities of the venous pole will not be reviewed extensively because there are just a few examples of animal mutants with defects in this region. In addition, the origin of these defects is still a matter of discussion for clinicians and embryologists. The only animal model with an exclusive defect in the venous pole is the knockout mouse for the steroid receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII). This mutant shows sinoatrial malformations and either poorly formed or collapsed cardinal veins.97 Early lethality in the littermate occurs because of congestive heart failure, which is presumably due to deficient blood circulation in the rapidly growing embryo.
Analysis of the
Table
suggests some general comments. The first is related to survival times.
Animal mutants with abnormalities in the arterial pole die
at around 3 specific periods: embryonic day 10, embryonic days 14 to
15, and perinatally. It may be that the vascular system maturation
proceeds according to a spatiotemporal sequence of events, whose
completion ensures the correct progression along the developmental
pathway. The establishment of a morphogenetic abnormality during this
process could not be tolerated if it did not guarantee a successful
outcome of embryogenesis. The first decision to be made by the forming
organism is related to OFT colonization by neural crest cells. The
second concerns the completion of OFT septation and the muscularization
of the septum. The third is the activation of pulmonary
circulation. Nothing is known about the ways in which such decisions
are made, and the use of the term heart failure to indicate the cause
of embryonic death may be not always adequate. Some data highlight the
role played by altered hemodynamic factors on inducing
cardiovascular malformations. The
physiological increases in blood volume, pressure,
and flow with their inherent increases of shear stress and wall
stretching may have a profound impact on the onset of
cardiovascular abnormalities. The establishment of an
abnormal pulmonary circulation is also a crucial event causing
sudden death. For instance, mice lacking connexin43 die neonatally as a
consequence of an obstruction of the subpulmonary
OFT.88 89
A second observation in the interpretation of complex knockout phenotypes is that we need to distinguish, whenever possible, between primary defects and secondary defects. Primary developmental defects originating in the heart can have dramatic consequences for the vessels and vice versa. For example, DORV, characterized by the persistence of an embryonic configuration in which septated aorta and pulmonary trunk drain into the pulmonary ventricle, is associated with VSD. In other cases, malformations of the great vessels can be the consequence of cardiac defects. For example, an abnormal cardiac looping, such as in the iv/iv mice, can lead to transposition of the great arteries, DORV, and VSD. The interdependence between cardiac and vascular development is well illustrated in the MEF2C knockout mouse, which exhibits myocardial and endocardial defects as well as abnormal vessels and atresia of the great vessels connected to the heart.76 77 In this model, the lack of the right ventricle and the development of an hypoplastic left ventricle reduces and finally blocks blood flow in the embryo. This results in vascular atresia of the aortic arch arteries that require the blood flow to maintain their normal lumen. In addition, hypoxia produces multiple effects, including the loss of mesenchymal cell and an increased VEGF expression, resulting in vessel enlargement for fusion of adjacent capillaries and altered vascular remodeling.
A third observation is that the same defect can be generated by mutations in different genes. For example, common trunk can be due to genes that act either on the neural crest cells or on the endocardial cushions, suggesting a functional cooperation among different cells in OFT septation. Conversely, one gene mutation can lead to a broad spectrum of abnormalities either because a gene controls the same function in multiple tissues or, more frequently, because a cellular compartment is involved in multiple functions. For example, mutations in genes of the endothelin-mediated pathway lead to aortic arch abnormalities, common trunk, and DORV,61 62 63 presumably because endothelin-1 released by the endothelium and the endocardium controls neural crest differentiation, endocardial cushion formation, and myocardialization, 3 closely related events.
Among the human pathologies that best reflect the spectrum
of abnormalities observed in these animal mutants are the DiGeorge
syndrome and velocardiofacial syndrome. The common features of these
syndromes are interrupted aortic arch, OFT malformations, hypoplastic
thymus, and parathyroids.98
Both diseases are due to haploinsufficiency of 
1 gene in the q11.2
region of chromosome 22. The minimal critical region that is deleted in
most DiGeorge patients has been mapped, but the identification of the
genes involved is complicated by the fact that some patients show
deletions in distinct nonoverlapping regions. Using the Cre-LoxP
system, Lindsay et
al92 generated a mouse that
carries a deletion (Df1) homologous to the human deleted region in
DiGeorge and velocardiofacial syndrome. The mouse mutant lacks 14 of
the almost 30 genes of the DiGeorge critical region and recapitulates
most of the human cardiovascular defects but lacks
thymic, parathyroid, and craniofacial abnormalities. Thus, it is likely
that the DiGeorge syndrome requires the deletion of a whole group of
genes and/or regulatory elements that control multiple genes in a
cluster.
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Future Directions |
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TopAbstractIntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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Our present knowledge about the biology and embryology of OFT and IFT does not allow for the assembling of data in a definitive picture. However, the discovery of new genes and the generation of models for gene function studies in vivo are making progress in this field faster. Identification of genes that regulate commitment and differentiation of SMCs will be essential in understanding how the vascular network arises and is organized. Unfortunately, this search is still in its infancy compared with analogous studies in cardiac and skeletal muscle, but it will certainly profit from the fact that genes involved in cardiac development can also have a profound impact on vascular development. In addition, it will be important to identify (1) the genes that control arterial and venous SMC diversification and (2) the genes involved in induction and maintenance of tissue boundaries in the connecting cardiovascular regions. The lesson derived from the discovery of the ephrin-Eph receptor system for vascular endothelium clearly indicates the direction.
On the other hand, a great effort has to be devoted to the generation of new animal models. The new inducible and conditional knockouts will be extremely useful in this respect. They will help to overcome problems of genes that control some morphogenetic events but cause a premature death. In addition, they will contribute in the dissection of a function whenever a single gene controls multiple morphogenetic events. Although some caution must be used when a direct correlation between mouse mutants (eg, the DiGeorge mouse models) and human diseases is made,99 100 101 the availability of more models for studies in vivo is certainly the strategy of choice for disclosing the mechanisms of cardiovascular abnormalities.
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Acknowledgments |
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Preparation of this review was supported by a grant from the Regione Veneto (1998–1999) to S.A and MURST (Role of Smooth Muscle Cells in Atherogenesis: Pharmacological Implications) to S.S. We wish to thank Adriana Gittenberger-de Groot, Department of Anatomy and Embryology, Leiden University Medical Center; Joseph Miano, Center for Cardiovascular Research, University of Rochester Medical Center; and Stefano Schiaffino and Marina Campione, Department of Biomedical Sciences, University of Padova, for critical reading of this review. We would also like to thank Sarah Hansen for her excellent editorial assistance.
Received October 25, 2000; accepted November 29, 2000.
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TopAbstractIntroductionA Snapshot of Cardiovascular...Cell Lineages in the...Morphological, Cellular, and...Cell Lineage and Tissue...Future DirectionsReferences |
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