Published online before print August 17, 2007, doi: 10.1161/CIRCRESAHA.107.152082
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© 2007 American Heart Association, Inc.
Molecular Medicine |
Coronary Vessel Development Is Dependent on the Type III Transforming Growth Factor ß Receptor
From the Departments of Pharmacology (L.A.C., D.A.P., J.V.B.) and Pediatrics (C.B.B.), Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Joey V. Barnett, PhD, Department of Pharmacology, Vanderbilt University Medical Center, Room 476 RRB, 2220 Pierce Ave, Nashville, TN 37232-6600. E-mail joey.barnett{at}vanderbilt.edu
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Abstract |
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Transforming growth factor (TGF)ß receptor III (TGFßR3), or ß-glycan, binds all 3 TGFß ligands and inhibin with high affinity but lacks the serine/threonine kinase domain found in the type I and type II receptors (TGFßR1, TGFßR2). TGFßR3 facilitates signaling via TGFßR1/TGFßR2 but also has been suggested to play a unique and nonredundant role in TGFß signaling. Targeted deletion of Tgfbr3 revealed a requirement for Tgfbr3 during development of the coronary vessels. Coronary vasculogenesis is significantly impaired in null mice, with few vessels evident and numerous, persistent blood islands found throughout the epicardium. Tgfbr3-null mice die at embryonic day 14.5, the time when functional coronary vasculature is required for embryo viability. However, in null mice nascent coronary vessels attach to the aorta, form 2 coronary ostia, and initiate smooth muscle recruitment by embryonic day 14. Analysis of earlier developmental stages revealed defects in the epicardium. At embryonic day 13.5, these defects include an irregular and hypercellular epicardium with abundant subepicardial mesenchyme and a thin compact zone myocardium. Tgfbr3-null mice also displayed other defects in coronary development, including dysmorphic and distended vessels along the atrioventricular groove and subepicardial hemorrhage. In null mice, vessels throughout the yolk sac and embryo form and recruit smooth muscle in a pattern indistinguishable from heterozygous or wild-type littermates. These data demonstrate a requirement for Tgfbr3 during coronary vessel development that is essential for embryonic viability.
Key Words: coronary vessels • transforming growth factor ß receptor • mice, null
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Introduction |
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Coronary artery disease is responsible for 54% of all cardiovascular disease in the United States.1 Coronary vessels have a unique derivation from mesothelial cells that form a transitory structure termed the proepicardium. Proepicardial cells are transferred to the heart, form the epicardium, and give rise to endothelial cells, smooth muscle cells, and cardiac fibroblasts (reviewed elsewhere2,3). Endothelial cells derived from the epicardium form a vascular plexus by the process of vasculogenesis. This vascular network attaches to the aorta and recruits epicardially derived mesenchyme to become vascular smooth muscle. The identification of the molecular and cellular processes that regulate coronary vessel development may provide insight into coronary vessel disease and reveal novel therapeutic opportunities.
The transforming growth factor (TGF)ß family of growth factors regulates cell growth and differentiation in the cardiovascular system during both development and disease.4–6 Three ligands, TGFß1, TGFß2, and TGFß3,7–9 bind 4 cell surface proteins. These include two transmembrane serine/threonine kinase receptors, the type I TGFß receptor (TGFßR1) and the type II TGFß receptor (TGFßR2).10–12 Several type I receptors, termed activin receptor–like kinases (ALKs), have been described. TGFßR2 has a constitutively active cytoplasmic kinase domain and an extracellular domain that binds TGFß1 and TGFß3 with high affinity.13 Ligand binding results in TGFßR2 phosphorylating TGFßR1 (specifically ALK5) and subsequent stimulation of ALK5 kinase activity.14 ALK5 phosphorylates specific receptor Smads that associate with Smad4 and enter the nucleus to alter gene transcription.15 A second class of TGFß binding receptors contains 2 transmembrane proteins, termed the type III TGFß receptor (TGFßR3), or ß-glycan, and endoglin. Both TGFßR3 and endoglin contain a short, highly conserved intracellular domains with no apparent signaling function.16–18
The targeted inactivation of several components of the TGFß signaling pathway result in specific vascular defects.19,20 The most severe phenotypes are seen after deletion of Tgfr2 or Tgfb1, which results in defects in vasculogenesis and embryonic death.21,22 Less severe defects characterized by deficits in angiogenesis are noted in mice null for ALK5,23 ALK1,24 endoglin,25 and smad5.26,27 The role of these molecules in angiogenesis is supported by studies of endothelial cells in culture that reveal TGFß1 signals via endoglin to regulate the activation of ALK1 and ALK5 to direct endothelial cell proliferation and migration.28–30 Furthermore, mutations in ENG and ALK1 are responsible for a human disease characterized by defective vascular remodeling, hereditary hemorrhagic telangiectasia.24,25,31,32 Deletion of the ligand that is uniquely bound with high affinity by TGFßR3, Tgfb2, results in a spectrum of severe cardiac defects that include double-outlet right ventricle, ventricular septal defect, and hyperplastic cushions8,33 but no defects in blood vessel development. A prior report of Tgfbr3 deletion noted only myocardial thinning and ventricular septal defect with embryonic lethality attributed to liver defects.34
Here we report that Tgfbr3 is required for coronary vessel development. In Tgfbr3 nulls, the proepicardium is transferred to the heart and the epicardium is formed. Endothelial cells are present, and vasculogenesis is initiated but to a lesser extent than in wild-type or heterozygote embryos. Nascent coronary vessels form properly placed ostia and recruit smooth muscle. However, the reduced coronary vessels are apparently unable to support the needs of the myocardium resulting in death at embryonic day (E)14.5. Vasculature outside of the coronary circulation appears normal.
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Materials and Methods |
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Generation of Null Mice
A targeting vector was made to delete exon 3 that encodes the N terminus, including a portion of the extracellular ligand binding domain. Construction and validation of the targeting vector is described in the online data supplement at http://circres.ahajournals.org (see supplemental Figure I).
Histology, Whole-Mount Immunohistochemistry, and ß-Galactosidase Staining
Detailed methodology is described in the online data supplement.
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Results |
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Deletion of Tgfbr3 Results in Embryonic Lethality
Exon 3 was targeted as depicted in the online data supplement (supplemental Figure I). Matings between heterozygous nulls failed to produce any live homozygous null embryos after E14.5, suggesting that the null allele is embryonic lethal (supplemental Table I). Embryos harvested before E14.0 appeared grossly normal. Examination of null embryos revealed defects in outflow tract (OFT) morphogenesis (Table). At E14.5, wild-type and heterozygous null mice have a septated OFT and a discrete aorta and pulmonary trunk with properly formed valves (Figure 1). Defects in null embryos ranged from overriding aorta to double-outlet right ventricle (Figure 1), suggesting defects in OFT wedging required for proper alignment over the left and right ventricles. Consistent with a prior report,34 we noted a high incidence of ventricular septal defect and thin compact zone myocardium (Table). Although significant, these defects are unlikely to be responsible for embryonic death at E14.5.
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Tgfbr3-Null Mice Display Defects in Coronary Vasculogenesis
Because embryonic death coincides temporally with the known dependency of embryo viability on the formation of the coronary circulation, we examined null embryos for the presence of coronary vessels. Whole-heart immunostaining for the vascular endothelial cell marker platelet endothelial cell adhesion molecule (PECAM) (also known as CD31) at E14.0 revealed dramatically decreased immunoreactivity in nulls (Figure 2A and 2B). The developing vascular plexus was much less pronounced in null embryos, and fewer vessels formed on both the ventral and dorsal surfaces of the heart (Figure 2). The large vessels present in wild-type and heterozygous hearts were absent in nulls. Null hearts often had PECAM-positive structures reminiscent of blood islands. Sectioning confirmed fewer PECAM-positive cells in the subepicardial space and myocardium of null mice (data not shown). No gross differences in heart size were noted among genotypes.
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We next asked whether the few coronary vessels found in nulls were patent with the systemic circulation. Coronary arteries formed by vasculogenesis attach to the systemic circulation around E14.0 via 2 coronary ostia that reside superior to the right and left aortic valve leaflets. Embryos were sectioned and examined for the presence of patent ostia (Figure 2C). Null embryos were scored relative to wild-type and heterozygous null littermates. In nulls, right and left ostia were seen in 15 of 16 embryos examined. In contrast to wild-type or heterozygous embryos, nulls exhibited persistent blood islands in the region of the coronary ostia. These data suggest that although vasculogenesis and vessel formation is impaired in null embryos, the resulting vessels properly attach to the systemic circulation.
Tgfbr3-Null Mice Have Abnormal Epicardium and Dysmorphic Coronary Vessels
The epicardium is derived from the proepicardium and contains coronary vessel precursor cells. At E13.5, the epicardium forms a tightly apposed monolayer on the surface on the atria and ventricles. In the region of the atrioventricular groove, the epicardium is separated from the myocardium by a layer of epicardial-derived mesenchyme (Figure 3A). The epicardium of heterozygous embryos was indistinguishable from wild-type embryos. However, we observed multiple defects in the epicardium of nulls. At E13.5, the separation between the epicardium and myocardium is expanded and contains numerous mesenchymal cells (Figure 3A). This thick, hypercellular layer expands across the surface of the ventricles and along the atria (Figure 4A and 4B). In contrast to the few, small blood islands still present in wild-type or heterozygous embryos, blood islands in the subepicardial space of nulls are large and abundant (Figure 4B [asterisk] and 4C [arrowheads]). Null embryos often had red blood cells in the ventricular subepicardium (Figure 3C).
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At E13.5, blood vessels can be seen forming in the subepicardial mesenchyme in the atrioventricular groove in wild-type and heterozygous embryos. The lumens of these vessels are round and enclosed by endothelial cells (Figure 3B). In contrast, vessels formed in nulls are irregularly shaped (Figure 3B and the Table). These defects in epicardium and blood vessel development are accompanied by a thin compact zone myocardium (Figure 3C).
Tgfbr3-Null Mice Initiate Recruitment of Smooth Muscle to Extracardiac and Coronary Vessels
TGFß has multiple roles during blood vessel formation, including vascular smooth muscle cell recruitment.35 To examine the association of vascular smooth muscle with blood vessels in nulls, heterozygous null mice were crossed to mice that express lacZ under the control of the smooth muscle 22
promoter (SM22lacZ).36 Whole-mount staining of E14.0 embryos produced by matings between Tgfbr3+/–; SM22lacZ mice revealed no gross difference in the pattern of lacZ expression in nulls when compared with wild-type and heterozygous nulls (Figure 5A). This is despite evidence of hemodynamic failure in nulls. Examination of the extraembryonic vasculature revealed no apparent difference in vascular patterning or smooth muscle recruitment in the yolk sac (Figure 5B). These data demonstrate that defects in vasculogenesis in nulls are limited to the coronary vasculature.
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After right and left coronary arteries attach to the systemic circulation at the aorta, smooth muscle recruitment commences at the coronary ostia and progresses distally. As noted in Figure 2, null mice form 2 coronary ostia, similar to wild-type mice, but die shortly after the start of smooth muscle recruitment. At E14.0, SM22lacZ-positive cells are not associated with large, subepicardial vessels in wild-type, heterozygous, or null hearts (Figure 6A and 6B). Transgene expression in the OFT is indistinguishable among genotypes. One day later in development at E15.0, lacZ-positive cells are associated with large subepicardial blood vessels on both the dorsal and ventral surfaces of the heart in wild-type embryos (supplemental Figure IIC); no nulls survive to E15.0. At E14.5, lacZ-positive cells surround both right and left coronary ostia in wild-type, heterozygous, and null embryos (Figure 6C). In addition, Sm22lacZ expression is also noted in a subpopulation of cells in the epicardial layer and subepicardial mesenchyme. Positive cells in the subepicardial mesenchyme are not associated with nascent vessels (supplemental Figure IIA). Null embryos have a similar pattern of lacZ expression, with abundant expression found in cells associated with blood-filled, dysmorphic vessels (supplemental Figure IIA). In all genotypes, at E14.0 blood islands are found at the apex of the heart associated with lacZ-positive cells (supplemental Figure IIB). Vascular smooth muscle recruitment appears to occur normally in all tissues examined, including nascent coronary vessels. However, because null mice die while smooth muscle recruitment is occurring, we cannot rule out a role for Tgfbr3 during later stages of coronary vascular smooth muscle recruitment.
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Discussion |
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Disruption of Tgfbr3 revealed a requirement for coronary vessel development and embryonic viability. Null embryos die at E14.5 with defects in coronary vessel development, whereas vasculature outside of the coronary circulation appears normal. Although greatly reduced in size, nascent coronary vessels attach to the aorta and initiate smooth muscle recruitment. Coronary vessel defects are coincident with epicardial abnormalities that include increased space between the epicardium and myocardium, abundant subepicardial mesenchyme, and persistent blood islands. In addition to coronary vessel anomalies, null embryos have OFT abnormalities and myocardial thinning. Presumably, the greatly reduced coronary vasculature in null embryos is not sufficient to adequately perfuse the heart resulting in embryonic death.
Despite the abundance of data implicating TGFß signaling in vasculogenesis and angiogenesis, these processes appear to occur normally outside of the coronary vessels in nulls. The localization of defects to the coronary vessels may be explained by the unique derivation of these vessels (reviewed elsewhere2,3). The proepicardium, adjacent to the liver rudiment, is transferred to the heart and gives rise to the epicardium as well as coronary endothelial cells, smooth muscle cells, and cardiac fibroblasts.37,38 Endothelial cells delivered to the heart form a vascular plexus, attach to the aorta, and recruit epicardially derived mesenchyme to form vascular smooth muscle. Null mice show defects at multiple stages of coronary vessel formation. In nulls, proepicardial cells are delivered to the heart, form an epicardium and undergo epithelial mesenchymal transformation. However, the epicardium is hypercellular, and the subepicardial space is widened with abundant subepicardial mesenchyme. In contrast, the myocardium is thin, consistent with reduced proliferation in the compact zone myocardium of null embryos.34 Because Tgfbr3 is expressed in both myocardium34 and epicardium (unpublished), and bidirectional signaling between the epicardium and myocardium is required for the proper formation of each,39–42 the defects described in these tissues may result from a requirement for Tgfbr3 in epicardium, myocardium, or both.
Although targeted gene deletion in mice has uncovered roles for several molecules in coronary vessel development, none has a phenotype similar to Tgfbr3 nulls. Deletion of vascular cell adhesion molecule-140 or the counter receptor 4 integrin43,44 results in the loss of the epicardium. Recently, WT-1 has been shown to regulate the expression of 4 integrin,45 which may explain phenotypic similarities after the loss of WT-146 or 4 integrin. Similarly, impairment of GATA4 and FOG2 function disrupts epicardial and myocardial interactions that support epicardial mesenchymal transformation.42,47 A subtle epicardial phenotype is seen in Cx43-null embryos, in which epicardial cells are rounded in contrast to the flattened shape seen in wild-type embryos.48 Thymosin ß4 is a G actin monomer–binding protein recently identified as a factor from the myocardium that is essential for coronary vessel development and promotes migration and differentiation of adult epicardial cells.49 Dysregulation of myocardial angiopoietin-1 expression results in 90% embryonic lethality attributable to failed coronary vessel development coincident with an absence of epicardium.50 Double knockout of Fgfr1 and Fgfr2 from the myocardium results in fewer coronary vessels, a morphologically normal epicardium, and impaired formation of subepicardial mesenchyme.51 Our findings in Tgfbr3 nulls that include a thickened epicardium with an apparent increase in subepicardial mesenchyme are dissimilar from these described phenotypes, suggesting that the role of TGFßR3 in the regulation of epicardial cell behavior may be distinct from that of previously identified molecules.
Defects in coronary vasculogenesis in Tgfbr3 nulls do not appear to result from defects in angioblast or endothelial differentiation because PECAM-positive cells do appear. A failure in coronary vasculogenesis could result from an insufficient population of angioblasts or endothelial cells, a possibility we cannot exclude because the numbers of these cells was not quantitated. At E14.5, we saw fewer vessels on the heart and a complete absence of large vessels formed by remodeling of the primary vascular plexus. This observation suggests a defect in angioblast or endothelial cell assembly or remodeling. TGFßR3 contains a cytoplasmic PDZ domain that has been shown to bind interacting protein c-terminus or synectin.52 In both zebrafish and mouse, deletion of synectin results in specific defects in arterial assembly and patterning,53 suggesting a possible pathway by which TGFßR3, acting through synectin, may regulate endothelial cell behavior. This is supported by the observation that mice deficient in Plxnd1, which also binds synectin,54 have excessive numbers of small, blood-filled vascular structures on the surface of the heart.55 The presence of patent coronary ostia in Tgfbr3 nulls suggests that divergent mechanisms control coronary vasculogenesis and ostia formation. Therefore, despite the greatly reduced size of the coronary vascular network, nascent vessels identify the correct location for ostia formation and presumably initiate the localized apoptosis required for ostia formation.56
The ability of TGFß to recruit vascular smooth muscle is intact in the absence of Tgfbr3 in coronary and noncoronary vascular beds. In coculture experiments, TGFß has been implicated in the recruitment of smooth muscle cells by endothelial cells.35,57 In vitro studies demonstrate that TGFß induces loss of epithelial character in both proepicardial58 and epicardial cells59 and smooth muscle differentiation in epicardial cells.59 The loss of epithelial character and expression of smooth muscle marker proteins requires ALK5 kinase activity, implicating the canonical TGFß signaling pathway. However, Smad activation is not sufficient to induce the effects of TGFß. Vascular smooth muscle differentiation and recruitment appears to occur normally in Tgfbr3 nulls demonstrating that Tgfbr3 is not required for these events in vivo. The requirement of coronary vessels for this receptor, whereas other vascular beds appear to form normally in the absence of TGFßR3 suggests that TGFßR3 may be a novel therapeutic target to direct coronary vessel repair or remodeling.
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Acknowledgments |
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We thank Drs Bin Zhou and Scott Baldwin for critically reading the manuscript and members of the laboratories of J.V.B. and C.B.B. for assistance and discussions. We also thank the Vanderbilt Ingram Cancer Center Embryonic Stem Cell Core.
Sources of Funding
This work was supported by NIH grants HL67105 (to J.V.B.), AHA0655129 (to J.V.B.), and GM07347 (to L.A.C.).
Disclosures
None.
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Footnotes |
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Original received March 27, 2007; revision received July 2, 2007; accepted August 7, 2007.
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