doi: 10.1161/CIRCULATIONAHA.106.619213
(Circulation. 2006;114:1985-1991.)
© 2006 American Heart Association, Inc.
Basic Science for Clinicians |
Hedgehog Morphogen in Cardiovascular Disease
From the Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam (M.F.B., C.A.S.), and Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen (M.P.P.), the Netherlands.
Correspondence to Maikel P. Peppelenbosch, Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands. E-mail m.peppelenbosch{at}med.umcg.nl
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Abstract |
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 Top Abstract A Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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In this review, we focus on the basic biology of the important developmental Hedgehog (Hh) protein family, its general function in development, pathway mechanisms, and gene discovery and nomenclature. Hh function in cardiovascular development and recent findings concerning Hh signaling in ischemia models are discussed in more detail, and future perspectives are proposed. In light of the recent discovery of Hh transport by insect lipophorin, we also hypothesize a role for low-density lipoprotein (LDL) in mammalian Hh transport, creating a surprising role for LDL in cardiovascular disease.
Key Words: angiogenesis • ischemia • signal transduction • receptors • hedgehog • cholesterol
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A Short Introduction to Morphogens |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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A cell located in its surrounding tissue—either in a developing organism or adult tissue—has no "map" or any other autonomous clue about its position. Consequently, the cell does not know where it is, what it has to do, how to change its expression pattern, when to proliferate, where to migrate to, or even when to die. For structures as complex as the vasculature, informing cells about their required action is not only a necessity but also a challenge.
Two main mechanisms inform cells about their position. By cell-cell interactions, cells receive information concerning their position from neighboring cells. Alternatively, gradients of signaling proteins called "morphogens" (reviewed in Ashe and Briscoe1) diffuse through tissue over time. In the illustration for the hypothetical morphogens signal A and signal B (Figure 1), cell 1 has a high concentration of signal protein A in its local environment, whereas cell 2 senses a lower concentration. On the basis of the simple information conveyed by a single morphogen gradient, these cells are already destined to different fates. This mechanism suffices in the developing neural crest, which gives rise to a variety of tissue, including the aortic arch.2 In addition to sensing a certain concentration of signal A, cell 3 also senses signal B and is able to act accordingly. In a nutshell, the interplay between different morphogen gradients has complex results—for instance, determining how extremities and digits are formed. However, in some situations, the mere presence of a morphogen rather than a gradient is enough for proper patterning or tissue repair. Although morphogen gradients are important in developing tissues, it appears that they are not that important in stable adult cells, in which cell-cell interactions predominate in determining cell fate.
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In humans, 4 families of morphogens are critical for providing almost all positional information. Hence, the expression "morphogenetic code" is used to describe the combined action of the 4 morphogen gradients that provide positional information to the differentiating cell. The first of these families is the wingless/Int (Wnt) family of extracellular glycoproteins, important in axis determination in the developing embryo3 (Figure 2A), heart valve formation,4 and colorectal cancer (through activating mutations in this signaling pathway).5 The second family is the group of hormones that belong to the transforming growth factor-ß/bone morphogenetic protein/activin family, involved in a plethora of events including immunosuppression, ovulation, and induction of apoptosis in the membranous sheets between the various digits during gestation6,7 (Figure 2B). Third, there is the fibroblast growth factor family, which is important in inducing stem cell proliferation in hematopoiesis and developing the blood islands during embryogenesis.8 Finally, there is the family of Hedgehog (Hh) proteins9 (Figure 2C), which consists of highly similar small, secreted proteins that function in the developing organism, adult physiology, and tumorigenesis. Each of these is discussed in more detail below.
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Some features unique in biology have been found for the Hh proteins, and therefore, Hh draws considerable attention from the research and medical community. It is particularly fascinating that the mature protein is derived from autocatalytic cleavage (ie, the protein cleaves itself) of a precursor protein, followed by the addition of a cholesterol and a palmitoyl group.10,11 Hh is the only known sterolated protein in the animal kingdom, and Hh proteins are one of the few palmitoylated proteins that are secreted (another example of secreted palmitoylated proteins is the Wnt proteins). Not unexpectedly, the lipophilic moieties limit the diffusion capacity of Hh in the aqueous medium that surrounds cells, leaving the mechanisms by which Hh is distributed throughout tissues subject to fierce debate.
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Discovery of the Hh Mutant in Drosophila melanogaster and New Homologs |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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In wild-type fruit fly (Drosophila melanogaster) larvae, a band of denticles runs across the anterior half of each segment, whereas the posterior half is smooth (naked cuticle). In screening for mutations that affect the segmental pattern of the fruit fly larvae, Nüsslein-Volhard and Wieschaus12 discovered a group of mutations that affected the patterning within segments but left the number of segments unaltered. One of these segment polarity mutants caused denticles to occur not only on the anterior but also on the posterior half of the segments, covering the back of the larvae with a continuous lane of bristles as shown in Figure 2C. Nüsslein-Volhard and Wieschaus were awarded the Nobel Prize for this discovery in 1995.
In 1993, a joint effort of 3 research groups (from the laboratories of McMahon, Tabin, and Mohler) resulted in reporting of the first vertebrate Hh genes.13,14 Echelard et al14 (and personal communication with Y. Echelard, PhD, 2003) used the cloned fruit fly Hh to identify 3 genes homologous to fruit fly Hh in mouse and chicken. As shown in Figure 3, these homologs were comically termed Sonic Hh (after a Sega arcade game character introduced in 1990), Desert Hh (after an Egyptian species of hedgehog, Hemiechinus auritus), and Indian Hh (after a hedgehog species endemic to the Indian peninsula, Hemiechinus micropus). The name Sonic Hh (Shh) was proposed by Robert Riddle and Randy Johnson, for it seemed to be the "all powerful" of the Hh homologs, just like Sonic the Hedgehog is all powerful in the arcade game of the same name. Although the playful nomenclature for the Hh homologs testifies to geneticists’ sense of humor, the number of Hh species with which to name Hh homologs appears to be depleted. One research group has now chosen to use "quahog" as homolog name15 in nematodes, and in fish, "Tiggy-Winkle" Hh is known.16 Although the above-mentioned proteins were found to share great homology, they did not colocalize in the developing organism, and it appears they have varying functions regardless of their similarity.
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Transduction of the Hh Signal to its Targets |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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Although many aspects of the molecular processes by which Hh binding to cells influences cellular fate have been clarified, it is fair to say that the Hh signal transduction pathway remains one of the least understood signaling systems in mammalian cells, and many aspects of this pathway remain obscure. It is evident that the Hh pathway is of unusual complexity and employs unconventional mechanisms not observed in other biological systems. A very brief representation of the Hh pathway in the absence or presence of Hh is shown in Figure 3A and 3B, respectively.
The primary receptor for Hh is the 12-transmembrane protein Patched17 (Ptc). A second receptor, a 7-transmembrane protein called Smoothened18 (Smo), actually transduces the signal. Smo is constitutively active in nature but is actively kept in a dormant state by the primary receptor Ptc in normal cells. On binding of Hh to Ptc, however, Ptc is internalized, and apparently this is sufficient to alleviate the inhibitory effect of Ptc on Smo, which then activates the Hh pathway.19 The exact mechanism of Smo inhibition by Ptc is still elusive, but it is a catalytic mechanism (ie, a single Ptc molecule can inhibit multiple Smo molecules), and Ptc and Smo do not need to bind or colocalize.20 Strong homology exists between Ptc and some bacterial transporter molecules, as well as the Niemann-Pick C1 (NPC1) protein, a transport protein involved in cholesterol homeostasis in humans.21 This homology gave rise to the concept that in the absence of Hh, Ptc translocates a compound to the extracellular compartment, where it binds to and inhibits Smo.20 This inhibitory molecule probably resembles various compounds already known to inhibit Smo by direct binding, such as cyclopamine.22,23
Downstream of Smo, the signal transduction cascade remains complex and only partly understood. Moreover, it is becoming increasingly clear that many mechanisms elucidated in fruit fly differ from their vertebrate counterparts.24 Figure 4 shows a summarized scheme of the known components involved in the Hh pathway. In the absence of Hh, when Ptc is actively repressing Smo, the downstream Gli transcription factors are somehow inhibited from activating transcription of target genes. Only when Hh binds to Ptc is the inhibition of Smo alleviated and the Gli transcription factors allowed to exert their transcriptional activities. In vertebrates, at least 3 different Gli transcription factors exist, and these differ in their preferential regulatory action.25–27 Gli3 is known to be bound in a protein complex by action of Fused (Fu, believed not to be essential in vertebrates), Costal2 (Cos2, argued not to be involved in vertebrates), and Suppressor of Fused (SuFu, presumably less important in fruit fly), but for other Gli proteins, this sequestering remains to be established. In this complex, vertebrate Gli3 and the Gli homolog Ci in fruit fly are prone to cleavage that yields a repressor fragment, which localizes to the nucleus and acts as a suppressor on Hh target genes (not shown). Gli1 and Gli2 are considered activators of target gene transcription and are presumably not cleaved.
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What is the nature of the Hh target genes? Before the microarray technique was used to identify target genes of the Gli transcription factors, the number of targets was rather limited and included hepatic nuclear factor 3-ß, Hox genes, various bone morphogenetic protein morphogens, Ptc, and Hh-interacting protein.9 Owing to the depth of this field, the interested reader would do best to examine the specialist reports on the varied group of Hh target genes.9,28–31 Microarray analysis has revealed that Hh target genes include molecules involved in cell cycle, cell adhesion, signal transduction, apoptosis, nerve formation, transcriptional regulators, Wnt signaling antagonists, protease inhibitors, and a metal binding protein, and interestingly, thrombomodulin was found to be upregulated in that study.28 Collectively, these studies suggest a very versatile role for Hh signaling; however, the actual in vivo relevance of these genes remains unclear. More functional studies, especially concerning the potential clinical relevance and the suitability of these genes as therapeutic targets for treating disease, are desirable.
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Function of the Hh Proteins |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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Long after its discovery as a segmental patterning protein in fruit fly, the Hh protein family is continuously found to be involved in new processes, many of which were previously attributed to other proteins or compounds or were simply unexplained. In situ hybridization and immunohistochemical studies showed that mammalian Hh homologues displayed intricate expression patterns during development and in adult organisms, especially in the vascular system. One of the first vertebrate functions of Sonic Hh to emerge was in the zone of polarizing activity.32 The zone of polarizing activity is a region at the posterior margin of the chick limb bud responsible for normal anteroposterior patterning. Hh was shown to colocalize with this previously described region, and ectopic expression of Hh can alter limb patterning in a way similar to zone of polarizing activity grafting. This role in limb patterning and successive digit formation is conserved throughout all vertebrates, but many other pattern-forming events, especially those involving endothelia and epithelia, prominently feature Sonic Hh signaling.
After almost 2 decades’ worth of research, functions of Hh proteins have been found to range from tooth and bone/cartilage development to neuronal development (excellently reviewed by Ingham and McMahon33). In the gastrointestinal tract, Hh plays an important role in developmental patterning and in adult morphostasis. In the developing embryo, Hh also regulates larger structural features such as lateral asymmetry, limb patterning, digit number and orientation, and differentiation and proliferation of muscle precursors. The role of Hh proteins in hematopoietic stem cell proliferation34 and recruitment of these cells via the blood stream to damaged tissues, where these stem cells participate in tissue repair, are both of great interest.35
The importance of proper Hh signaling is stressed by some sterol disorders that affect development. Of these disorders, Smith-Lemli-Opitz syndrome36 is known to affect the Hh pathway either by improper sterolation of the Hh protein or by reduced responsiveness of cells to Hh,37 and the other sterol disorders are anticipated to act on the Hh pathway in a similar manner. Mutations that affect the activity of Hh proteins cause varying degrees of holoprosencephaly and a range of other abnormal facial features. More common are diseases that result from excessive Hh signaling, most often leading to cancer5 but also to such diseases as Gorlin syndrome. These Hh gain-of-function–related diseases can arise from an Smo mutation that renders it insensitive to the inhibitory action of Ptc, or more commonly, to a mutation in Ptc, which cripples its inhibitory action on (functional) Smo.
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Function of the Hh Proteins in Cardiovascular Development |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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Especially interesting to the scope of this review is the involvement of Hh in the morphogenesis of the heart and blood vessels. A clue to this involvement was the ability of Shh to induce vascular endothelial growth factor and angiopoietins in human fibroblasts,30 but a more definite answer came from studies in mice deficient for Hh pathway components. Seemingly, Hh proteins (mainly Ihh [Indian Hh] and Shh) are of pivotal importance to vascular remodeling in the yolk sac of the developing mouse (excellently reviewed in Byrd and Grabel38). In the mesoderm, so-called blood islands, the first hallmarks of vascular structures in the yolk sac, are formed in response to fibroblast growth factor,8 although in vitro, a requirement for Smo and Ihh was found. These blood islands are lined by angioblasts, cells that will later form the endothelium, and are filled with hematopoietic cells, primitive erythrocytes. These blood islands then fuse to a honeycomb-like network (the primary capillary, or vascular plexus), and the angioblasts differentiate to become endothelium. In Smo mutant mice, the activating receptor for the Hh pathway, development stops here, and there is no further development of the vasculature.39 The capillary plexus in mice genetically deficient for Hh proteins will be remodeled to early vessels; however, these are clearly smaller and less organized than in the wild-type vasculature. The responsiveness to Hh of endothelial cells or endothelial precursor cells themselves is not yet clear. Although most groups show unresponsiveness to Hh for these cells and suggest the action of intermediate cells in translating the Hh signal to, for instance, vascular endothelial growth factor or angiopoietins,39,40 others have been able to induce capillary morphogenesis in endothelial cells by Hh in vitro.41
The development of the heart starts very early in the developing embryo, as progenitor cells in the mesoderm form the primitive cardiac tube. The straight tube then undergoes rightward looping, and subsequently, the atrial and ventricular chambers appear and mature. Owing to the function of Hh proteins in determining left/right asymmetry,42,43 heart tube looping is critically dependent on proper Hh processing.44 In Shh–/– mice embryos, numerous defects in cardiac development are seen, which are briefly summarized in the following section.
Although the atrial and ventricular chambers are formed (which suggests completed heart looping) in Shh mutant mice, they differ from wild type in many aspects. For instance, a single common atrium is seen, and a pulmonary valve is absent. The right ventricle is reduced, whereas the left ventricle is extended. Furthermore, the heart is positioned on the left side of the thorax, and the shape of the heart indicates a laterality defect. Surprisingly, although heart looping is delayed and incomplete in these animals, the direction of heart looping is unchanged. In Gli2–/–,Gli3+/– double-mutant mice (thus lacking 2 of 3 Hh transcription factors), disturbed cardiac development very similar to that found in Shh mutants is observed.45 In Shh and Ihh double mutants and Smo mutants, no heart looping with successive heart development was observed at all. Because these mice are arguably most deficient in Hh signaling, the severe phenotype argues for an absolute requirement for Hh signaling in cardiac development.46 Mice mutant for the inhibitory Hh pathway component SuFu showed inverted heart looping, which indicates that heart looping is not only affected by diminished Hh function but also by aberrantly increased pathway activity.47
Later in cardiac development, cells from the neural fold (neural crest cells) are recruited to form the aortic arches, the cardiac outflow tract, and the proximal great vessels. In addition to the anomalous cardiac development described above, Shh–/– mice embryos show defects in neural crest cell localization and increased cell death, which leads to the absence of the ductus arteriosus, abnormal subclavian arteries, and a single midline carotid artery. It is remarkable that Shh signaling is pivotal in 2 different events in cardiac development, and it is testimony to its relevance in the developing organism.
In the previously mentioned patients with Smith-Lemli-Opitz syndrome, who have a diminished Hh pathway activity, congenital heart disorders are common, including most of the defects found in Shh–/– mice.36 Cardiomyogenesis has also been found to be dependent on Hh signaling, and the addition of Hh to P19 pluripotent embryonic teratocarcinoma cells in vitro is able to transform these cells to cardiomyocytes.48 Also, the positioning of cardiac progenitors is regulated by an Hh gradient.49 Many more examples of Hh involvement in cardiovascular development have been described, but more interestingly, it has become clear that Hh signaling remains active during cardiovascular maintenance in the adult.
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Hh in Ischemia |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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As mentioned previously, Hh proteins have long been known to act in the developing organism and to remain active in adult physiology (eg, in the histostability of the gastrointestinal tract).50 Among Hh-regulated processes in adults, revascularization of ischemic tissue is of utmost clinical importance. The previously described Hh signaling in the development of certain elements of the cardiovascular system pointed to a vascularizing or patterning role for Shh. In recent years, this vascularizing role appears to be only one of the beneficial effects that the Hh pathway can confer to ischemic tissue.
Two recent papers by Pola et al30,40 established a strong role for Hh signaling in adult cardiovascular pathophysiology. They showed that Hh mediates a profound upregulation of target genes involved in angiogenesis, which indicates the responsiveness of adult tissue to Hh. Remarkably, vascular endothelial growth factor and the angiopoietins Ang-1 and Ang-2 were simultaneously upregulated in response to Shh, and concomitantly, Shh was found to be a potent inducer of vascularization in a cornea model. After in vitro experiments, the authors found that endothelial cells did not respond to Hh, and, as mentioned above for the developing embryo, this suggests an intermediate action of mesenchymal cells. As previously mentioned, Byrd and coworkers39 confirmed that Hh responsiveness is confined to mesothelial and smooth muscle cells. The authors extended their findings and managed to salvage ischemic hind limbs in mice by injecting Shh in the afflicted muscle. Later, the specificity and mechanism behind this salvage were further elucidated, and the Hh response to ischemia was found to be an endogenously occurring process.40
In an elegant experimental setup, Kusano et al35 recently demonstrated that intramyocardial gene transfer of Shh promoted recovery and preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization and recruitment of bone marrow–derived endothelial progenitor cells. Reduced fibrosis and cardiac apoptosis was observed after Shh gene transfer. In this myocardium model, the endogenous role of Shh in ischemia was again confirmed, which suggests that the observed salvage by injection of Shh DNA is not an artificially created situation but rather an augmentation of a naturally occurring phenomenon. The obvious potential of endogenous Hh to induce significant tissue alterations and cell recruitment raises questions as to the involvement of Hh in the development of (rare) angiomyosarcomas, fibrosarcomas, or rhabdomyosarcomas.51
In cerebral ischemia, a positive role for Hh-mimicking molecules has also been shown in limiting the damage caused by artificial vessel occlusion in rats.52–52b Together, these data strongly support the notion that Hh aids in the rescue of ischemic tissue, especially in its revascularization. This Hh-dependent revascularization probably reflects a physiological response to ischemic stress, although what exactly drives this Hh response (eg, hypoxia or inflammation) is not yet known. Many signals that are generated in ischemic tissue, ranging from cytokines to acidity, might trigger Hh expression. Also, we do not know which specific areas in the ischemic tissue activate Hh expression, the degree of tissue damage still considered "salvageable" enough for the Hh pathway to function, or whether the complex Hh pathway remains intact in damaged cells
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Lipophorin Transport of the Hh Protein |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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As stated previously, Hh is particularly hydrophobically modified. For this reason, Hh diffusion capacity is strongly limited in the aqueous medium that surrounds cells. Hh, however, is capable of long-range signaling, and various models have been proposed to explain Hh distribution in tissue.52–54 An attractive mechanism by which Hh is transported has been reported recently: Drosophila Hh was found to be carried by lipophorin.55 An enticing implication of the Drosophila data is the hypothesis that Hh might be loaded on the mammalian equivalent of lipophorin, low-density lipoprotein (LDL).56 Indeed, if this hypothesis was confirmed and LDL was found to transport Hh throughout the vertebrate body, Hh could change our understanding of the role of LDL in atherosclerosis.
Atherosclerosis involves deposits of fatty substances, cholesterol, cellular waste products, calcium, and fibrin in the inner lining of medium and larger arteries57 and is a major cause of morbidity and mortality in cardiovascular disease. Because excess cholesterol both initiates and exacerbates atherosclerotic plaque development, LDL has long been considered the "bad" cholesterol carrier because of its role in transporting cholesterol from hepatic to peripheral tissues. However, the transport of Hh by lipophorin leads us to hypothesize that LDL might transport Hh through the mammalian blood stream. If subsequently LDL is incorporated into an atherosclerotic plaque (as suggested in Figure 5), any Hh present on LDL might exert a positive role by inducing revascularization of surrounding tissue (ie, through the formation of collateral vessels) or other functions as summarized in Figure 5. Of course, these suggestions are all hypothetical, because the presence of Hh on mammalian LDL (or other particles) remains to be established.
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Future Perspectives |
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TopAbstractA Short Introduction to...Discovery of the Hh...Transduction of the Hh...Function of the Hh...Function of the Hh...Hh in IschemiaLipophorin Transport of the...Future PerspectivesReferences |
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Once the practicalities that surround the different variants of gene therapy have been overcome, it is very likely that Shh DNA will provide treatment options for patients who have survived an initial myocardial ischemia. Should DNA transfer remain a problem in the future because of the potential danger of horizontal transfer or genome incorporation, an interesting role for RNA-based therapies might emerge. Because RNA is very unlikely to be reverse transcribed after transfer, issues with horizontal gene transfer or chromosome integration are avoided.
The current problems with RNA stability and delivery, however, pose challenges that preclude application at this time. Before wide-scale injection of Shh protein or DNA would be feasible, problems involving costs and the intricacy of uniformly injecting compounds into the myocardium must be overcome. Although the development of chemically synthesized small-molecule agonists for the Hh pathway may provide a thrust forward, their distribution could prove too systemic in practice. The use of a molecule that specifically recognizes ischemic tissue coupled to an Hh agonist can provide us with a specific, potent, and relatively affordable therapeutic option (resembling the aptamer approach developed for specific targeting of cancer cells61). Targeting Smo rather than Ptc with small molecules (for instance, with purmorphamine) eliminates any Smo-independent effects. Also, this should further enhance specificity and potency, because it eliminates the inhibitory actions on Smo of yet unidentified Smo-inhibitory proteins (Ptc2 is known, for instance,62 but others might arise). The involvement of Hh in enhancing myocardial influx of bone marrow–derived progenitor cells was evident from the report by Kusano et al.35 As this naturally occurring population of cells find their way to the damaged myocardium, they could perhaps confer specificity to the action of systemically administered Hh. Of course, this would not be feasible when Hh is, in fact, the recruiting factor for these cells. Also, bone marrow–derived stem cells have been implicated in tumorigenesis (for instance, in the stomach63), and thus, overly enhanced proliferation of such circulating stem cells might not necessarily prove beneficial in the long run.
In summary, we predict that through intense research efforts, our understanding of Hh pathway mechanisms and the participation of the Hh pathway in cardiovascular development will continue to develop. Together with progress in technologies such as gene therapy and diagnostics, this will aid in applying our knowledge to clinical practice and will offer us a means to combat cardiovascular disease in the adult and the developing child.
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Acknowledgments |
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Disclosures
None.
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References |
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