doi: 10.1161/CIRCRESAHA.108.191239
© 2009 American Heart Association, Inc.
Reviews |
Shared Circuitry
Developmental Signaling Cascades Regulate Both Embryonic and Adult Coronary Vasculature
From the Department of Developmental Biology, Washington University School of Medicine, St Louis, Mo.
Correspondence to David M. Ornitz, Washington University School of Medicine, Department of Developmental Biology, Campus Box 8103, 660 S Euclid Ave, St Louis, MO 63110. E-mail dornitz{at}wustl.edu
This Review is part of a thematic series on Arterial Specification: A Finishing School for the Endothelium, which includes the following articles:
Role of Crosstalk Between Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Pathways in Artery–Vein Specification [2008;103:571–577]
Branching Morphogenesis [2008;103:784–795]
Brothers and Sisters: Molecular Insights into Arterial–Venous Heterogeneity [2008;103:929–939]
Shared Circuitry: Developmental Signaling Cascades Regulate Both Embryonic and Adult Coronary Vasculature
Guidance of Vascular Development: Lessons From the Nervous System
Arterial–Venous Specification During Development
Michael Simons Guest Editor
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Abstract |
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 Top Abstract IntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Ischemic heart disease is the most common cause of heart failure and is among the leading causes of mortality worldwide. Therapies used for the treatment of this disease aim to restore blood flow to severely narrowed or occluded coronary arteries by either catheter-based or surgical means. Although these strategies prove efficacious for many patients, a substantial number of individuals fail to improve following these procedures. Recently, a noninvasive strategy has been proposed, focusing on the use of endogenous growth factors that trigger the growth of new coronary arteries. Using the developing heart as a model, several groups have identified some of the key pathways that not only govern the development of the coronary vascular system but also promote the growth of the adult coronary vasculature. Here, we review the major morphological events and signaling cascades that mediate the formation of the coronary vasculature in the embryo. We further describe the mechanism by which many of these same pathways also regulate the adult coronary vasculature and their potential use in the treatment of ischemic heart disease.
Key Words: fibroblast growth factor • hedgehog • VEGF • angiopoietin • coronary vascular development
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Introduction |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Current therapies used for treating ischemic heart disease and myocardial infarction are aimed at improving and, when possible, restoring blood flow to ischemic cardiac tissue. Coronary artery bypass grafting and percutaneous coronary interventions are the mainstays of treatment for these patients and have been shown to significantly reduce morbidity and mortality.1 Unfortunately, approximately 10% of patients are ineligible for these procedures because of the presence of diffuse, complicated, or intractable lesions. Furthermore, a significant number of diabetic patients who undergo these procedures demonstrate insufficient improvement. Without treatment, many of these patient do poorly, with mortality rates of up to 8% to 10% per year.2 Moreover, improved blood flow on a macrovascular level does not necessarily translate to restoration of myocardial perfusion as significant impairment and injury to the microvasculature may be present.3
Recently, a less invasive approach aimed at promoting growth of new coronary blood vessels, including collaterals, has been proposed to treat patients who either are not eligible for, or who have failed, coronary artery bypass grafting and percutaneous coronary interventions. This strategy, termed pharmacological revascularization or therapeutic angiogenesis, involves either systemic or local administration of proangiogenic agents that promote growth of the established vasculature and/or formation of new coronary blood vessels. The search for molecules that possess this activity is actively underway.
Over the past several years, it has been realized that a number of known proangiogenic factors can promote coronary vessel growth in animal models. Overexpression of fibroblast growth factor (FGF)2, vascular endothelial growth factor (VEGF)A, and angiopoietin (ANG)2 in the myocardium of adult mice leads to significant increases in coronary artery number and density.2,4–9 Since these initial observations, the effects of Fgf2, Fgf4, and VegfA in the adult heart have been intensively investigated and proposed as candidates for the treatment of ischemic heart disease.2,10 However, despite the ability of Fgf2, Fgf4, and VegfA to promote new blood vessel growth in both normal and ischemic hearts, clinical trails using either protein or gene therapy overall have been disappointing.2,11–13 Multiple clinical trials investigating both protein-based (FIRST, FGF2; VIVA, VEGFA) and gene therapy-based (AGENT, Fgf4) applications have resulted in no significant change in mortality and ventricular function and negligible improvement in either exercise tolerance or anginal symptoms.2
In light of these disappointing results, it has been hypothesized that monoagent therapies may not be able to efficiently stimulate the signaling pathways necessary to trigger an adequate and therapeutic level of blood vessel growth in the adult human heart.2 Moreover, coordinated blood vessel growth and guidance must occur for meaningful improvement in tissue perfusion. With this in mind, it has been proposed that treatment with combinations of proangiogenic agents may be required to accomplish these goals. Consistently, transgenic mice that overexpress both VEGFA and ANG2 demonstrate significantly greater levels of vascular growth than does overexpression of either factor alone.8 Importantly, despite greater increases in vascular density in these double transgenic mice, an undesirable amount of myocardial edema was also present. These data highlight the point that blood vessel growth in response to external stimuli must occur in a coordinated fashion that includes both vascular proliferation, as well as maturation and may not necessarily be achieved by forced long-term expression of potent proangiogenic factors. To this end, combination therapy is currently being tested and new proangiogenic agents capable of achieving robust and coordinated vascular growth are actively being pursued.
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Insights From the Developing Heart |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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An alternative approach to identify new signaling pathways that can effectively promote coronary vascular growth is to investigate how the coronary vascular system develops. Because developmental programs are often recapitulated in adult physiology and tissue repair, this approach offers an opportunity to identify and develop novel or improved therapeutic agents. Several FGFs (FGF1, FGF2, FGF9, FGF16, and FGF20), VEGFs (VEGFA and VEGFB), and ANGs (ANG1 and ANG2) are expressed in the embryonic heart during coronary vessel formation.14–17 However, until recently, little was known about whether or how these molecules orchestrate the development of the coronary vascular system.
We and others have postulated that an understanding of how these and other yet unidentified signaling pathways regulate coronary blood vessel formation in the embryonic heart may provide important information to guide the development of novel therapeutics.18,19 With this goal in mind, we have set out to delineate more clearly the mechanism by which FGFs, VEGFs, and ANGs control coronary development and identify additional molecules that may coordinately control the expression of these and other proangiogenic factors in the embryonic heart. Moreover, we have investigated whether reactivation of signaling pathways that promote coronary development can similarly trigger coronary vessel growth in the adult heart and whether such pathways are necessary for coronary growth and maintenance in the adult.
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Cardiac Development |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Cardiac development can be subdivided into early, midgestation, and late (growth and maturation) stages. Early cardiac development begins at approximately embryonic day (E)8.0 in the mouse and includes such events as cardiac progenitor cell specification (primary and secondary heart fields), morphogenesis of the linear heart tube, and cardiac looping. These processes have been reviewed in great detail previously.20,21 Midgestational heart development begins following looping of the linear heart tube, commencing at approximately E10.5 and ending at approximately E16.5. Late gestational and neonatal stages ensue at E16.5 and at birth, respectively, and, for the most part, involve growth and maturation of the myocardium and other cardiac structures that formed during previous stages.
Important processes that occur during midgestational heart development include formation of the epicardium, myocardial proliferation and growth, coronary vascular development, endocardial cushion formation, ventricular septation, and trabeculation.22 Before midgestation, both the linear and looping heart tube are composed of only 2 distinct layers of cells: an outer layer of myocardial cells (myocardium) and an inner layer of endothelial cells (endocardium). Commencing at E10.5 in the mouse, the developing heart becomes enveloped by a population of mesothelial cells that will give rise to the third and outermost cardiac layer, the epicardium. As is highlighted below, proper formation and function of the epicardium is essential for several developmental events that occur during midgestation, specifically myocardial proliferation and coronary vascular development.
Among these important midgestational events, myocardial growth and coronary vascular development have been well characterized on both the morphological and molecular levels. Between E11.5 and E13.5, the developing heart undergoes a dramatic increase in size. This growth is attributable to cardiomyoblast proliferation, because mutants that display defects in cardiac growth demonstrate decreased proliferation.23,24 Formation of the coronary vascular system occurs concurrently with this period of rapid cardiac growth. Coronary vascular development can be divided into 2 stages: vascular plexus formation and vascular remodeling. The coronary plexus is formed between E11.5 and E13.5 and is remodeled between E14.5 and E16.5 to give rise to the mature coronary vascular system (Figure 1). The following sections discuss the mechanism by which coronary vascular development occurs and the signaling pathways that control these critical processes.
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Development of the Coronary Vascular System |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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In general, blood vessel growth and development are governed by 2 distinct and sequentially acting processes: vasculogenesis and angiogenesis. Vasculogenesis is defined as the de novo formation of blood vessels via differentiation of either angioblast or hemangioblast precursors, whereas angiogenesis is defined as the growth or remodeling of previously established blood vessels. Moreover, vascular systems tend to undergo a stereotyped pattern of development beginning with the initial formation of a primary capillary plexus that is later remodeled to give rise to the mature vasculature. It is thought that the primary capillary plexus forms by vasculogenesis and is later remodeled via angiogenesis.25–27
Similar to other vascular systems, coronary development begins with the formation of a plexus-like vascular network that is later remodeled, giving rise to the mature coronary tree.28,29 The initial coronary vascular plexus consists of 2 sets of blood vessels located within the subepicardial mesenchyme (space between the epicardium and myocardium) and the myocardial wall. Intriguingly, these 2 sets of blood vessels are interconnected via small branching vascular structures, reminiscent of arterial–venous vascular beds (Figure 1). The initial stimulus driving the formation of the coronary vascular plexus and the expression of molecules that mediates its growth (described below) is not yet precisely defined. However, hypoxia may serve as one of the key forces underlying this important event. Intriguingly, the embryonic mouse heart develops in a relatively hypoxic environment up until approximately E11.5, correlating with the onset of vascular plexus formation and growth.30
Many of the morphological events involved in the formation of the coronary vascular system have been well described, especially in avian models.29,31,32 Coronary development ensues following envelopment of the heart by the epicardium. Before stage 14 in the chick (E9.5 in the mouse), the heart consists of 2 layers, an outer myocardial layer and inner endocardial layer. At stage 18 in the chick (E10.5 in the mouse), the third cardiac layer, the epicardium, migrates to and envelops the embryonic heart. Lineage tracing studies in avian species demonstrate that the majority of epicardial progenitors are derived from the proepicardial organ (an epithelium associated with the septum transversum), which travels as either individual cells or as a sheet to envelop the developing heart.33 Some studies have also shown possible neural crest and secondary heart field contribution to the epicardium.
Several gene products have been implicated in the formation of the epicardium, including factors required for proepicardial organ formation (GATA4, β-catenin), epicardial progenitor cell survival (WT1), as well as epicardial progenitor cell migration and attachment (vascular cell adhesion molecule-1, 
4β1 integrin).34–40
In addition to forming the outermost cell layer of the developing and adult heart, the epicardium physically contributes perivascular and interstitial cell types to the heart through a process of epithelial-to-mesenchymal transformation (EMT). Epicardial EMT initiates at stage 26 in the chick (embryonic day 11.5 in the mouse) and progresses in a spatiotemporal manner beginning at the base of the heart and proceeding in a wave-like pattern toward the cardiac apex. Epicardial EMT leads to the formation of a mesenchyme situated between the epicardium and myocardium (subepicardial space). Epicardial-derived cells subsequently either reside within the subepicardial mesenchyme or migrate into the myocardium in a perivascular distribution. Within the subepicardial mesenchyme and myocardial wall, endothelial cells coalesce to form vascular channels that are later ensheathed by smooth muscle cells and perivascular fibroblasts.
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Epicardial Lineage |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Lineage tracing of the proepicardial organ in chicken and quail models demonstrate that cells contained within the proepicardial organ give rise to perivascular fibroblasts, vascular smooth muscle cells, and endothelial cells of the coronary blood vessels.41–43 Intriguingly, both cell labeling and genetic lineage analysis of the epicardium revealed contributions to only perivascular fibroblast and smooth muscle cell lineages but not the coronary endothelial cell lineage.24,44,45 Together, these lineage studies suggest that the proepicardial organ contains a mixed population of vascular smooth muscle cell and fibroblast progenitors, as well as endothelial progenitors, each of which migrate to the heart. On reaching the heart, these progenitor populations segregate such that vascular smooth muscle cell and fibroblast progenitors reside within the epicardium, whereas endothelial progenitors occupy an additional location. This possibility is supported by experiments demonstrating that these lineages can be independently identified by immunohistochemical analysis of the migrating proepicardial organ.45 Interestingly, it has recently been reported that epicardial progenitor cells (Wt1-positive cells or cells marked with Tbx18-Cre) may also contribute some (7% to 10%) cells to the cardiomyocyte lineage.46,47
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Epicardial Signaling |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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In addition to physically contributing cells to the developing heart, the epicardium serves as a critical structure for several important events that occur during midgestation. Removal of the epicardium in avian species leads to an arrest in both cardiomyoblast proliferation and coronary development.29,31,32 Moreover, deletion of genes necessary for epicardial development in the mouse (Gata4, β-catenin, Wt1, Vcam1, and
4β1 integrin) similarly leads to a profound defect in both cardiomyoblast proliferation and coronary vascular development.34–40 These studies indicate that the epicardium supplies either a critical factor(s) or cell type(s) that is absolutely essential for these processes. Several key experiments have implicated that the epicardium governs myocardial proliferation and coronary vascular development via an epicardially based paracrine signaling mechanism.
Initial studies in chick and quail demonstrated that the proepicardial organ and the epicardium are required for coronary development because removal of either structure severely perturbs coronary vessel formation.48 More recently, genetic analysis in the mouse has confirmed this observation. Removal of genes required for formation (Gata4) and migration or attachment (Vcam1, 4β1 integrin) of epicardial precursors to the myocardium leads to severe defects in coronary development.34–36 In addition, deletion of genes necessary for survival, integrity, or differentiation of epicardially derived lineages (p300, Wt1, BAF180, β-catenin) leads to similar phenotypes.37–40,49,50
It has been previously proposed that the epicardium supports coronary vascular development by physically contributing vascular cell types (specifically endothelial cells) to the heart through EMT.41–43 However, as mentioned above, lineage analysis, both in avian and mouse models, does not support such a contribution to the coronary endothelium. The epicardium contributes smooth muscle and fibroblast cell lineages to the developing coronary vasculature, whereas endothelial cells are derived from another source.44,45
An additional explanation for the requirement of the epicardium for coronary development is that the epicardium acts as a signaling center. Support for this hypothesis stems from the important initial observation that the epicardium promotes cardiomyoblast proliferation by secreting mitogens.51,52 Interestingly, not only is retinoic acid signaling in the epicardium necessary for the secretion of such mitogens but also is required for coronary development.23,24 One class of molecules that have been identified as secreted epicardial mitogens are FGFs. FGF9, FGF16, and FGF20 promote myocardial proliferation, and Fgf9 has been shown to be regulated by retinoic acid.17 From this and extensive studies showing that FGF signaling can promote vascular formation and growth,53–55 it has been hypothesized that retinoic acid signaling within the epicardium may regulate coronary development by controlling the expression of proangiogenic factors such as FGFs. Close examination of the Fgf9–/– and Fgfr1/2Mlc2v (myocardial specific knockout of FGF receptors 1 and 2) mouse models revealed that not only is FGF9 (and likely FGF16 and FGF20) essential for cardiomyoblast proliferation,17 but it also is necessary to promote coronary vascular formation and growth.53–55
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FGF and Hedgehog Signaling Pathways Control Proangiogenic Factor Expression and Coronary Development |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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The use of conditional gene targeting, transgenic mouse models, and ex vivo organ culture assays have demonstrated that a FGF- (Figure 2A) and hedgehog (HH)-based (Figure 2B and 2C) signaling pathway controls the expression of multiple proangiogenic molecules, including vascular endothelial growth factors (VegfA, VegfB, and VegfC) and ANGs (Ang2) and the formation of the coronary vascular system (Figure 3).18
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FGFs signal directionally and often reciprocally across epithelial/mesothelial–mesenchymal boundaries. Specificity is regulated by the alternative splicing of FGF receptors (FGFRs) and the specificity of individual FGFs for specific splice forms of FGFRs.56,57 Mesenchymal tissues, such as myocardium and interstitial fibroblasts, express "c" splice forms of FGFR1 and FGFR2, whereas epithelial and mesothelial tissues, such as the epicardium, express "b" splice forms of FGFR1 and FGFR2. Fgfr1 and Fgfr2 are the only FGFRs that have been identified in the myocardium and epicardium during midgestation stages of development.17
FGF9, FGF16, and FGF20 are members of a subfamily of the 22 known FGFs. In vitro studies show that these FGFs activate mesenchymal splice forms of FGFRs (FGFR1c, FGFR2c, and FGFR3c) and FGFR3b.56,58 Genetic analysis in mice showed that FGFR1c and FGFR2c are the primary and likely sole mediators of the FGF9 signal in the myocardium. FGFR2 is also expressed in the epicardium, but it is not known whether a reciprocal FGF signal from the myocardium to the epicardium functions during midgestation heart development. Following ligand binding and receptor dimerization, autophosphorylation activates the FGFR and allows it to bind and phosphorylate intracellular signaling molecules. The 2 primary pathways activated by the FGFR are the RAS-RAF-MAPK kinase pathway and the phospholipase (PL)C-
pathway (reviewed elsewhere59) (Figure 2A).
Epicardial and endocardial sources of FGF ligands control coronary development by signaling to the cardiomyoblast through redundant function of FGFR1 and FGFR2c. Myocardial FGF signaling regulates coronary vascular development by triggering a wave of HH activation that progresses from the atrial-ventricular groove (at E12.5) to the apex of the ventricles (at E13.5), closely tracking the progression of the developing coronary vascular plexus. The mechanism by which myocardial FGF signaling regulates epicardial HH signaling is not known.
The HH signaling system is comprised of three ligands: sonic (S)HH, indian (I)HH, and desert (D)HH. All 3 HH ligands are expressed in the embryonic and adult heart, with SHH being the most abundant.18,19 HH ligands signal by binding to the cell surface receptor Patched (PTC) (Figure 2B and 2C), which in the absence of ligand, functions to inhibit Smoothened (Smo). Binding of a HH ligand to the PTC receptor activates the downstream effector, SMO, which in turn signals through a complex pathway involving several different molecules (fused, suppressor of fused, protein kinase A), eventually leading to the direct activation of GLI transcription factors (GLI2, GLI3).60,61 HH ligands signal to the cardiomyoblast and perivascular mesenchymal cell and induce the expression of multiple proangiogenic molecules, including VegfA, VegfB, VegfC, and Ang2. Together, these growth factors, as well as potentially additional yet unidentified molecules, signal to the developing vascular endothelial cell and result in the formation of the coronary vascular plexus.
Intriguingly, this FGF, HH, and VEGF/ANG signaling cascade coordinately controls the growth of both subepicardial and intramyocardial blood vessels.18 Recent studies using transgenic mice that mark specific vascular lineages indicate that these 2 sets of blood vessels represent distinct vascular subtypes: veins and arteries, respectively.62 These data are consistent with corrosion casting of the developing and mature coronary vascular tree in the rat, which revealed that coronary veins are positioned within the outer myocardium, whereas coronary arteries are located deeper within the myocardial wall.63 It is currently unclear exactly when arterial and venous lineages are established in the developing heart; however, arterial and venous lineage–specific markers are segregated as early as E11.5 in the mouse. Interestingly, coronary arterial and venous growth is coordinately regulated during development through HH signaling to the pericyte and the cardiomyocyte, respectively. Moreover, coronary arterial and venous endothelial cells may be derived from distinct lineages because coronary veins appear to be derived from hemangioblasts resident in the subepicardial space, whereas coronary arteries appear to be derived from another source.62
Despite the identification of several key components of this signaling axis, a number of important questions remain unanswered. For instance, do additional receptor tyrosine kinase (RTK) ligands function in parallel with FGFs? This is clearly a possibility as loss of FGF signaling leads to a delay, but not an arrest, in both Shh expression and coronary vascular development. Additionally, it is unclear how FGF signaling controls the expression of Shh and activation of HH signaling and whether VEGF ligands and ANG2 are direct targets of HH signaling. It is also not known how this signaling axis might interact with that of classic angiogenic pathways, such as hypoxia-inducible factor 1, and whether this signaling axis functions during remodeling of the coronary vascular plexus.64,65
Several studies have provided evidence that HH signaling functions more broadly in vascular development. Mouse embryos lacking Smo (an obligate transducer of HH signaling) and zebrafish embryos lacking Shh display defects in vasculogenesis. SHH promotes vascular plexus formation in cell culture, and activation of HH signaling in the adult mouse is sufficient to promote neovascularization in several different tissues.66–69 Based on these studies demonstrating that HH signaling promotes vascular growth by inducing expression of various VEGF and ANG molecules, it is likely that HH governs blood vessel formation and growth throughout the embryo and potentially in the adult organism by activating a conserved set of growth factors with complementary functions.
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Other Pathways That Regulate Coronary Development |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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The overwhelming majority of mutations that result in coronary vascular defects are attributable to defects in epicardial formation, loss of epicardial integrity, or disruption of epicardially based signaling pathways, highlighting the critical role of the epicardium in this process. One exception to this trend was unveiled by genetic analysis of Fog2. Mutations in Fog2 (deletion or inability to interact with GATA4) result in severe defects in myocardial proliferation and coronary development despite a normal appearing epicardium.70,71 Furthermore, Fog2 mutant hearts failed to undergo epicardial EMT. Importantly, these phenotypes could be rescued by transgenic expression of Fog2 in the myocardium, suggesting that signals from the myocardium regulate epicardial EMT.
Interestingly, the myocardial hypoplasia and coronary defects seen in Fog2–/– hearts are reminiscent of the phenotypes seen in hearts lacking myocardial FGF signaling. Given these similarities, it is intriguing to postulate that FOG2 and FGF signaling may be functionally related. For example, FOG2 may be necessary for the cardiomyoblast to receive FGF signaling. Alternatively, it is possible that FOG2 and GATA4 may regulate the expression of key epicardial signals such as FGFs and HHs. Consistent with these possibilities, several interactions between FGF and GATA signaling have been identified.72–76
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HH-Mediated Vessel Growth and Maintenance in the Adult Heart |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Activation of HH signaling is both necessary for coronary development and sufficient to promote formation of new coronary vessels in the embryonic and adult heart. We and others have discovered that activation of HH signaling in the adult heart promotes coronary neovascularization and protects from ischemia.18,19 Moreover, Shh gene therapy can similarly trigger coronary growth and protect from ischemic injury in rodent and large animal models.19 These studies directly implicate the HH signaling pathway as a potential therapeutic target for pharmacological revascularization and make a compelling case for the potential use of HH agonists in patients with ischemic heart disease.
In the adult, HH signaling orchestrates coronary neovascularization by controlling the expression of multiple proangiogenic genes, including VegfA, VegfB, VegfC, Ang1, and Ang2, a similar set of factors to those activated in the embryo. Based on findings indicating that HH signaling regulates coronary vascular formation, promotes neovascularization in the adult heart, and induces expression of numerous signaling molecules, it is likely that the HH pathway represents a potentially key regulatory mechanism capable of orchestrating coronary vascular growth in various settings.
Therapeutics targeting the HH pathway have the potential to succeed where other pharmacological modalities have failed. It has been postulated that monotherapy with FGF2, FGF4, or VEGFA165 has been unsuccessful because expression of multiple factors are required for efficient coronary neovascularization.2 In support of this notion, coexpression of VegfA and Ang2 in the myocardium causes significantly more robust increases in coronary vessel density than that of VegfA or Ang2 alone.8 Intriguingly, HH signaling regulates expression of not only VegfA and Ang2 but also VegfB and VegfC, making HH signaling an attractive candidate for a therapy aimed at promoting coronary vascular growth. Highlighting the importance of controlling multiple proangiogenic factors, coapplication of VEGFA and ANG2 are required to rescue coronary development in hearts treated with a HH antagonist.18 Furthermore, unlike VEGF agonist therapies, activation of HH signaling promotes the growth of multiple blood vessel types, including both larger smooth muscle encased vessels and capillaries, whereas VEGF agonists only promote the growth of capillary-sized blood vessels.8,19
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HH-Mediated Vessel Growth in Other Organ Systems |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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In addition to the heart, activation of the HH pathway has been to shown to promote therapeutic blood vessel growth in various other tissues, including the cornea, skin, skeletal muscle, and peripheral nerve. Similar to what has been observed in the heart, activation of HH signaling in other tissues promoted growth of multiple blood vessel types compared to the uniform increase in capillary-sized blood vessels after treatment with VEGF agonists.66
Consistent with the ability of HH signaling to promote the growth of functional vasculature, several studies have demonstrated that activation of HH signaling protects from ischemic damage and leads to functional improvements in a diversity of tissues. Injection of a HH small molecule agonist decreased infarct size by 40% to 50% and led to improved behavior and body weight in a middle cerebral artery occlusion model.60 Moreover, treatment of diabetic mice with recombinant SHH protein not only promoted vascular growth in the skin and peripheral nervous tissue but also resulted in accelerated wound healing and improved peripheral nerve conduction velocity, 2 processes that are defective at baseline in diabetic mouse models.77,78 These data implicate the HH signaling pathway as a useful target for therapeutics aimed to minimize ischemic damage and improve tissue function in conjunction with both macrovascular and microvascular disease.
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Potential Clinical Applications of HH Agonists |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Data published thus far clearly implicate the potential therapeutic use of HH agonists in multiple clinical settings. However, before HH agonists are used in such circumstances, several issues need be addressed. First, it is currently unclear which type of HH agonist is best suited for clinical use. To date, there are no studies comparing the efficacy of recombinant SHH protein, gene therapy, and small molecule agonists on coronary growth in either normal or ischemic animal models. Moreover, selection of dosing, length of treatment and route of administration are, for the most part, unexplored. Key points include whether systemic or local administration of HH agonists is most efficacious and whether the effects of HH on the vasculature are lost on discontinuation of the therapeutic agent.
Importantly, whether activation of HH signaling either locally or systemically has deleterious consequences and whether small molecule HH agonists have undesirable off-target effects have not been adequately explored. This is important, given the prominent role of HH signaling in several neoplastic processes.60 Moreover, whereas acute activation of HH signaling seems to be therapeutic and potentially protective for the heart, it is not known whether chronic activation of HH signaling is equally advantageous or potentially harmful. Studies addressing these issues will need to be addressed before HH agonists can be evaluated for clinical efficacy.
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Endogenous Functions of HH in the Adult Heart |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Currently, HH antagonists are being developed for the treatment of several cancers, including basal cell carcinoma, pancreatic carcinoma, prostate carcinoma, chondroblastoma, and medulloblastoma.79–86 Given that SHH expression is induced during myocardial and skeletal muscle ischemia,19,87 it is possible that HH signaling may be an important endogenous regulator of vascular growth and potentially maintenance. This possibility is further supported by the finding that inhibition of HH activity, using neutralizing anti-SHH antibodies, adversely affected recovery in a hindlimb ischemia model.87 Given these important issues and their clear implications, it is imperative to determine whether endogenous HH signaling fulfills such a role in the adult heart before the use of these HH antagonists in the clinic.
To this end, we have investigated whether endogenous HH signaling is necessary for maintaining cardiac function and/or homeostasis in the mouse by examining the consequences of acutely removing HH signaling from the adult mouse heart.88 Temporal and tissue specific deletion of the essential HH signaling component Smo from the adult heart resulted in coronary blood vessel dropout and significant reductions in the expression of multiple proangiogenic growth factors, including VegfA, VegfB, VegfC, Ang1, and Ang2. Reductions in coronary vascular density consequently led to myocardial hypoxia, cardiomyocyte apoptosis, ventricular failure and, in some cases, lethality.
Furthermore, endogenous HH activity is critical for recovery from myocardial ischemia. Following myocardial infarction, treatment of wild-type mice with neutralizing anti-SHH antibodies led to depressed ventricular function, increased infarct area, and enhanced mortality compared to mice that received isotype control antibodies. Importantly, the dose of anti-SHH antibody delivered closely matched that used in animal studies evaluating the efficacy of anti-SHH therapies as chemotherapeutic agents. Because the prevalence of heart disease in the adult oncology population is considerable, these studies raise the possibility that therapeutic reductions in HH signaling may result in adverse cardiovascular effects in a significant proportion of these patients.
Given the profound effect of removing HH signaling from the adult myocardium and deleterious effects of reducing HH signaling following myocardial infarction in animal models, caution should be taken in the development and application of pharmaceuticals targeting the HH pathway. Importantly, although it is possible that therapeutic effects of HH antagonists may be achieved at levels of HH inhibition that do not impair cardiac function, the use of HH antagonists in patients with prior or ongoing cardiac disease may significantly increase the risk of further injury and should only proceed following thorough investigation.
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HH Signaling Represents a Conserved Pathway Essential for Both the Embryonic and Adult Vasculature |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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As described in detail above, the signaling axis composed of HH, VEGF, and ANG pathways controls the formation of the coronary vascular system during embryonic development and promotes the growth and maintenance of the coronary vasculature in the adult.18 Together, these findings indicate that both the embryonic and adult coronary vasculature are regulated by a conserved genetic pathway. The existence of a conserved signaling system that governs coronary vascular growth, both in the embryo and adult, exemplifies that considerable insight into adult cardiac physiology and potential disease states can be gained by studying embryonic heart development.
Although there is great similarity between embryonic and adult coronary vascular growth, some important differences exist. In contrast to embryonic coronary vessel growth, where HH signaling controls Ang2 expression, in the adult heart, HH signaling regulates both Ang1 and Ang2 expression. Given that ANG1 activates the TIE2 receptor and ANG2 antagonizes TIE2 receptor activation,15 these data suggest that signaling through the TIE2 receptor is differentially required for embryonic and adult coronary vascular growth. Consistent with this, overexpression of Ang1 in the adult heart inhibits VEGF-induced coronary vessel growth, whereas overexpression of Ang2 enhances coronary vessel growth.8
Interestingly, deletion of Smo in the adult myocardium led to a specific decrease in the coronary arterial but not venous vasculature, suggesting that coronary arteries and veins are supported through distinct mechanisms. Whether coronary veins are maintained through a Vegf-dependent mechanism or by another mechanism is unclear. However, transgenic mice that specifically express VegfA in the myocardium demonstrate selective increases in coronary arteries but not veins, indicating that coronary veins might not be a target of VEGF signaling in the adult heart.8
Determination of whether and which VEGF receptors are expressed in coronary endothelial cells will be required to adequately address this question. It is possible that in addition to lymphatic vessels, coronary veins express VEGFR3. This would have interesting ramifications, suggesting potential coregulation of venous and lymphatic growth. Consistent with this, in zebrafish, developing veins express VEGFR3.89 Moreover, based on in vitro studies, VEGFA and VEGFB can bind and activate VEGFR1 and VEGFR2, whereas neither ligand has been reported to bind VEGFR3.9 Alternatively, coronary veins could be controlled via a VEGF-independent mechanism.
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Outstanding Questions |
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TopAbstractIntroductionInsights From the Developing...Cardiac DevelopmentDevelopment of the Coronary...Epicardial LineageEpicardial SignalingFGF and Hedgehog Signaling...Other Pathways That Regulate...HH-Mediated Vessel Growth and...HH-Mediated Vessel Growth in...Potential Clinical Applications...Endogenous Functions of HH...HH Signaling Represents a...Outstanding QuestionsReferences |
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Despite progress in identifying signaling pathways that coordinately regulate the development and growth of the coronary vasculature in the embryo and adult, several outstanding questions remain. Little is known regarding the factors and conditions that might regulate HH ligand expression in the adult heart. It is intriguing to hypothesize that HH ligand expression is regulated in the adult heart by a similar mechanism to that of the embryonic heart. Consistent with this hypothesis, GATA4 function is not only required for embryonic coronary growth but also can promote blood vessel growth in the adult heart.70,90,91 Whether FGFs and/or other RTK pathways are regulated by GATA4 in the adult heart and whether these pathways might control HH ligand expression in the adult remain unanswered.
Furthermore, functions of FGF signaling in the adult heart are largely unexplored. Several FGFs, including FGF2, FGF4, FGF9, and FGF16, are expressed in the adult heart.16,92 Unfortunately, there are few reports describing adult-specific functions of these factors. Analysis of Fgf2–/– mice has revealed deficits in the response to pressure overload and defects in infarct repair; however, it is unclear whether these phenotypes are a result of embryonic and/or adult functions of FGF2.93,94 Similarly, transgenic expression of FGF1 and FGF2 have suggested a potential role in cardiomyocyte hypertrophy and coronary growth; however, these experiments are equally confounded by possible embryonic and neonatal effects.4,16,95,96 Interestingly, Fgf16–/– mice display defects in myocardial growth and ventricular function.97 Temporal and tissue-specific conditional gene targeting and forced expression will be required to define what roles these factors may truly play in the adult heart.
Finally, although HH signaling appears to be a critical and central pathway regulating embryonic and adult coronary growth, it is possible that additional molecules and pathways are capable of promoting coronary development and growth. Such factors may function by controlling VEGF and ANG expression or may do so by governing the expression of yet unidentified proangiogenic growth factors. Moreover, whether and how HH signaling might interact with other known proangiogenic signaling pathways such as hypoxia-inducible factor 1, PGC1, and PR39 remains unexplored.98–101 Such discoveries will undoubtedly uncover important and potentially clinically useful insights into the mechanisms that regulate the coronary vasculature.
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Acknowledgments |
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We thank S. Davis for helpful comments.
Sources of Funding
This work was funded by NIH grant HL076664.
Disclosures
None.
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Footnotes |
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Original received August 29, 2008; resubmission received November 17, 2008; revised resubmission received December 2, 2008; accepted December 11, 2008.
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References |
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