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Transforming growth factor beta in cardiovascular development and function

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Abstract

Transforming growth factor betas (TGFβs) are pleiotropic cytokines involved in many biological processes. Genetic engineering and tissue explanation studies have revealed specific non-overlapping roles for TGFβ ligands and their signaling molecules in development and in normal function of the cardiovascular system in the adult. In the embryo, TGFβs appear to be involved in epithelial–mesenchymal transformations (EMT) during endocardial cushion formation, and in epicardial epithelial–mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. In the adult, TGFβs are involved in cardiac hypertrophy, vascular remodeling and regulation of the renal renin–angiotensin system. The evidence for TGFβ activities during cardiovascular development and physiologic function will be given and areas which need further investigation will be discussed.

Introduction

TGFβs are closely related members of a large family of structurally similar polypeptides referred to as the transforming growth factor beta (TGFβ) superfamily. Members of this superfamily include the activins, inhibins, bone morphogenetic proteins (BMPs), müllerian inhibiting substance, Drosophila decapentaplegic gene complex, and Xenopus Vg-1 gene [1]. The TGFβs 1, 2 & 3 exhibit a variety of proliferative, inductive and regulatory functions [2] and exhibit both overlapping and distinct spatial and temporal patterns of expression throughout development and in the adult, with pronounced embryonic expression in areas undergoing morphogenesis [3], [4]. Knockout (KO) mice for these ligands display dozens of non-overlapping phenotypes in most major organ systems [5], [6], indicating a high degree of functional specificity.

There is considerable evidence that TGFβs can signal through multiple pathways (Fig. 1). The three TGFβ cytokines are secreted as latent complexes that are activated by mechanisms only partially understood. Among the general mechanisms that can activate TGFβs are enzymatic mechanisms which include proteases such as plasmin, calpain and matrix metalloproteinases, conformation changing protein interactions with molecules such as thrombospondin and integrin αvβ6, physicochemical mechanisms such as pH, radiation and reactive oxygen species, and drugs such as antiestrogens, retinoids and glucocorticoids (reviewed in [7]). There are three classes of TGFβ receptors, the transmembrane serine–threonine kinase receptors, TGFβRI and TGFβRII [1], [8] and TGFβRIII receptors which include an ubiquitous extracellular β-glycan [9] and the membrane glycoprotein endoglin (CD105) [10], [11]. Since TGFβ2 has a lower affinity to TGFβRII than does TGFβ1 or 3, its stronger interaction with β-glycan facilitates its interaction with the TGFβRII/I complex [9], although a shed form of β-glycan may be inhibitory [12]. In addition, a splice variant of the TGFβRII allows TGFβ2 ligand–receptor interaction in the absence of the TGFβRIII [13]. In contrast, endoglin interacts with TGFβ1 and TGFβ3, but has low affinity for TGFβ2 [10]. In several cell types endoglin is inhibitory to TGFβ1 function [14], [15]. The ligand–receptor complexes signal through SMAD proteins that exhibit regulatory (SMAD2 and 3), co-regulatory (SMAD4) and inhibitory (SMAD6 and 7) activities on TGFβ signaling [1], [16].

As there is only partial ligand–receptor specificity, the functional specificity of TGFβs probably depends to a large degree upon extracellular ligand activation [7], differences in intracellular SMAD interactions [1], [16], interactions with other signaling pathways such as the Ras/MAPK pathway [17], and interaction between SMADs and transcriptional co-activators and co-repressors [18]. TGFβ signaling can also occur through SMAD-independent pathways (e.g. MAPK and Ca2+) [19] and through a non-transcriptional pathway (e.g. platelet aggregation) [20].

Many members of the TGFβ superfamily that play important roles in the heart have been reviewed elsewhere [21], [22], [23]. This review will concentrate specifically on TGFβ1, TGFβ2 and TGFβ3 and their functions in the cardiovascular system where their importance has been evident for over a decade [24]. This review will subdivide the cardiovascular functions of the three TGFβs into two major categories: cardiovascular development and physiology. Because the TGFβ literature is so vast, we will limit our review for the most part to in vivo studies carried out primarily in chicken and genetically engineered mice.

Section snippets

Cardiovascular development

The propagation of the symmetrical embryonic cardiac tube into an asymmetrical four-chambered heart with proper alignment of the atrio-ventricular (AV) segments and the great vessels with their respective chambers requires considerable morphogenetic and remodeling processes. Cardiac looping, formation of endocardial cushions, and their remodeling, in which myocardialization plays a primary role, are all required for proper inflow and outflow tract (OT) alignment, cardiac septation, and valve

Cardiovascular physiology

Cell culture studies have indicated that TGFβ1 inhibits mitotic growth of cardiomyocytes [89], and stimulates hypertrophic growth [90], fibrosis [90], [91] and re-expression of the fetal isoforms of myofibrillar protein genes [92]. TGFβ1 is secreted from cultured cardiomyocytes and fibroblasts during cyclic stretch [93]. In the vascular system TGFβ1 switches the response of angiotensin II (Ang II)-stimulated cultured VSMC from mitotic to hypertrophic growth [94], TGFβ1 treatment affects Ca2+

Perspectives

Analysis of genetically engineered mouse models of TGFβ deficiencies and overexpression have revealed numerous in vivo functions for TGFβs in cardiovascular development and physiology. Nonetheless, there remain many aspects of cardiovascular development for which the roles of TGFβ have yet to be determined. It is not clear how TGFβs are involved in molecular specification and formation of early endocardial and myocardial precursors from the primary heart forming fields or in the recruitment of

Acknowledgements

Grant support for the studies presented here: NIH grants HD26471, HL70174, HL58511, ES06096 to TD; INSERM and Association Claude Bernard to PM; VA Merit Review to GWD; NHS: ECCARD to ACG.

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