Role of carotenoids and retinoids during heart development

Abstract

The nutritional requirements of the developing embryo are complex. In the case of dietary vitamin A (retinol, retinyl esters and provitamin A carotenoids), maternal derived nutrients serve as precursors to signaling molecules such as retinoic acid, which is required for embryonic patterning and organogenesis. Despite variations in the composition and levels of maternal vitamin A, embryonic tissues need to generate a precise amount of retinoic acid to avoid congenital malformations. Here, we summarize recent findings regarding the role and metabolism of vitamin A during heart development and we survey the association of genes known to affect retinoid metabolism or signaling with various inherited disorders. A better understanding of the roles of vitamin A in the heart and of the factors that affect retinoid metabolism and signaling can help design strategies to meet nutritional needs and to prevent birth defects and disorders associated with altered retinoid metabolism. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

Keywords: Cardiogenesis; Embryonic development; Retinoic acid; Vitamin A.

Figure 1.

Vitamin A uptake and metabolism. All-trans-retinol is transported in the circulation by serum retinol binding protein (RBP4) in association with transthyretin (TTR) and as retinyl esters incorporated in lipoproteins (not shown). In target cells, RBP4/TTR-bound retinol is taken up via the bidirectional cellular receptor STRA6 and delivered to the cellular cytosol where it binds cellular retinol binding proteins (CRBP1 shown). Provitamin A carotenoids circulating in association with lipoproteins are taken up via scavenger receptors class B CD36 (also known as SCARB3) or by the related receptor SCARB1. Provitamin A carotenoids that contain substituted rings such as β-cryptoxanthin are cleaved by the asymmetric beta-carotene-dioxygenase 2 (BCO2) to produce β−10’-apocarotenal, which together with β-cryptoxanthin can be converted by beta-carotene-dioxygenase 1 (BCO1) to all-trans-retinaldehyde. All-trans-retinaldehyde is reduced to all-trans-retinol via the NADPH dependent dehydrogenase reductase 3 (DHRS3). Alltrans-retinol can be esterified by lecithin:retinol acyltransferase (LRAT) and stored in intracellular lipid droplets, or it can be secreted for use by other cells, or it can be oxidized to all-trans-retinaldehyde by the NAD+ dependent retinol dehydrogenase 10 (RDH10) which associates with DHRS3. RA is produced by the oxidation of all-trans-retinaldehyde by retinaldehyde dehydrogenases 1–3 (RALDH1–3). RA then binds cellular RA binding proteins (CRABP1–2) and is transported to the nucleus to activate RAR/RXR, or it can be oxidized to 4hydroxy-RA and other oxidized metabolites by CYP26A1-C1. Feedback regulation by RA leads to downregulation of the expression of genes whose activity lead to increased RA production (proteins indicated in red font) and the upregulation of the expression of genes whose activity could limit RA production or catalyze its degradation (proteins shown in green font).

Figure 2.

Role of RA during early cardiogenesis (up to early somite stage). Left, cardiogenic regions of the HH7–8 chick embryo (E7.5 in mouse) include the cardiac crescent, first heart field (FHF) shown in blue, and the second heart field (SHF) which is further subdivided in anterior (orange) and posterior (red) domains. RA production by regions posterior to the heart tube and then later by cardiac precursors themselves generates a caudo-rostral gradient of RA [78]. RA signaling defines the posterior border of the SHF and the ratio between FHF and SHF and pattern the inflow/outflow tract. Right, the regionalization of the looped heart tube based on the contributions of the FHF and the anterior and posterior SHF (image adapted from [435]).

Figure 3.

The role of the epicardium in heart development. Left, HH17–18 chicken embryo (equivalent to E9.5–10 mouse) showing the proepicardium (red) making villous projections towards the dorsal myocardium. Middle top, shows the epicardium migrating ventrally to envelop the myocardium to establish the epithelial epicardium (red) and subepicardium (green). Middle bottom, by HH20 (E10.5–11 in mouse, Carnegie Stage 15 human) the epicardium has completely enveloped the heart and epicardial and subepicardial cells begin to undergo EMT to infiltrate the myocardium as epicardial-derived cells (EPDCs green). Right, EPDCs give rise to various epicardial derivatives, chiefly of which coronary vascular smooth muscle cells (VSMCs, green) and fibroblasts (blue) that contribute to the adventitial layer of vessels, the interstitium and annulus fibrosus as well as the parietal leaflet of the antrioventricular valves (purple).