Intraluminal valves: development, function and disease

Figures

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  Fig. 1.. Stepwise development of cardiac valves in mice. (A) The heart initially forms as a simple tube with an inner endocardial (blue) and outer myocardial (red) layer. The atrium (‘A’) is yet to separate into the left and right chambers by septation, and the ventricle is a single chamber [the future left (LV) and right (RV) ventricles are depicted]. The outflow tract (OFT) has yet to separate into the pulmonary artery and dorsal aorta. The cardiac cushions (CCs) form at the atrioventricular (right box) and RV-OFT (left box) junctions. Mitral and tricuspid valves develop from the atrioventricular cushion and are collectively known as the atrioventricular valves (AVVs). The aortic (AoV) and pulmonic valves develop from the RV-OFT cushion and are collectively known as semilunar valves. For simplicity, the development of an AoV and an AVV is shown in B-D. (B) During endothelial-to-mesenchymal transition (EndMT), the endocardial cells gain a mesenchymal-cell-like characteristic and migrate into the CC. These cells are known as valvular interstitial cells (orange cells). (C) Valvular interstitial cells proliferate and secrete ECM proteins, which results in the bending of primitive valves…

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  Fig. 2.. Structural and molecular features of intraluminal valves. (A) Schematic of a single leaflet of the aortic valve (AoV). Ao represents the aorta, M represents the myocardial layer of the left ventricle and A represents the annulus, which is a fibrous ring that supports the AoV. The small arrows point to the three inner layers of the valve: ventricularis (V), spongiosa (S) and fibrosa (F). The orange stars represent the ECM-producing activated valvular interstitial cells. The nucleated cells are the endothelial cells of the AoV. The thick arrow indicates the direction of blood flow from the left ventricle to the aorta. The endothelial cells directly facing the blood flow (upstream side) are in red and their expression profile is presented in the red box. The endothelial cells on the downstream side of the AoV are in yellow; their expression profile is presented in the light green box. (B) Scanning electron micrograph (SEM) of the downstream side of the AoV of a dog, showing the elongated morphology of the endothelial cells. Image reproduced with permission from Deck (1986). The sample is approximately 270 µm in length (left to right). (C) SEM of endothelial-to-mesenchymal transition…

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  Fig. 3.. Development of mouse lymphovenous valves (LVVs). (A) Schematic of the junction that forms between the lymph sacs (LS; green), the internal jugular vein (IJV), external jugular vein (EJV), subclavian vein (SCV) and superior vena cava (SVC) in an E12.0 mouse embryos. The head and the heart are respectively located anterior and posterior to this location. LVVs (arrowheads) develop at the two sites of contact between the LS and the veins. (B-D) Cross-section of the junction between the LS and veins in the developing mouse embryos. (B) LVV-forming endothelial cells (LVV-ECs; red) differentiate at E12.0. Immediately after differentiation, LVV-ECs delaminate into the lumen of the vein (towards the right of this picture). Lymphatic endothelial cells (LECs) in close proximity to LVV-ECs have a distinct molecular profile relative to LECs in the LS (green), and are depicted in yellow. (C) LVV-ECs quickly reaggregate and the entire valve complex invaginates into the vein. (D) LVVs undergo further maturation by recruiting mural cells (orange) to the space between LVV-ECs and the specialized LECs. Pictures were adapted with permission from Geng et al. (2016).

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  Fig. 4.. Development of mouse lymphatic valves (LVs) and venous valves (VVs). (A) Top: schematic sagittal section of a VV (red cells) located within the venous lumen (depicted in blue). Bottom: an LV (red cells) located within a mesenteric lymphatic vessel (depicted in green). VVs of central veins start developing at E14.5 and VVs of peripheral veins start developing at postnatal day (P)1. LVs of the mesentery start developing at E16. Images modified with permission from Bazigou and Makinen (2013). (B-D) Despite differences in their developmental time points, the morphogenesis of VVs and LVs are similar. For simplicity, a schematic of developing VVs is presented. The developmental time points corresponding to the appropriate valves are presented at the top of the pictures. The arrow within the lumen of the vessel represents the direction of fluid flow. (B) The valvular endothelial cells undergo circumferential reorientation along the rim of the vessels. (C) ECM (yellow) is organized in between the valvular endothelial cell layers. (D) The valve leaflets elongate along the direction of fluid flow to form mature valves. Images modified with permission from Bazigou et al. (2014).

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  Fig. 5.. An integrated model for valve development. A model of the various molecules that regulate valve morphogenesis and their functional relationships. Oscillatory shear stress activates Klf2 expression and its downstream target genes during cardiac valve development in zebrafish and mice. During lymphatic valve development, oscillatory shear stress enhances the expression of multiple molecules, such as ITGA9, ephrin-B2 (EFNB2), GATA2, FOXC2, CX37 and β-catenin (CTNNB1). Oscillatory shear stress also antagonizes CX43 expression. β-catenin is upstream of GATA2 and FOXC2. Shear-stress-activated GATA2 is upstream of FOXC2 and ITGA9. PROX1 expression is not regulated by oscillatory shear stress. However, both GATA2 and β-catenin could enhance PROX1 expression in an oscillatory-shear-stress-independent manner. CX37 regulates NFATC1 activity through the calcineurin (Cn) signaling pathway. Laminar shear stress inhibits the planar cell polarity molecules VANGL2 and CELSR1 through syndecan-4 (SDC4). PECAM1 acts in parallel with SDC4 to regulate the reorientation of valve-forming endothelial cells.