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New Concepts in the Development and Malformation of the Arterial Valves

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New Concepts in the Development and Malformation of the Arterial Valves Journal of Cardiovascular Development and Disease Review New Concepts in the Development and Malformation of the Arterial Valves Deborah J. Henderson * , Lorraine Eley and Bill Chaudhry Biosciences Institute, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; [email protected] (L.E.); [email protected] (B.C.) * Correspondence: [email protected] Received: 28 August 2020; Accepted: 23 September 2020; Published: 24 September 2020 Abstract: Although in many ways the arterial and atrioventricular valves are similar, both being derived for the most part from endocardial cushions, we now know that the arterial valves and their surrounding structures are uniquely dependent on progenitors from both the second heart field (SHF) and neural crest cells (NCC). Here, we will review aspects of arterial valve development, highlighting how our appreciation of NCC and the discovery of the SHF have altered our developmental models. We will highlight areas of research that have been particularly instructive for understanding how the leaflets form and remodel, as well as those with limited or conflicting results. With this background, we will explore how this developmental knowledge can help us to understand human valve malformations, particularly those of the bicuspid aortic valve (BAV). Controversies and the current state of valve genomics will be indicated. Keywords: arterial valve; semilunar; outflow cushion; leaflet; EndMT; second heart field; neural crest cells; signalling; bicuspid aortic valve 1. Anatomy, Histology and Nomenclature of the Mature Arterial (Semilunar) Valves The aortic and pulmonary valves, which sit within the arterial roots between the myocardium of the left and right ventricular outflow tracts and the aorta and pulmonary trunk, respectively, are structurally similar to one another, and are closely comparable in humans and mice [1–3]. Thus, in the mature heart both the aortic and pulmonary valves have three superficially similar leaflets that form the moving parts of the valve. The right (R) and left (L) sinuses of the aortic valve each host the ostium of a coronary artery, whilst the third non coronary/non-facing/posterior (N) and the three pulmonary valve sinuses are almost never associated with a coronary artery—even in congenitally malformed hearts. However, we now recognise the valve complexes to include more than just the three moving leaflets, with additional components including: the hinges, the attachment points of the leaflets to the wall; the commissures, the points of apposition of the leaflets close to the wall; the sinuses, pockets that form between the leaflets and the wall; and the interleaflet triangles, the regions of the wall that lie upstream (on the ventricular side) of the hinges, but are distal to the base of the sinuses that are found on the arterial side (Figure1). The nomenclature used to describe the arterial roots is controversial. For example, the outflow tract has been divided by some authors into a proximal conus and a distal truncus, although this terminology is falling out of practice and three rather than two components are increasingly recognised. In this nomenclature, the distal component represents the intra-pericardial arterial trunks and the proximal component comprises the ventricular outflow tracts, with the valve complex appearing in the intermediate part [2]. In other contexts, anatomically artificial “rings” are described for clinically important measurements, although some publications have highlighted the misuse of these descriptions for developmental and anatomical purposes [4,5]. Thus, the development of this highly complex area remains the topic of speculation and controversy. J. Cardiovasc. Dev. Dis. 2020, 7, 38; doi:10.3390/jcdd7040038 www.mdpi.com/journal/jcdd J. Cardiovasc. Dev. Dis. 2020, 7, 38 2 of 27 J. Cardiovasc. Dev. Dis. 2020, 7, x 2 of 27 andOne controversy. longstanding One conundrum longstanding is, whatconundrum are the is, similarities what are the and similarities differences and between differences arterial between and arterialatrioventricular and atrioventricular valve development, valve development, particularly thoseparticularly that relate those to theirthat pathology?relate to their How pathology? does the valveHow does achieve the anvalve undulating achieve crown-likean undulating attachment, crown-like crossing attachment, the arterial–myocardial crossing the arterial–myocardial boundary? How boundary?do the outflow How cushions do the remodeloutflow tocushions form the remodel sculpted to valve form leaflets? the sculpted Overall, valve thequestion leaflets? ofOverall, how aortic the valvequestion malformations of how aortic relate valve to othermalformations cardiovascular relate malformations, to other cardiovascular both congenital malformations, and apparently both congenitalacquired, has and not apparently been answered. acquired, The has answer not been to all answered. these puzzles The may answer lie with to all the these progenitor puzzles cells may that lie withform thethe arterialprogenitor roots. cells Thus, that a re-evaluationform the arterial of arterial roots. valve Thus, development a re-evaluation focusing of onarterial the second valve developmentheart field (SHF) focusing and neural on the crest second cells heart (NCC) field may (SHF) explain and theneural relationships crest cells between(NCC) may these explain different the relationshipselements and between make sense these of differen abnormalitiest elements in transgenic and make animal sense of models abnormalities and human in transgenic malformations. animal models and human malformations. Figure 1. Anatomy of the arterial roots. (A) The arterial valve complex is made up of: three moving Figure 1. Anatomy of the arterial roots. (A) The arterial valve complex is made up of: three moving leaflets; the hinges, the attachment points of the leaflets to the wall; the commissures, the points of leaflets; the hinges, the attachment points of the leaflets to the wall; the commissures, the points of apposition of the leaflets close to the wall; the sinuses, pockets that form between the leaflets and the apposition of the leaflets close to the wall; the sinuses, pockets that form between the leaflets and the wall; and the interleaflet triangles, the regions of the wall that lie upstream (on the ventricular side) wall; and the interleaflet triangles, the regions of the wall that lie upstream (on the ventricular side) of the hinges, but are distaldistal toto thethe basebase ofof thethe sinusessinuses thatthat areare foundfound onon thethe arterialarterial side.side. GreenGreen == cardiomyocytes, blueblue == smooth muscle cells, yellowyellow == fibrousfibrous tissue, purple == valve leaflet. leaflet. The dotted line represents the position of the cross sectionsection throughthrough thethe valvevalve complex.complex. (B) Wholemount view of the adult mousemouse aorticaortic root.root. TheThe leafletsleaflets have have been been removed removed to to allow allow the the view view of of the the other other structures structures of ofthe the valve valve complex. complex. (C (,CD,D) Masson’s) Masson’s trichrome trichrome images images of of the the mouse mouse aorticaortic rootroot atat P21P21 inin longitudinal and transverse planes. Red Red staining staining is is muscle muscle tissue, tissue, blue blue staining staining is is fibrous fibrous tissue. tissue. c c= =commissure,commissure, h =h hinge,= hinge, ilt ilt= interleaflet= interleaflet triangle, triangle, l = lleaflet,= leaflet, s = ssinus,= sinus, sw sw= sinus= sinus wall. wall. Cre-lox-based lineage tracing technology in the developing mouse has indicated how cells originating in in the the SHF SHF and and NCC NCC are are involved involved in the in thedev developmentelopment of the of outflow the outflow wall, wall,as well as as well septal as andseptal valve and structures. valve structures. It is clear It is that clear the that hinges the hinges and the and leaflets the leaflets have contributions have contributions from both from SHF- both derivedSHF-derived cells and cells NCC and [3,6]. NCC Similarly, [3,6]. Similarly, above the above undulating the undulating leaflet hinge, leaflet the hinge, sinus the wall sinus is made wall up is ofmade vascular up of smooth vascular muscle smooth cells muscle (SMC) cells that (SMC)also derive that alsofrom derive NCC and from SHF. NCC Within and SHF. the roots, Within SHF- the derivedroots, SHF-derived cells predominate, cells predominate, whilst more whilst distally more the distally entire the tunica entire media tunica is media of NCC is oflineage. NCC lineage. In the transition, these progenitors maintain separation as a thinning inner layer of NCC-derived SMC, and a thickening outer layer of SHF-derived SMC [3,7,8]. Proximal to the root, the myocardium is also J. Cardiovasc. Dev. Dis. 2020, 7, 38 3 of 27 In the transition, these progenitors maintain separation as a thinning inner layer of NCC-derived SMC, and a thickening outer layer of SHF-derived SMC [3,7,8]. Proximal to the root, the myocardium is also derived from the SHF. Thus, the supporting structures for the leaflets, the hinge attachments and the interleaflet triangles, the fibroblasts and SMC at the base of the sinus and the subaortic and sub pulmonary myocardium, all arise from SHF progenitors and NCC to a greater or lesser extent. The question of the undulating attachment of the leaflets must be expanded to ask, how do the SHF-derived cells on the arterial side of the hinge become SMC whilst those on the ventricular side become
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