Malformation of the aortic valve, a relatively common defect, can lead to cardiovascular disease. However, the embryonic mechanisms at work and their genetic determinants remain unclear. An Inserm team has recently gained insight into these processes.
The heart comprises several valves which prevent blood from rushing back in the wrong direction during its contraction cycle (see diagram). When the latter fail to open and/or close correctly, valve disease may develop.
The heart valve located at the beginning of the aorta (the artery which carries blood from the heart to the rest of the body) comprises three leaflets. However, in some individuals, it may only have two: this phenomenon is known as bicuspid aortic valve. "This is one of the most common congenital malformations, affecting 0.5 to 1.4% of the population according to studies. Although the majority of individuals with bicuspid aortic valve live normal lives, 30% go on to develop early valve dysfunction", explains Stéphane Zaffran.
At Hôpital de La Timone, in Marseille, his team* is exploring the, as yet relatively unclear, mechanisms leading to this malformation. The team is approaching the problem from several angles. The researchers have set out to identify the genes potentially involved, in collaboration with the Adult Cardiology Department at the hospital. "We have managed to recruit the largest cohort in Europe: 350 patients diagnosed with bicuspid aortic valve", states Stéphane Zaffran. This cohort also allows clinical and prognostic aspects of this defect to be examined. The team also uses animal models (particularly mice), together with in vitro cell methods, to explore the embryonic mechanisms at work. The latter approach gave rise to the results recently published in Development.
During embryo development, heart valves form from cells present in the primitive heart, but also from "migrating" cells originating from an embryonic formation which will develop into the nervous system: the neural tube. In a previous research project, the team showed that a transcription factor found in these neural cells, factor Krox20, plays a role in aortic valve hypertrophy. To shed more light on the formation of abnormal valves, the researchers therefore used animals with or without the Krox20 gene, together with various cell marking techniques. This entailed monitoring the fate of the cells during valve formation. As a result, the markers made it possible to identify and locate, for the very first time, a subpopulation of neural tube cells expressing Krox20, which migrates to the leaflets of the developing valvules. More specifically, these cells colonize the periphery of the leaflets, together with the site where they attach to the arterial wall.
One of several mechanisms
The analyses also showed that, in animals without Krox20, excessive numbers of neural cells migrate to the leaflets, resulting in hypertrophy. "Hypertrophy pushes the leaflets together during embryogenesis, until fusion occurs in certain cases, thus resulting in bicuspid aortic valve", explains Stéphane Zaffran. The researcher points out that this is one of the mechanisms for the development of bicuspid aortic valve, but other mechanisms more than likely exist. Furthermore, other teams have evidenced the role of cardiac cells in this defect.
This research, still in the very fundamental stages, also provided an opportunity to develop a new animal model for the remainder of this exploration. One of its aims is to shed light on the effects of bicuspid aortic valve on blood flow, and possibly therefore to explain the premature degeneration of these abnormal valves. By combining fundamental research and follow-up of a cohort of patients, the team is also attempting to find more effective ways of linking the various classes of valve defects to various known diseases.
G. Odelin et coll. Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve. Development, (2018) 145, dev151944. doi:10.1242/dev.151944 (édition en ligne du 3 janvier 2018)