The Endocardium as a Master Regulator of Ventricular Trabeculation
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Ventricular chamber morphogenesis, characterized by trabeculae formation, is crucial for cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. The ang1-Tie2 pathway is required for normal heart chamber development, but its molecular effectors are not well defined. Here we show that loss of Tie2 in endocardial cells (EC) results in mid-gestation lethality due to heart defects including hyperplastic myocardium trabeculation (fewer but thicker trabeculae), thinner compact myocardium and simplified endocardial network. The thicker trabeculae phenotype results from enhanced proliferation of trabecular cardiomyocytes. Meanwhile, endocardial loss of Tie2 reduces proliferation and production of ECs and impairs endocardial sprouting, which provides necessary support for trabecular assembly and extension, thus resulting in a dramatically simplified trabecular meshwork. These findings reveal two seemingly apposing functions of Tie2 in myocardium trabeculation: ensuring normal trabeculation by supporting EC proliferation and sprouting while preventing hypertrabeculation by inhibiting trabecular cardiomyocyte proliferation.
KeywordsTie2 Endocardium Myocardium trabeculation RA signaling Conditional knockout
Congenital heart diseases are some of the most common human birth defects. In many congenital heart diseases, genetic defects lead to impaired embryonic heart development or growth. A key development process in cardiac ontogeny is ventricular chamber formation. One of the first signs of chamber development is the formation of trabeculae . Lack of trabeculation frequently causes embryonic lethality in mice and excess trabeculation causes cardiomyopathy and heart failure in humans . A number of signaling molecules from myocardium, endocardium and cardiac extracellular matrix (ECM) have been implicated in trabeculation and an intimate communication between endocardium and myocardium promotes cardiomyocyte (CM) proliferation and differentiation leading to trabeculae formation . The Notch signaling pathway has been the most intensely investigated in this process with Bmp10, Nrg1 and EphrinB2 identified as downstream targets of Notch signaling during trabeculation . However, the molecular and cellular mechanisms controlling trabeculation are still poorly understood.
The Tie (tyrosine kinase with immunoglobulin-like and EGF homology) receptors, Tie1 and Tek/Tie2, are type 1 transmembrane protein receptor tyrosine kinases (RTKs) . Along with the vascular endothelial growth factor (VEGF) receptors, these are the only known endothelial cell (EC)-specific RTKs. Although deficiency in Tie1 results in cardiovascular demise in utero [5, 6, 7], Tie1 is dispensable for cardiac trabeculation. Mutations in Tie2 have been described to cause ventricular septal defects and cutaneomucosal venous malformations in humans [8, 9]. Previous reports have suggested a role for Tie2 signaling in trabeculation because Tie2-null embryos have no trabeculae [5, 10] and deficiency of Ang1; the primary agonist for Tie2 results in a marked reduction in cardiac trabeculation [11, 12]. However, the molecular basis for these phenotypes has remained elusive. In addition, Tie2-deficient mouse embryos with abnormal trabeculation also had lethal vascular defects raising the question of whether the cardiac defects observed were primary or secondary to more global vascular compromise. Here, we show that loss of endocardial Tie2 results in embryonic heart failure that is characterized by impaired endocardial growth and hyperplastic trabeculation.
52.2 Mouse Models for Endocardial Specific Gene Deletion
52.3 Tie2 Is Essential for Ventricular Chamber Development
52.4 Future Directions and Clinical Implications
Despite the absolute requirement for functional Tie2 signaling in normal cardiovascular development as well as its essential role in the progression of adult heart and vascular diseases, there is a paucity of information delineating the mechanism(s) of Tie2 activation or the subsequent signaling events that modulate heart ontogeny. This work reveals a critical role for the endocardium in the orchestration of ventricular trabeculation which is dependent on endocardial RTK Tie2 signaling. Tie2 not only plays a primary autocrine function in support of EC proliferation and angiogenic sprouting and touchdown but also is instrumental in the generation of paracrine signaling that results in inhibition of trabecular CM proliferation that prevents hypertrabeculation. Further investigation on this project will focus on delineating downstream targets of Tie2 activation in both endocardium (cell autonomous effect) and myocardium (paracrine effect) during ventricular trabeculation. These new insights will be important in further defining mechanisms of disease pathology related to ventricular chamber morphogenesis and function and will ultimately be critical in elucidating the etiology of congenital heart diseases.
This work was supported by grants from NHLB/NIH: RL1HL0952551 (H.S.B.).
- 8.Szot JO, Cuny H, Blue GM, Humphreys DT, Ip E, Harrison K, Sholler GF, Giannoulatou E, Leo P, Duncan EL, Sparrow DB, Ho JWK, Graham RM, Pachter N, Chapman G, Winlaw DS, Dunwoodie SL. A screening approach to identify clinically actionable variants causing congenital heart disease in exome data. Circ Genom Precis Med. 2018;11(3):e001978.CrossRefGoogle Scholar
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