5 Retinoic Acid Signaling and Heart Development
121
Despite the history of investigating how RA signaling regulates heart development, there remains much work to be done in this domain. Here, we highlight the
roles of RA signaling in heart development, provide an overview of the historical
progress and current state of this important field, and discuss future directions for
research in this area.
History
Establishing the Importance of VA in Heart Development
The pathogenesis of VAD was first studied in the 1920s (Wolbach and Howe 1925).
A decade later the pleiotropic malformations resulting from maternal VAD were
first recognized (Hale 1935). However, it was the pioneering work by Wilson and
Warkany, two founders of the field of teratology, which soon followed in the 1940s
and 1950s, that demonstrated effects of VAD on normal heart development. Their
groundbreaking studies demonstrated that outflow tract (OFT) and aortic arch defects
were found in rat embryos harvested from dams fed a VAD diet (Wilson and Warkany
1949, 1950a, b; Wilson et al. 1953). Several decades later, a developmental study
of the heart and vascular system in VAD quail embryos showed that these embryos
exhibited cardia bifida and even hearts with a single enlarged ventricle (Heine et al.
1985). Hence, Hein et al. corroborated Wilson and Warkany’s results and provided
evidence for a conserved requirement of VA in normal vertebrate heart development.
At about the same time as Wilson and Warkany’s studies of VAD, Cohlan demonstrated that excessive intake of VA, which can pathologically manifest as hypervitaminosis A, also causes a spectrum of congenital anomalies, in rats (Cohlan 1953).
Following their VAD studies, Warkany et al. showed that hypervitaminosis A, due to
dietary supplementation, caused OFT and septal defects in murine models (Kalter and
Warkany 1961). This study was perhaps the first to suggest that the levels of Vitamin
A need to be tightly-regulated for the establishment of normal heart development.
Subsequently, it was shown that RA, the most active metabolic product of VA,
itself is a potent teratogen (Durston et al. 1989; Sive et al. 1990). Moreover, excess
embryonic RA from maternal hypervitaminosis A, which can occur due to hypersupplementation, excess liver intake, or RA therapy (e.g. as a common treatment of
chronic acne) can result in RA embryopathy and congenital heart diseases (CHDs)
that include OFT and septal defects (Lammer et al. 1985; Rizzo et al. 1991; Finnell
et al. 2004; Pan and Baker 2007).
121
Despite the history of investigating how RA signaling regulates heart development, there remains much work to be done in this domain. Here, we highlight the
roles of RA signaling in heart development, provide an overview of the historical
progress and current state of this important field, and discuss future directions for
research in this area.
History
Establishing the Importance of VA in Heart Development
The pathogenesis of VAD was first studied in the 1920s (Wolbach and Howe 1925).
A decade later the pleiotropic malformations resulting from maternal VAD were
first recognized (Hale 1935). However, it was the pioneering work by Wilson and
Warkany, two founders of the field of teratology, which soon followed in the 1940s
and 1950s, that demonstrated effects of VAD on normal heart development. Their
groundbreaking studies demonstrated that outflow tract (OFT) and aortic arch defects
were found in rat embryos harvested from dams fed a VAD diet (Wilson and Warkany
1949, 1950a, b; Wilson et al. 1953). Several decades later, a developmental study
of the heart and vascular system in VAD quail embryos showed that these embryos
exhibited cardia bifida and even hearts with a single enlarged ventricle (Heine et al.
1985). Hence, Hein et al. corroborated Wilson and Warkany’s results and provided
evidence for a conserved requirement of VA in normal vertebrate heart development.
At about the same time as Wilson and Warkany’s studies of VAD, Cohlan demonstrated that excessive intake of VA, which can pathologically manifest as hypervitaminosis A, also causes a spectrum of congenital anomalies, in rats (Cohlan 1953).
Following their VAD studies, Warkany et al. showed that hypervitaminosis A, due to
dietary supplementation, caused OFT and septal defects in murine models (Kalter and
Warkany 1961). This study was perhaps the first to suggest that the levels of Vitamin
A need to be tightly-regulated for the establishment of normal heart development.
Subsequently, it was shown that RA, the most active metabolic product of VA,
itself is a potent teratogen (Durston et al. 1989; Sive et al. 1990). Moreover, excess
embryonic RA from maternal hypervitaminosis A, which can occur due to hypersupplementation, excess liver intake, or RA therapy (e.g. as a common treatment of
chronic acne) can result in RA embryopathy and congenital heart diseases (CHDs)
that include OFT and septal defects (Lammer et al. 1985; Rizzo et al. 1991; Finnell
et al. 2004; Pan and Baker 2007).