Retinoic acid administration is associated with changes in the extracellular matrix and cardiac mesenchyme within the endocardial cushion

Abstract

Retinoic acid has been associated with a number of cardiac defects, some of which seem to be related to changes in the endocardial cushions. Studies in mice and older chick embryos have suggested that these defects may be associated with a decrease in mesenchymal cell formation within the cushion. In a previous report we showed that retinoic acid lowered the number of mesenchymal cells in a culture bioassay of mesenchyme formation and that this response was due to retinoic acid modifying the production of particulate matrix from the myocardium. In this study, we have extended these observations to the embryo by implanting a retinoic acid coated bead into the embryo and examined the effect on cardiac mesenchyme formation and in the production of the particulate matrix. In all cases the addition of retinoic acid resulted in a decrease in the number of mesenchymal cells invading the endocardial cushions. In addition retinoic acid increased the production of hLAMP-1 and fibronectin but not transferrin, confirming our earlier report. Finally, we measured the volume of the cushion and calculated the cell density of both the inferior and superior cushions. The results suggest that the superior cushion is more sensitive to retinoic acid treatment than the inferior cushion. Collectively, these results support our earlier work that suggests that the mechanism of retinoic acid cardiac abnormalities involves a disruption in the production of particulate matrix from the myocardium and a subsequent decrease in cardiac mesenchyme cells that results in a malformed cardiac cushions. Anat Rec 263: [53][54][55][56][57][58][59][60][61] 2001.

Retinal Dehydrogenase-2 Is Inhibited by Compounds that Induce Congenital Diaphragmatic Hernias in Rodents

“…28 -30 Further, retinoic acid has been shown to be involved in regulating extracellular matrix formation, mesenchymal cell migration, and establishment of dorsoventral polarity, all of which could be key components of early diaphragm embryogenesis. 31,32 However, a determination of the specific cells responsible for the embryological origins of the pleuroperitoneal fold will be necessary before ascertaining the role of retinoid signaling and its perturbation by CDH-inducing teratogens.…”

“…Immunolabeling for RALDH2 and HPLC analyses demonstrate that there are gradients of retinoic acid levels within the cervical mesenchyme. 31,32 Further, the levels of retinoic acid and associated activation of RAREs necessary for regulating retinoid-mediated transcription varies among genes in a dose-dependent manner. 31 Thus, it is conceivable that the safety margin for retinoic acid-mediated regulation of primordial diaphragm development is relatively low and thus more susceptible to perturbations compared with other tissues.…”

Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development

“…Consequently, the AV canal forms two boundaries: one with the ventricle and another with the atrium. Consistent with mouse (Webb et al, 1998) and avian (Yan and Sinning, 2001) nomenclature, we refer to the region of the AV canal adjacent to the inner curvature of the ventricle as the Development 132 (18) Research article superior (i.e. anteriormost) EC-forming region (ECFR), and the region adjacent to the outer curvature of the ventricle as the inferior ECFR.…”

Coronary artery embryogenesis in cardiac defects induced by retinoic acid in mice

“…Retinoic acid (RA), an active derivative of vitamin A, plays a crucial role in regulating cardiac morphogenesis and normal development of the embryo (Yan and Sinning, 2001;Zile, 2001). A balance between the exogenous supply of vitamin A and fetal tissue demand for it, as well as the endogenous synthesis of RA and activity of its receptors (Niederreither et al, 2001;Zile, 2001), are important for proper development of the heart, circulatory system, hindbrain specification (patterning of the central nervous system), limb development, and so on.…”

“…A balance between the exogenous supply of vitamin A and fetal tissue demand for it, as well as the endogenous synthesis of RA and activity of its receptors (Niederreither et al, 2001;Zile, 2001), are important for proper development of the heart, circulatory system, hindbrain specification (patterning of the central nervous system), limb development, and so on. An excess or deficiency of vitamin A or its derivative RA may cause various cardiac malformations (Yan and Sinning, 2001;Zile, 2001) and malformations of other organs (i.e., exencephaly, spina bifida, hydrocephalus, cleft palate, cleft lip, brachygnathia, and great vessel malformations) (Kalter and Warkany, 1961). When RA is administered to mice at a dose of 60 -70 mg/kg of body weight (bw) on 8.5 days postcoitus (dpc), it causes specific abnormalities within the endocardial cushions of the outflow tract (Yasui et al, 1995;Nakajima et al, 1996;Yan and Sinning, 2001).…”