ENDOGENOUS RETINOIC ACID SIGNALING COLOCALIZES WITH ADVANCED EXPRESSION OF THE ADULT SMOOTH-MUSCLE MYOSIN HEAVY-CHAIN ISOFORM DURING DEVELOPMENT OF THE DUCTUS-ARTERIOSUS

During fetal development, a specialized vessel, the ductus arteriosus, shunts blood from the pulmonary artery to the aorta, thus bypassing t he lungs. The ductus differs primarily from the great vessels in that it is a muscular rather than an elastic artery, and the etiology of th is differential development remains controversial. We present evidence that retinoic acid (RA) may contribute to the unique muscle phenotype of the ductus arteriosus. Using a transgenic mouse carrying an RA res ponse element-lacZ transgene that expresses beta-galactosidase (beta-g al) in response to endogenous RA signals during embryonic and fetal de velopment, we observe a strong beta-gal signal in the ductus arteriosu s. By immunofluorescence, this signal colocalizes with the expression of the adult-specific smooth muscle myosin heavy chain isoform, SM2. T he beta-gal signal is present throughout fetal development and persist s in the neonate until the ductus arteriosus is completely closed. bet a-Gal-positive cells are first detected by immunofluorescence at 13.5 days postcoitum (dpc) in the mesenchyme surrounding the ductus. By 15. 5 dpc, very intense beta-gal staining localizes to the ductus arterios us but is absent or minimal in the pulmonary trunk and aortic arch; by 17.5 dpc, the smooth muscle layers of the tunica media in the ductus arteriosus exhibit positive beta-gal staining. Immunostaining with ant ibodies against smooth muscle myosins shows that, while SM1 is express ed in all embryonic vessels, SM2 is precociously expressed in the duct us arteriosus. Furthermore, SM2 expression can be detected in the duct us as early as 15.5 dpc. In the neonate, the beta-gal signal persists in the smooth muscle layer of the ductus and immunostaining colocalize s with SM2 expression. These data suggest that RA may play a role in i nducing and maintaining smooth muscle differentiation in the developin g ductus arteriosus and may promote precocious expression of the adult vascular phenotype.