We have demonstrated that chronic stimulation of the prostaglandin E 2 -cAMP-dependent protein kinase A (PKA) signal pathway plays a critical role in intimal cushion formation in perinatal ductus arteriosus (DA) through promoting synthesis of hyaluronan. We hypothesized that Epac, a newly identified effector of cAMP, may play a role in intimal cushion formation (ICF) in the DA distinct from that of PKA. In the present study, we found that the levels of Epac1 and Epac2 mRNAs were significantly up-regulated in the rat DA during the perinatal period. A specific EP4 agonist, ONO-AE1-329, Prostaglandin E 2 (PGE 2 )3 is the most potent vasodilatory lipid mediator in the ductus arteriosus (DA), a fetal arterial connection between the pulmonary artery and the descending aorta (1). PGE 2 increases the intracellular concentration of cAMP, which activates cAMP-dependent protein kinase A (PKA), resulting in vasodilation in the DA (1, 2). In addition to its vasodilatory effect, our recent study has identified that chronic PGE 2 stimulation has another essential effect on DA development, namely intimal cushion formation (ICF) (3). Briefly, via EP4, a predominant PGE 2 receptor in the DA, the PGE 2 -cAMP-PKA stimulation up-regulates hyaluronic acid (HA) synthases, which increases HA production. Accumulation of HA then promotes smooth muscle cell (SMC) migration into the subendothelial layer to form intimal thickening. ICF then leads to luminal narrowing, helping adhesive occlusion of the vascular lumen and thus complete anatomical closure of the DA.A new target of cAMP, i.e. an exchange protein activated by cAMP, has recently been discovered; it is called Epac (4).

In order to evaluate the contribution of FBN1, FBN2, TGFBR1, and TGFBR2 mutations to the Marfan syndrome (MFS) phenotype, the four genes were analyzed by direct sequencing in 49 patients with MFS or suspected MFS as a cohort study. A total of 27 FBN1 mutations (22 novel) in 27 patients (55%, 27/49), 1 novel TGFBR1 mutation in 1 (2%, 1/49), and 2 recurrent TGFBR2 mutations in 2 (4%, 2/49) were identified. No FBN2 mutation was found. Three patients with either TGFBR1 or TGFBR2 abnormality did not fulfill the Ghent criteria, but expressed some overlapping features of MFS and Loeys-Dietz syndrome (LDS). In the remaining 19 patients, either of the genes did not show any abnormalities. This study indicated that FBN1 mutations were predominant in MFS but TGFBRs defects may account for approximately 5-10% of patients with the syndrome.

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