The unique differentiation program of the ductus arteriosus (DA) is essential for its specific task during fetal life and for the adapting circulation after birth. Phenotypic changes occur in the DA during the normal maturation and definitive closure. Morphological abnormalities of the vessel wall characterize the persistent DA (PDA) in older children. Here, we give an overview of the animal models of DA regulation and remodeling. Genetic research has identified the cause of syndromic forms of PDA, such as the TFAP2B mutations in Char syndrome. Genes that interfere with the remodeling of vascular smooth muscle cells (VSMCs) of the ductal media are affected in virtually all of these anomalies. Therefore, the pivotal regulatory role of VSMCs is emphasized. A better understanding of the genetic background of this developmental process may help develop new strategies to manipulate the DA in premature infants, neonates with duct-dependent anomalies, and patients with syndromic and non-syndromic PDA.

Objective-Arterial calcification is considered a major cause of death and disabilities worldwide because the associated vascular remodeling leads to myocardial infarction, stroke, aneurysm, and pulmonary embolism. This process occurs via poorly understood mechanisms involving a variety of cell types, intracellular mediators, and extracellular cues within the vascular wall. An inverse correlation between endothelial primary cilia and vascular calcified areas has been described although the signaling mechanisms involved remain unknown. We aim to investigate the signaling pathways regulated by the primary cilium that modulate the contribution of endothelial cells to vascular calcification. Approach and Results-We found that human and murine endothelial cells lacking primary cilia are prone to undergo mineralization in response to bone morphogenetic proteins stimulation in vitro. Using the Tg737 orpk/orpk cillium-defective mouse model, we show that nonciliated aortic endothelial cells acquire the ability to transdifferentiate into mineralizing osteogenic cells, in a bone morphogenetic protein-dependent manner. We identify β-CATENIN-induced SLUG as a key transcription factor controlling this process. Moreover, we show that the endothelial expression of SLUG is restricted to atheroprone areas in the aorta of LDLR −/− mice. Finally, we demonstrate that SLUG and phospho-homolog of the Drosophila protein, mothers against decapentaplegic (MAD) and the Caenorhabditis elegans protein SMA (from gene sma for small body size)-1/5/8 expression increases in endothelial cells constituting the vasa vasorum in the human aorta during the progression toward atherosclerosis. Conclusions-We demonstrated that the lack of primary cilia sensitizes the endothelium to undergo bone morphogenetic protein-dependent-osteogenic differentiation. These data emphasize the role of the endothelial cells on the vascular calcification and uncovers SLUG as a key target in atherosclerosis.

Closure of the ductus arteriosus (DA) at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2%±7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of α-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%±1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure.

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