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Primary cilia are mechanosensors for fluid shear stress, and are involved in a number of syndromes and congenital anomalies. We identified endothelial cilia in areas of low shear stress in the embryonic heart. The objective of the present study was to demonstrate the role of primary cilia in mechanosensing. Ciliated embryonic endothelial cells were cultured from the heart, and non-ciliated cells from the arteries. Nonciliated cells that were subjected to fluid shear stress showed significantly less induction of the shear marker Krü ppel-Like Factor-2, as compared to ciliated cells. In addition, ciliated cells from which the cilia were chemically removed show a similar decrease in flow response. This shows that primary cilia sensitize endothelial cells for fluid shear stress. In addition, we targeted and stabilized the connection of the cilium to the cytoplasm by treatment with Colchicine and Taxol/Paclitaxel, respectively, and show that microtubular integrity is essential to sense shear stress. Developmental Dynamics 237:725-735, 2008.

Objective-Maternal hypercholesterolemia is associated with a higher incidence and faster progression of atherosclerotic lesions in neonatal offspring. We aimed to determine whether an in utero environment exposing a fetus to maternal hypercholesterolemia and associated risk factors can prime the murine vessel wall to accelerated development of cardiovascular disease in adult life. Methods and Results-To investigate the epigenetic effect in utero, we generated genetically identical heterozygous apolipoprotein E-deficient progeny from mothers with a wild-type or apolipoprotein E-deficient background. A significant increase in loss of endothelial cell volume was observed in the carotid arteries of fetuses of apolipoprotein E-deficient mothers, but fatty streak formation was absent. Spontaneous atherosclerosis development was absent in the aorta and carotid arteries in adult life. We unilaterally placed a constrictive collar around the carotid artery to induce lesion formation. In offspring from apolipoprotein E-deficient mothers, collar placement resulted in severe neointima formation in 9 of 10 mice analyzed compared with only minor lesion volume (2 of 10) in the progeny of wild-type mothers. Conclusions-We conclude that the susceptibility to neointima formation of morphologically normal adult arteries is already imprinted during prenatal development and manifests itself in the presence of additional atherogenic risk factors in adult life. Future research will concentrate on the mechanisms involved in this priming process, as well as on prevention strategies. Key Words: atherosclerosis Ⅲ carotid arteries Ⅲ pregnancy Ⅲ risk factors Ⅲ hypercholesterolemia P ostnatal risk factors of atherosclerosis are well defined, and mechanisms contributing to lesion formation are increasingly understood. Previous studies showed that the atherogenic process in humans can already start during fetal development. 1 In a morphometric postmortem analysis of atherosclerosis in fetuses and children (Fate of Early Lesions in Children Study), 2 it was demonstrated that specifically maternal hypercholesterolemia was associated with a higher incidence of atherosclerotic lesions during the fetal period and a faster progression of these atherosclerotic lesions after birth even under conditions of normocholesterolemia in the offspring. A causal role for maternal hypercholesterolemia in fetal lesion formation was demonstrated in a genetically nonhomogeneous rabbit model of diet-induced hypercholesterolemia and confirmed in a low-density lipoprotein receptor-deficient mouse model (Ldlr Ϫ/Ϫ ). 3,4 Raised cholesterol intake of pregnant Ldlr Ϫ/Ϫ mice accelerated the progression of spontaneous atherosclerotic lesions in the Ldlr Ϫ/Ϫ progeny. Because these mice have elevated plasma cholesterol levels independent of the maternal cholesterol levels during postnatal life, they are genetically prone to develop atherosclerotic lesions. The question remains whether solely environmental atherogenic risk factors present in utero can prime the developing vascu...

We recently demonstrated that neointima formation of adult heterozygous apolipoprotein E (apoE(+/-)) offspring from hypercholesterolemic apoE(-/-) mothers was significantly increased as compared with genetically identical apoE(+/-) offspring from normocholesterolemic wild-type mothers. Since atherosclerosis is the consequence of a complex microenvironment and local cellular interactions, the effects of in utero programming and type of postnatal diet on epigenetic histone modifications in the vasculature were studied in both groups of offspring. An immunohistochemical approach was used to detect cell-specific histone methylation modifications and expression of accompanying lysine methyltransferases in the carotid arteries. Differences in histone triple-methylation modifications in vascular endothelial and smooth muscle cells revealed that the offspring from apoE(-/-) mothers had significantly different responses to a high cholesterol diet when compared with offspring from wild-type mothers. Our results suggest that both in utero programming and postnatal hypercholesterolemia affect epigenetic patterning in the vasculature, thereby providing novel insights regarding initiation and progression of vascular disease in adults.

In this review, we briefly summarize the possible signals crossing the placental barrier and discuss the molecular mechanisms of epigenetic programming in the developing fetus leading to increased athero-susceptibility of the vessel wall.