Transcriptional and posttranscriptional mechanisms contribute to the dysregulation of elastogenesis in Schimke immuno-osseous dysplasia.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.

[Intrauterine growth retardation and vascular changes in neonates]. / Intrauterin veksthemming og vaskulaere forandringer hos nyfødte.

BACKGROUND: Cardiovascular disease (arteriosclerosis) is one of the most common causes of premature illness and death in industrialized countries. The established risk factors for its development are dyslipidemia, hypertension, diabetes mellitus, positive family history and smoking. The fetal programming hypothesis (i.e. that prenatal conditions are important for the development of cardiovascular diseases) has been used to explain causal mechanisms of arteriosclerosis, such as biological disturbances in the blood vessels of growth-retarded neonates. This hypothesis differs from the more traditional explanation that health in adulthood is more or less determined by accumulated incidents throughout life. MATERIAL AND METHODS: The article is based on a review of relevant literature retrieved from PubMed (from 1980-2007), including all references in the English articles, and own research. RESULTS AND INTERPRETATIONS: Arteriosclerosis is a lifelong process, with a number of wellknown risk factors. The last 10-15 years have provided sound evidence for the connection between low birth weight and early morphological and physiological changes in vessels. This may explain why individuals with low birth weight have an increased risk of developing arteriosclerosis and provide a link between low birth weight and an increased mortality rate due to cardiovascular diseases in adult life.

Intrauterine growth, the vascular system, and the metabolic syndrome.

There is substantial evidence linking birth size with the risk of developing cardiovascular disease and its major biological risk factors in adulthood. The fetal origins hypothesis proposes that these diseases originate through adaptations, which the fetus makes when it is undernourished. These adaptations may be cardiovascular, metabolic, or endocrine. They permanently change the structure and function of the body. Prevention of the diseases may depend on prevention of imbalances in fetal growth or imbalances between prenatal and postnatal growth, or imbalances in nutrient supply to the fetus. The purpose of this article is to examine some of the more recent epidemiological associations between low birth weight and adult atherosclerotic vascular disease and its risk factors. We will also discuss mechanisms that might explain these associations.

Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries.

BACKGROUND: Atherosclerotic lesions in intracranial arteries occur later and are less extensive than in extracranial arteries. To investigate potential mechanisms responsible for this difference, in particular the atherogenic response to hypercholesterolemia and LDL oxidation, we compared the extent of fatty streak formation and the composition of these very early lesions in intracranial arteries of human fetuses from normocholesterolemic and hypercholesterolemic mothers with those in extracranial arteries. METHODS AND RESULTS: Lesions were quantified by computer-assisted image analysis of 30 oil red O-stained sections, each from the middle cerebral, basilar, and common carotid arteries and the abdominal aorta of human fetuses (spontaneous abortions and premature newborns who died within 12 hours of birth; both of fetal age 6.2+/-1.3 months) from 43 hypercholesterolemic mothers and 34 normocholesterolemic mothers. Macrophages, apolipoprotein B, and 2 epitopes of oxidized LDL in lesions were determined immunocytochemically. Activities of superoxide dismutase, catalase, and glutathione peroxidase in the arterial wall were also determined. Lesion numbers and sizes were dramatically greater in the abdominal aorta (area of the largest lesion per section: 66.5+/-10.9 x10(3) microm2) and the carotid (11. 6+/-5.3 x10(3) microm2) than in the basilar and middle cerebral artery (0.4+/-0.1 and 0.8+/-0.2 x10(3) microm2, respectively; P<0. 0001). Hypercholesterolemia resulted in a significant increase of lesion size in extracranial arteries but only a marginal increase in intracranial arteries. In analogy, hypercholesterolemia induced a much greater increase in the intimal presence of macrophages, apolipoprotein B, and oxidized LDL (oxidation-specific epitopes) in extracranial than in intracranial arteries. Immunocytochemistry did not indicate that lesions of intracranial arteries contain relatively less oxidized LDL than similar-size lesions of extracranial arteries. Activities of Mn-superoxide dismutase but not of Zn-superoxide dismutase, catalase, or glutathione peroxidase were significantly higher in both intracranial arteries. CONCLUSIONS: Exposure to hypercholesterolemia during fetal development results in extensive formation of fatty streaks in extracranial but not intracranial arteries. The fact that such a difference in lesion formation occurs in the absence of many other atherogenic risk factors found later in life suggests that differences in the atherogenic response to hypercholesterolemia are an important contributor to the slower onset of the disease in intracranial vessels in adults. Fetal arteries may allow elucidation of the mechanisms responsible, for example, better protection of intracranial arteries against free radical-mediated atherogenic processes.

Pathophysiological events during pregnancy influence the development of atherosclerosis in humans.

Pathophysiological events occurring during fetal development are increasingly recognized as influencing atherosclerosis throughout childhood and adolescence. Maternal hypercholesterolemia during pregnancy markedly increases fatty streak formation in human fetal arteries. Although fetal fatty streaks partially regress under normocholesterolemic conditions, progression of atherosclerosis in children of hypercholesterolemic mothers is much faster than in children of normocholesterolemic mothers. This cannot be accounted for by conventional risk factors of atherosclerosis or inherited genetic differences. The nature of the persistent changes in the fetal arterial wall responsible for increased atherogenesis in children and the mechanisms by which maternal hypercholesterolemia induces these changes need to be investigated, because they may offer important insights into the pathogenesis of atherosclerosis and because targeted interventions in mothers during pregnancy may yield considerable long-term benefits.

Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2+/-1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P < 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651+/-87,449 and 451,255+/-37,448 micron2 per section, respectively; mean+/-SD) than aortas from normocholesterolemic mothers (61,862+/-9,555 micron2; P < 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde- and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and OxLDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo.

The development of preatherosclerotic coronary artery lesions in perinatal piglets.

The fine structure and ultrastructure of the anterior descending coronary artery were studied in a series of perinatal piglets at 1 week prior to birth, and at 8, 24, 72 and 168 h after birth. In the anterior descending coronary artery, at or just distal to the branch point of the left circumflex artery, early plaque-like intimal lesions were present in the majority of animals. These consisted of subendothelial edema, fragmentation and dissolution of the internal elastic lamella, and the appearance of intimal myoid cells known as modified smooth muscle cells (MSMCs). These changes were present in all piglets at and before 8 h of age. They persisted and progressed during the first week of life in about half of the piglets. Beginning at 72 h and continuing through 168 h, there was an increase in MSMCs and the appearance of fibroblasts. Both fibroblasts and MSMCs were associated with the elaboration of dense collagen fibrils. Foamy macrophages appeared within the subendothelial intima having the appearance of lipophages. While the prevalence of these changes at birth indicates that they may be part of normal development, their persistence in half the piglets and structural features suggest reaction to intimal injury beginning prenatally. The lesions may be precursive of coronary atherosclerosis later in life and may parallel the early stages of atherogenesis in humans.

[The phenotypes of arterial smooth-muscle cells during ontogeny and in atherosclerotic plaques]. / Fenotipy gladkomyshechnykh kletok arterii v protsesse ontogeneza i v ateroskleroticheskikh bliashkakh.

Smooth-muscle cell (SMC) myosin expression, SMC alpha-actin, h-caldesmon and calponin expression were studied in developing SMC of embryonic aorta as well as in adult human aorta and coronary arteries. It was found that ontogenesis is associated with SMC phenotypic modulations. In 8-23-week embryos SMC express SMC myosin and alpha-actin. In adult humans arterial SMC express all the markers studied. Normal subendothelium contains a heterogeneous SMC population. SMC heterogeneity is most marked in atherosclerotic plaques in the form of clusters of homogeneous cells different by expression of contractile system proteins. It is suggested that SMC heterogeneous population in atherosclerotic plaques may arise due to proliferation of phenotypically different precursors cells.

The effect of blood flow on the surface morphology of the human endothelium.

The endothelial lining from the aortae of three 17 week human fetuses was examined by scanning electron microscopy. Orientation of the endothelial cells, particularly in the region above the aortic valve, was related to known flow patterns. Endothelial morphology showed regional variation noticeably at the mouths of arteries and at the aortic bifurcation. The possibility that this morphological change may be a hitherto unrecognised risk factor related to the site of atheromatous deposition is discussed.

Idiopathic arterial calcification of infancy without intimal proliferation.

A case of idiopathic arterial calcification is described in a dysmature infant dying of massive pulmonary haemorrhage on the fourth day after a gestation of 36 weeks. The mother had disseminated lupus erythematosis and lupus nephritis treated with large amounts of prednisolone. Unlike most of the previously recorded cases of idiopathic arterial calcification of infancy subintimal proliferation of fibrous tissue and involvement of the coronary arteries did not occur. It is suggested that this non-occlusive form of arterial calcification may be a distinct entity.

Yolk lipids of developing atherosclerosis susceptible White Carneau and atherosclerosis resistant Show Racer pigeon embryos.

The lipid composition of yolks of developing embryonic atherosclerosis-susceptible White Carneau (WC) and -resistant Show Racer (SR) pigeons was analyzed to determine whether embryonic nutrition might be a factor in the difference in susceptibility to aortic atherosclerosis. The yolks of 1-day and 18-day old embryos were analyzed, and the amounts of phospholipid, sterol, non-esterified fatty acid, triglyceride, cholesteryl ester, and hydrocarbon were determined. On the first day of development in both breeds, triglycerides composed 80% of the total lipid content of the yolk; phospholipids, cholesteryl ester, sterols and non-esterified fatty acids comprised the rest. There was no difference between breeds in the amount of lipid in each class or in the total lipid. Therefore, the initial lipid diet of these embryos is not a factor in development of the disease. Examination of the yolk just prior to hatching, revealed that in both breeds there was a significant decrease in total yolk lipids, but unequal utilization of lipid constitutents between breeds. Significantly higher amounts of phospholipids remained in the yolk of the WC pigeons. During embryogenesis, the SR pigeons consumed significantly more of each lipid than the atherosclerosis-susceptible breed. This may indicate that there is a difference between the two breeds in lipid metabolism.

Coronary arteries in infants up to the age of ten years. I. Chronology of adaptive intimal changes.

In the coronary arteries of old fetuses the presence of musculo-elastic and elastic hyperplastic layers was firstly detected in the branching pads of aortic ostia and the emergence of the left anterior descending branch. These layers appeared constantly more developed in the left than in the right coronary bed. During the first six months of the extrauterine life the coalescence of pads revealed a passage from localized to diffuse adaptive changes in the main branching sites and in their immediate vicinity. Then, in the first decade of life, a progressive extension of the musculo-elastic and elastic hyperplastic layers was observed, leading to the well known aspect of diffuse intimal thickening.