Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life.
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.


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.
Alkemade
Fanneke E
FE
Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Gittenberger-de Groot
Adriana C
AC
Schiel
Anja E
AE
VanMunsteren
J Conny
JC
Hogers
Bianca
B
van Vliet
Leontien S J
LS
Poelmann
Robert E
RE
Havekes
Louis M
LM
Willems van Dijk
Ko
K
DeRuiter
Marco C
MC
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000196:embryology / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000150:complications / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D018392:Genomic Imprinting; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications* / Q000196:embryology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018810:Magnetic Resonance Angiography; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D012720:Severity of Illness Index; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000473:pathology
D001057:Apolipoproteins E; D014280:Triglycerides; D002784:Cholesterol