In utero programming of adult vascular function in transgenic mice lacking low-density lipoprotein receptor

• Published in: American journal of obstetrics and gynecology 2008-08, Vol.199 (2), p.165.e1-165.e5
• Main Authors: Langenveld, Josje, MD, Lu, Fanxian, MD, Bytautiene, Egle, MD, Anderson, Garland D., MD, Saade, George R., MD, Longo, Monica, MD, PHD
• Format: Article
• Language: English
• Subjects: Animals; arteriosclerosis; Biological and medical sciences; Blood Vessels - embryology; Carotid Arteries - physiology; Disease Models, Animal; Dose-Response Relationship, Drug; Female; fetal programming; Gynecology. Andrology. Obstetrics; Hypercholesterolemia - embryology; Hypercholesterolemia - physiopathology; In Vitro Techniques; low-density lipoprotein receptor mice; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; Obstetrics and Gynecology; Phenylephrine - pharmacology; Pregnancy; Pregnancy Complications, Cardiovascular - physiopathology; Receptors, LDL - physiology; Vasoconstrictor Agents - pharmacology
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2008.01.057

Objective The objective of this study was to examine the role of maternal hypercholesterolemia in fetal programming of adult vascular function using transgenic mice lacking the low-density lipoprotein receptor (LDLR). Study Design Homozygous LDLR knockout mice (B6.129S7- Ldlrtm1Her /J, LDLR-/-KO ) and their wild-type controls (C57BL/6J, LDLR+/+WT ) were cross-bred to produce 4 litter groups: LDLR-/-KO , maternally derived heterozygous (LDLR±Mat ), paternally derived heterozygous (LDLR±Pat ) and LDLR+/+WT . Female and male offspring were killed at 10-12 weeks of age, and carotid arteries were used for in vitro experiments. Results The dose responses to phenylephrine were significantly higher in LDLR-/-KO and LDLR±Mat male offspring. The contractile responses to phenylephrine in female mice were significantly increased only in the LDLR-/-KO offspring. Maximal Ca2+ contraction was higher in LDLR-/-KO male and female offspring. Conclusion Despite being genomically similar, heterozygous offspring that developed in a hypercholesterolemic maternal environment had abnormal vascular responses later in life compared with those that developed in a normal environment.