An essential role for angiotensin II Type 1a receptor in pregnancy‐associated hypertension with intrauterine growth retardation

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Abstract
Little is known about an in vivo significance of angiotensin II Type-1 receptor (AT1) for pregnancy-associated diseases, including hypertension and intrauterine growth retardation (IUGR). We previously demonstrated that female mice carrying the human angiotensinogen gene (hAG(+/+)), when mated with human renin transgenic (hRN(+/+)) male mice, displayed hypertension in late pregnancy due to secretion of human renin from the fetal side into the maternal circulation. In the present study, to investigate a role for AT1 in pregnancy-associated hypertension, we generated a new strain of hAG(+/+)/mAT1a(-/-) mice by genetically deleting the AT1a gene from hAG(+/+) mice. When mated with hRN(+/+) male mice, excessive increases in human renin, angiotensin, and plasma renin activity were detected in the plasma of pregnant hAG(+/+)/mAT1a-/mice as found in that of pregnant hAG(+/+) mice. Surprisingly, however, blood pressure of hAG(+/+)/mAT1a-/-mice was not elevated in late pregnancy despite the presence of AT1b, a subtype of AT1. The maternal and fetal defects, such as cardiac and placental abnormalities, and IUGR observed in pregnant hypertensive hAG(+/+) mice were not recognized in pregnant hAG(+/+)/mAT1a-/mice. The limited term administration of AT1 antagonists to hypertensive hAG(+/+) mice in late pregnancy dramatically improved hypertension and IUGR, showing the clinical importance of AT1a.
Funding Information
  • Japan Society for the Promotion of Science (JSPS–RFTF 97L00804)
  • Ministry of Health, Labour and Welfare