Cardiovascular Function in Mice During Normal Pregnancy and in the Absence of Endothelial NO Synthase

Abstract

Abstract-In humans, the increased cardiovascular demands of pregnancy are met by increases in cardiac output (CO), stroke volume (SV), plasma volume (PV), and cardiac and aortic inner dimensions and a concurrent decrease in arterial pressure that indicates a fall in total peripheral vascular resistance. The mechanisms responsible for these changes are incompletely understood, but NO synthase (NOS) is believed to play a central role. We assessed whether C57Bl/6J (B6) mice show similar changes and whether these changes are altered in mice lacking the gene for endothelial NOS (eNOS). The CO of B6 mice increased 28% by day 9.5 of gestation because of a 25% increase in SV, and increased 48% by day 17.5 because of a 41% increase in SV. The increase in SV at day 17.5 was associated with a 27% increase in PV, a 15% decrease in arterial pressure, and 10% to 15% increases in aortic and left-ventricular inner dimensions. In the absence of eNOS, CO increased 22% by day 9.5 because of increases in SV (14%) and heart rate (9%), but increased no further by day 17.5. SV near term was lower than B6 mice despite similar 26% increases in PV and 14% decreases in arterial pressure in association with blunted left-ventricular chamber enlargement. Key Words: nitric oxide synthase Ⅲ pregnancy Ⅲ cardiac output Ⅲ arterial pressure Ⅲ blood flow velocity Ⅲ echocardiography Ⅲ remodeling I n the first half of pregnancy, the maternal cardiovascular system preadapts in anticipation of the physiological demands of pregnancy and the growing perfusion and exchange requirements of the conceptus and changes further in the last half of gestation when the most rapid growth of the conceptus occurs. Failure to make or to sustain these changes may result in impaired fetal growth and/or preeclampsia, the 2 most common and serious complications of human pregnancy. 1,2 Although the mechanisms are not fully understood, there is considerable evidence that NO plays an important role in mediating maternal cardiovascular changes during pregnancy in humans, rats, and other species. [3][4][5][6] During pregnancy in humans, there is a 30% decrease in the circulating levels of asymmetrical dimethylarginine, 7 an endogenous inhibitor of NO synthase (NOS) activity. Furthermore, a nonselective NOS inhibitor caused a greater decrease in blood flow in the forearm circulation of pregnant versus nonpregnant women, 3 which suggests that an increase in bioactive NO contributes to the decrease in peripheral vascular resistance during pregnancy in humans. NO also appears to be important in rats during pregnancy because plasma and urinary levels of nitrites and nitrates (metabolites of NO) and cGMP (second messenger of NO) are increased in pregnant rats, 5,8 although whether similar changes occur in human pregnancy is less certain. 5,9 Furthermore, treatment of rats in late pregnancy with nonselective NOS inhibitors blunts or indeed reverses the normal decrease in arterial blood pressure, 4,6 abolishes the normal increase in plasma volume, 6 and causes fetal intrauterine growt...

Endothelial Nitric Oxide Synthase Deficiency Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Mice

“…This result suggested that uterine vascular resistance was elevated in eNOS KO(ko) pregnancies. This result is consistent with lower uterine artery blood flows (Figures 1 and S1) and similar arterial blood pressures during pregnancy 7,8 in mice lacking the eNOS gene relative to WT controls.…”

“…Despite considerable evidence implicating eNOS in preeclampsia, eNOS knockout (KO) mice do not develop the hallmark signs, gestational hypertension [7][8][9] or proteinuria. 9 Indeed, arterial pressure in eNOS KO mice decreases during pregnancy to become similar to that of pregnant wild-type controls.…”

“…9 Indeed, arterial pressure in eNOS KO mice decreases during pregnancy to become similar to that of pregnant wild-type controls. [7][8][9] Nevertheless, there is a marked blunting of the normal increase in cardiac output 7 and blunting of the enlargement of the heart and aorta 7 and uterine artery 10 in eNOS KO mice, suggesting an important role for eNOS in systemic cardiovascular changes in pregnancy. However, whether uteroplacental blood flow or placental oxygenation is abnormal in eNOS KO mice and whether the maternal and/or conceptus genotype is responsible are unknown.…”

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

“…19 Mouse models have promoted understanding of mechanisms regulating gestational changes to the cardiovascular system. 20 Comparisons of micro-ultrasound measurements of placental growth and blood flow velocity between normal and mutant mice (i.e. Nos3 −/− ) revealed significant similarities to human pregnancies.…”

“…Nos3 −/− ) revealed significant similarities to human pregnancies. [20][21][22] Those mouse strains examined by micro-ultrasound have not lacked SA modification, a characteristic of mice deficient in uNK cells. This phenotype is reversible by transplantation of marrow genetically deficient for T and B cell differentiation (ie, NK+, T−B− marrow).…”