Chronic carbon monoxide inhalation during pregnancy augments uterine artery blood flow and uteroplacental vascular growth in mice

Abstract

End-tidal breath carbon monoxide (CO) is abnormally low in women with preeclampsia (PE), while women smoking during pregnancy have shown an increase in CO levels and a 33% lower incidence of PE. This effect may be, in part, due to lowered sFLT1 plasma levels in smokers, and perhaps low-level CO inhalation can attenuate the development of PE in high-risk women. Our previous work showed maternal chronic CO exposure (<300 ppm) throughout gestation had no maternal or fetal deleterious effects in mice. Our current study evaluated the uteroplacental vascular effects in CD-1 maternal mice that inhaled CO (250 ppm) both chronically, gestation day (GD) 0.5 to 18.5, and acutely, 2.5 h on each of GD 10.5 and 14.5. We demonstrated, using microultrasound measurements of blood velocity and microcomputed tomography imaging of the uteroplacental vasculature, that chronic maternal exposure to CO doubled uterine artery blood flow and augmented uteroplacental vascular diameters and branching. This finding may be of benefit to women with PE, as they exhibit uteroplacental vascular compromise. The ratio of VEGF protein to its FLT1 receptor was increased in the placenta, suggesting a shift to a more angiogenic state; however, maternal circulating levels of VEGF, sFLT1, and their ratio were not significantly changed. Doppler blood velocities in the maternal uterine artery and fetal umbilical artery and vein were unaltered. This study provides in vivo evidence that chronic inhalation of 250 ppm CO throughout gestation augments uterine blood flow and uteroplacental vascular growth, changes that may protect against the subsequent development of preeclampsia.

Characterization of the adverse effects of nicotine on placental development: in vivo and in vitro studies

“…However, in our model, nicotine did not affect either VEGF and FLT-1 or VEGF/FLT-1 in either the circulation or the placenta. Hence, these data substantiate previous studies suggesting that nicotine is not the agent that confers PE protection in pregnant women and suggest that it is more likely that tobacco combustion products and not nicotine are the ingredients in cigarette smoke that protect against PE (56,61).…”

“…Indeed, cigarette smoking is thought to protect against the development of PE by decreasing levels of the circulating factor sFLT-1 and hence, increasing the VEGF/sFLT-1 ratio, which favors an improved placental angiogenesis (56). However, in our model, nicotine did not affect either VEGF and FLT-1 or VEGF/FLT-1 in either the circulation or the placenta.…”

Carbon Monoxide Prevents Hypertension and Proteinuria in an Adenovirus sFlt-1 Preeclampsia-Like Mouse Model

“…Further, in vivo , we have identified a dose of CO (250 ppm) that can be delivered to maternal mice without fetal gross morphological or developmental detriments, and which leads to maternal levels of CO similar to those of smoking women [22]. We have also shown that maternal mouse exposure to this dose of CO results in an increase of utero-placental blood flow and vascularity of the placenta [23]. Therefore, we hypothesized that the use of CO would prevent the development of HTN and proteinuria in the AdsFlt-1 rodent model of PE.…”

Angiogenesis in the Placenta: The Role of Reactive Oxygen Species Signaling

“…Exposure of placental explants to cigarette smoke extracts has also been shown to shift the balance between proangiogenic (promoted by placental growth factor, PlGF) and antiangiogenic factors (fms-like tyrosine kinase-1, sFlt-1) [ 3 ]. Moreover, a number of animal studies have demonstrated that maternal chronic exposure to carbon monoxide, a major combustion product produced by cigarette smoke, increases uterine blood flow and uteroplacental vascular growth by shifting the placenta to a more proangiogenic state [ 45 ]. However, some controversy still exists with respect to the proangiogenic effects of smoking during pregnancy; several studies report a reduction in the number of placental capillaries among smokers [ 46 , 47 ].…”