Circulatory and Renal Consequences of Pregnancy in Diabetic NOD Mice

Apr 24, 2015, 13:01 PM by User Not Found

Pregnant women with diabetes have an elevated risk of circulatory complications. However, little is known about the mechanisms that underlie such risks. Previous research suggests that the adaptive physiologic changes required for successful pregnancy may be susceptible to impairment in pregnancy complicated by diabetes. Placental insufficiency occurs more often in pregnant women with diabetes, suggesting the possibility of inadequate uterine spiral artery (SA) remodeling. (SA remodeling occurs during pregnancy to change arteries into the high-flow, low-resistance vessels needed to ensure the fetus and placenta can develop properly.) The presence of diabetes during pregnancy in women can also increase the frequency and severity of preeclampsia (which is characterized by hypertension and often damage to the kidneys), as well as late miscarriage and fetal growth restriction.

To learn more about the association between diabetes and physiologic impairments in pregnancy, preclinical researchers have begun to evaluate whether pregnant non-obese diabetic (NOD) mice may be an appropriate model for human pregnancy in diabetic women. NOD mice are already a well-established model of autoimmune Type 1 diabetes in humans. Researchers have previously shown that in a comparison with pregnant non-diabetic mice, pregnant diabetic NOD mice had impaired SA remodeling and fewer uterine natural killer (uNK) cells (lymphocytes that should be abundant during early pregnancy, as they play an important role in remodeling the SAs). Pregnant diabetic NOD mice also exhibited dysfunctional interactions in vitro between endothelial cells and lymphocytes (similar to the effect often seen in human Type 1 diabetes). Additionally, many of the NOD fetuses were growth-restricted, suggesting diabetes-induced placental insufficiency.

Based on these findings, the researchers monitored signs of preeclampsia by measuring cardiovascular parameters and renal function in normoglycemic and overtly diabetic pregnant NOD mice. The researchers hypothesized that overtly diabetic pregnant NOD mice would develop hypertension and renal dysfunction, thus providing evidence for NOD mice as a promising model for future pharmacologic interventions. For the study,1 the female mice were implanted with blood pressure transmitters so the researchers could continuously monitor hemodynamic changes. Hemodynamic baseline data were collected and starting at 12 weeks (the typical age at which NOD mice do or do not spontaneously develop diabetes), blood glucose measurements were collected biweekly. The NOD mice that developed diabetes were paired with age-matched non-diabetic pregnant NOD mice for comparison purposes. Then the female mice were mated with normoglycemic males and physiologic data were collected before and during pregnancy. Physiologic data included hemodynamic parameters: mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), pulse pressure (PP), heart rate (HR), activity; and renal parameters: urinalysis, serum biochemistry, renal histopathology.

Results showed that before mating, normoglycemic and diabetic female NODs had similar hemodynamic profiles. During pregnancy, normoglycemic mice showed hemodynamic profiles similar to other inbred strains: an early decline in arterial pressure until mid-pregnancy, and no difference throughout pregnancy on assessments of MAP, SAP, DAP, HR, PP, or activity levels. Renal parameters were also normal in normoglycemic mice. Diabetic NODs had normal BP until mid-pregnancy then became mildly hypotensive and severely bradycardic. They also showed signs of acute kidney injury. The health of the diabetic NODs did not rebound post-partum and offspring were growth restricted.

As expected, diabetic NOD mice did exhibit signs of cardiovascular and renal dysfunction. However, impairment did not present as expected. Instead of displaying the obvious preeclamptic signs that typically occur in human pregnancy, the main cardiovascular dysfunctions were low blood pressure and slow heart rate. The authors suggested that further studies will be needed to identify the mechanisms behind these findings, but pointed out that the study provided evidence that impaired cardiovascular adaptation may go beyond hypertension and that the lingering post-partum abnormalities do suggest that vascular dysfunction occurred, as in preeclampsia studies. The authors concluded by asserting “While understanding of the full scope of the alterations occurring in maternal circulatory mechanisms and required for preservation of fetal circulation remain to be achieved, the findings from the study of this animal model provide new insights into cardiovascular complications in diabetic pregnancy.”

The researchers used DSI solutions to acquire and analyze the physiologic parameters at the core of this study. PhysioTel PA-C10 implants were used to simultaneously detect arterial pressures, PP, HR, and activity and the Dataquest A.R.T.™ acquisition system was used to monitor and analyze the data, resulting in a detailed hemodynamic profile.

1 Burke, S. D., Barrette, V. F., David, S, Khankin, E. V., Adams, M. A., & Croy, B. A. (2011). Circulatory and Renal Consequences of Pregnancy in Diabetic NOD Mice. Placenta, 32 (4): 949-955. Doi: 10.1016/j.placenta.2011.09.018

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