Preeclampsia affects 3-5% of pregnancies and contributes significantly to maternal and neonatal morbidity and mortality. We have generated a novel hypothesis regarding the development of pre-eclampsia that postulates that two primary features contribute independently to its development. One feature is a pre-pregnancy phenotype that includes reduced plasma volume, elevated sympathetic tone, reduced utenne blood flow and enhanced platelet activation. This feature has been suggested by the association of a specific genetic polymorphism of angiotensinogen (TT235) with an increased risk for pre-eclampsia. This polymorphism has been linked in our preliminary data to key pathophysiologic features of pre-eclampsia, previously thought to be exclusive to pregnancy, in women who are examined prior to pregnancy. The second feature is the physiologic volume expansion of pregnancy. We have theorized that the overt clinical manifestations of pre-eclampsia become apparent in late pregnancy as a result of either 1) a normal volume expansion in women unable to tolerate it due to a chronic adaptation to low intravascular volume (abnormal prepregnancy phenotype) or 2) an excessive volume expansion in women with a normal prepregnancy phenotype (i.e. twins, molar pregnancies). In this grant we propose to examine 3 primary specific aims, employing detailed whole body physiologic measurements in women, that will support this pathophysiologic view of the development of preeclampsia; 1) We will confirm that the angiotensinogen genotype that has been linked to preeclampsia in Caucasians and Asians is associated with reduced plasma volume in a nulligravid population and that this plasma volume constriction is associated with elevated sympathetic tone, reduced uterine blood flow and heightened platelet activation prior to pregnancy, 2) As we follow these women into pregnancy we will demonstrate; a) that low prepregnancy plasma volume is associated with elevated sympathetic tone and reduced uterine blood flow in early pregnancy (12 weeks) predisposing to abnormal placentation despite similar plasma volume expansion, and b) that prepregnancy plasma volume is indirectly related to both the change in mean arterial pressure (corrected for plasma volume expansion) and degree of platelet activation in the third trimester, 3) Finally, we will demonstrate that pregnancy results in an increase in both post-puerperal plasma volume and arterial compliance Iowering the risk for both preeclampsia in future pregnancies and hypertension in later life. This will be a controlled prospective longitudinal study examining an integrated pathophysiologic mechanism underlying the development of preeclampsia. This study proposes to evaluate a novel hypothesis that synthesizes apparently contradictory data into a single coherent theory.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL071944-01A1
Application #
6720436
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Barouch, Winifred
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$290,475
Indirect Cost
Name
University of Vermont & St Agric College
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Phillips, Julie; McBride, Carole A; Morris, Erin et al. (2018) Adiposity, but not Obesity, Is Associated With Arterial Stiffness in Young Nulliparous Women. Reprod Sci 25:909-915
Howe, Lindsay; Hammer, Erica; Badger, Gary et al. (2018) Effect of Pregnancy Interval on Second Pregnancy Blood Pressure Following Prior Preeclampsia. Reprod Sci 25:727-732
Phillips, Julie K; McBride, Carole A; Hale, Sarah A et al. (2017) Examination of Prepregnancy and Pregnancy Urinary Protein Levels in Healthy Nulliparous Women. Reprod Sci 24:407-412
Bernstein, Ira M; Hale, Sarah A; Badger, Gary J et al. (2016) Differences in cardiovascular function comparing prior preeclamptics with nulliparous controls. Pregnancy Hypertens 6:320-326
Morris, Erin A; Hale, Sarah A; Badger, Gary J et al. (2015) Pregnancy induces persistent changes in vascular compliance in primiparous women. Am J Obstet Gynecol 212:633.e1-6
Chow, Daniel S; Ha, Richard; Filippi, Christopher G (2015) Increased rates of authorship in radiology publications: a bibliometric analysis of 142,576 articles published worldwide by radiologists between 1991 and 2012. AJR Am J Roentgenol 204:W52-7
Miloushev, V Z; Chow, D S; Filippi, C G (2015) Meta-analysis of diffusion metrics for the prediction of tumor grade in gliomas. AJNR Am J Neuroradiol 36:302-8
McBride, Carole A; Hale, Sarah A; Subramanian, Meenakumari et al. (2014) The relationship of a family history for hypertension, myocardial infarction, or stroke with cardiovascular physiology in young women. Reprod Sci 21:509-16
Buhimschi, Irina A; Nayeri, Unzila A; Zhao, Guomao et al. (2014) Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Sci Transl Med 6:245ra92
Foley, Jonathan H; Orfeo, Thomas; Undas, Anetta et al. (2013) From principle to practice: bridging the gap in patient profiling. PLoS One 8:e54728

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