There is compelling evidence that adaptive changes in the maternal vascular endothelium are important fornormal pregnancy and that endothelial dysfunction contributes to the pathogenesis of preeclampsia (PE).The reasons for these changes, however, are not fully understood. Endothelial health ultimately represents abalance between injury and repair. New data have demonstrated populations of bone-marrow derivedendothelial progenitor cells (EPCs) in the adult circulation that differentiate into endothelial cells lining thelumen of blood vessels and/or release growth factors that act in a paracrine fashion to support theendothelium. Risk factor-induced suppression of EPC number and function is now thought to contribute tothe progression of cardiovascular disease. The overarching hypothesis of the proposal is that the numberand angiogenesis-retated activities of EPCs obtained from the maternal circulation increase with normalpregnancy, and that failure of these changes, made more likely by pre-pregnancy obesity, contributes todevelopment of PE.
Aim 1 is to test whether EPC number and function are suppressed at 18-20 weeksgestation in obese (high-risk) women who later develop PE compared to obese and nonobese womenwhose pregnancies remain normal, consistent with a role for EPCs in PE. We will also ask if 3rd trimesterEPC phenotype follows the pattern (most to least optimal) of nonobese normal pregnant > obese normalpregnant > nonobese PE > obese PE, and whether EPC dysfunction in vitro can be reversed by nitric oxide(NO) donors.
Aim 2 is to see if EPCs are upregulated (in concert with improved vascular function asassessed in Project II and Core B) in obese women at gestational weeks 18-20 after 3 weeks of oralsupplementation with L-arginine (endogenous substrate for nitric oxide synthase (NOS)).
Aim 3 is to examinethe effects free fatty acids and ADMA (endogenous NOS inhibitor), obesity-related serum factors increasedby the 2nd trimester in women who later develop PE, that we hypothesize will compromise EPC function.
Aim4 is to collaborate with Project V to show that EPCs are adversely affected by obesity and ADMA in thegravid mouse, correlating with abnormal vascular function, and that the effects of obesity are reduced intransgenic mice over-expressing the enzyme (DDAH) responsible for ADMA removal. As EPC function ismodifiable, this groundbreaking study could provide clues to prevention or treatment of preeclampsia.
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| Hux, Vanessa J; Roberts, James M; Okun, Michele L (2017) Allostatic load in early pregnancy is associated with poor sleep quality. Sleep Med 33:85-90 |
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