There is compelling evidence that adaptive changes in the maternal vascular endothelium are important for normal 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 a balance between injury and repair. New data have demonstrated populations of bone-marrow derived endothelial progenitor cells (EPCs) in the adult circulation that differentiate into endothelial cells lining the lumen of blood vessels and/or release growth factors that act in a paracrine fashion to support the endothelium. Risk factor-induced suppression of EPC number and function is now thought to contribute to the progression of cardiovascular disease. The overarching hypothesis of the proposal is that the number and angiogenesis-retated activities of EPCs obtained from the maternal circulation increase with normal pregnancy, and that failure of these changes, made more likely by pre-pregnancy obesity, contributes to development of PE.
Aim 1 is to test whether EPC number and function are suppressed at 18-20 weeks gestation in obese (high-risk) women who later develop PE compared to obese and nonobese women whose pregnancies remain normal, consistent with a role for EPCs in PE. We will also ask if 3rd trimester EPC phenotype follows the pattern (most to least optimal) of nonobese normal pregnant >obese normal pregnant >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 as assessed in Project II and Core B) in obese women at gestational weeks 18-20 after 3 weeks of oral supplementation with L-arginine (endogenous substrate for nitric oxide synthase (NOS)).
Aim 3 is to examine the effects free fatty acids and ADMA (endogenous NOS inhibitor), obesity-related serum factors increased by the 2nd trimester in women who later develop PE, that we hypothesize will compromise EPC function.
Aim 4 is to collaborate with Project V to show that EPCs are adversely affected by obesity and ADMA in the gravid mouse, correlating with abnormal vascular function, and that the effects of obesity are reduced in transgenic mice over-expressing the enzyme (DDAH) responsible for ADMA removal. As EPC function is modifiable, this groundbreaking study could provide clues to prevention or treatment of preeclampsia.
|Gandley, Robin E; Althouse, Andrew; Jeyabalan, Arundhathi et al. (2016) Low Soluble Syndecan-1 Precedes Preeclampsia. PLoS One 11:e0157608|
|Schmella, Mandy J; Clifton, Rebecca G; Althouse, Andrew D et al. (2015) Uric Acid Determination in Gestational Hypertension: Is it as Effective a Delineator of Risk as Proteinuria in High-Risk Women? Reprod Sci 22:1212-9|
|Hux, Vanessa J; Roberts, James M (2015) A potential role for allostatic load in preeclampsia. Matern Child Health J 19:591-7|
|Schmella, Mandy J; Ferrell, Robert E; Gallaher, Marcia J et al. (2015) The -93T/G LPL Promoter Polymorphism Is Associated With Lower Third-Trimester Triglycerides in Pregnant African American Women. Biol Res Nurs 17:429-37|
|Founds, Sandra; Zeng, Xuemei; Lykins, David et al. (2015) Developing Potential Candidates of Preclinical Preeclampsia. Int J Mol Sci 16:27208-27|
|Hassis, Maria E; Niles, Richard K; Braten, Miles N et al. (2015) Evaluating the effects of preanalytical variables on the stability of the human plasma proteome. Anal Biochem 478:14-22|
|Tan, Hong Chang; Roberts, James; Catov, Janet et al. (2015) Mother's pre-pregnancy BMI is an important determinant of adverse cardiometabolic risk in childhood. Pediatr Diabetes 16:419-26|
|Luiza, John W; Gallaher, Marcia J; Powers, Robert W (2015) Urinary cortisol and depression in early pregnancy: role of adiposity and race. BMC Pregnancy Childbirth 15:30|
|Founds, Sandra A; Ren, Dianxu; Roberts, James M et al. (2015) Follistatin-like 3 across gestation in preeclampsia and uncomplicated pregnancies among lean and obese women. Reprod Sci 22:402-9|
|Sween, Lindsay K; Althouse, Andrew D; Roberts, James M (2015) Early-pregnancy percent body fat in relation to preeclampsia risk in obese women. Am J Obstet Gynecol 212:84.e1-7|
Showing the most recent 10 out of 245 publications